THE SCIENCE AND TECHNOLOGY OF LONGEVITY
A comprehensive document for the benefit of people interested in living very long healthy lives and who are willing to adapt emerging knowledge personally to do so. And, for the health professionals who serve them.
By Vincent E. Giuliano
Initial online draft, May 15, 2008
FORWARD – VIEW
FROM JULY 2014
More than six years have elapsed from drafting the initial version of this treatise and despite many updates parts of it show age. Many topics and insights I would now include are missing. The original concept of this treatise was to look at the main existing scientific theories of aging, see what they have in common, see what each has to say about steps that could be taken to halt or delay aging, and combine these steps into an overall "antiaging firewall." That firewall would define practical lifestyle and dietary interventions that would create long-lasting health and longevity based on the known science. This was a good concept and it has personally served me well. However, my thinking about health and aging has continued to become more sophisticated and nuanced and the science itself has also evolved significantly during the period. Also, my personal anti-aging lifestyle and dietary interventions have continued to evolve in a way not captured here. I will eventually rewrite this treatise from a different perspective. Meanwhile, if you would like to understand how my thinking has evolved in the last five years, you can check out my May 2014 blog entry FIVE-YEAR PROGRESS REPORT ON MAJOR TRENDS IMPACTING ON LONGEVITY. Here is a brief history of what has happened and where to look for my latest thoughts:
The birth of the blog
Seven years ago, I thought that I could continue to update this treatise as I followed the key scientific streams related to health and aging. Soon, I discovered that for older people, creating health and creating longevity amount to the same thing. And, to know how to do that based on new scientific discoveries, it was necessary to consider vast, disparate and detailed bodies of scientific knowledge. Over 1 million potentially relevant scientific papers are now published every year.
It would be completely impossible to encompass even summaries of the relevant knowledge in this one treatise. So, I created the Aging Sciences Blog as a vehicle for communicating about particularly relevant topics. The blog rapidly became my main vehicle for writing up what I have learned. It served the initial objective of making sure that I understand a topic by forcing me to lay it out in writing in comprehensive form. Soon, a second objective emerged for the blog - communicating this information to a wider audience, getting feedback and networking myself with other researchers. Research, communicating personally about research and writing for the blog became my major activities, and further updating of this treatise became increasingly secondary. As time has progressed my appreciation and understanding of the detailed sciences involved in aging and health have multiplied severalfold. And yet, the more I learn the more obvious it is that there is much more yet to be learned. It seems that for everything I learn, I discover there are at least two new things yet to be learned.
At first, few people read the blog, but over the years it’s readership as well as the attention it has received from the scientific community have been increasing exponentially. Early-on, I started posting longer blog posts that go into considerable depth. The blog now (July 3, 2014) includes over 472 posts and thousands of comments. On the average, 5,000 to 6,000 readers access the blog daily, with an average of 2.3 blog entries viewed per user access.. That is, there are about 14,000 blog accesses every day. About half of the usage is international. Other strong and highly informed intellectual contributors have joined me in researching and authoring materials for the blog, Jim Watson in particular as a very strong partner. Also I need mention Melody Winnig, a researcher-writer who performs important daily research literature surveillance for me and Jim.
As time progressed, the process of updating this treatise has became increasingly daunting, in part because its organization no longer reflects how I now think about longevity or longevity-related interventions. By about mid 2012 I was updating this treatise only selectively and somewhere in the middle of 2013 I gave up doing that completely except for listing blog entry links. Other than for this FORWARD, I am now only listing new blog entries in the updates>
This treatise does not adequately cover a large number of important topics, mainly ones of newer science. Many of these are, however, covered fairly comprehensively in blog entries. These include progress in stem cell research, many topics of epigenetics, several key gene-activation pathways, mitochondrial dynamics, redox related pathways, telomere-related pathways, health-producing properties of plant polyphenols, stress-responses and hormesis, quorum sensing in biofilms, microtubules, bacterial communications, nano delivery of therapeutic substances, quantum biology, systems biology, human bacterial biomes, roles of RNA species, age-related diseases including Alzheimer’s, Parkinson’s, diabetes and cancers, evolutionary origins of our signaling systems, exosomal communication systems, cell senescence, signaling gasses, interspecies communications, circadian regulation and progress towards creating a Grand Unified Theory of biology and aging - to mention just a few. Readers with particular interests are invited to check over the listings of blog entries included here. You can use your browser’s search function on this page to find and link to particular entries.
As to shift over time of my overall perspective, a central observation is that I no longer view the theories of aging described here as independent or even necessarily fundamental. They are all part of an emerging new grand unified theory (GUT) of biology. For example, REDOX processes, central to the first theory of aging, actually play significant roles in each of the other theories. Some of the theories are more basic and “upstream” of the others. Some like lipofuscin accumulation, telomere shortening and tissue glycation and even cancers and heart diseases are definitely downstream in the causal chain. I expect to be forwarding the development of that GUT in close cooperation with Jim Watson, and at some point this will become the subject of a new book.
Another key observation is the importance of researching and drawing together discoveries from across a wide spectrum of disciplines – be the publications drawn from the literatures of genetics, epigenetics, cancer research, research in other specific diseases, cell components like mitochondria or microtubules, stem cells, plant biology, dose-responses, biogerentology, biochemistry of proteins, etc. Relatively few of our citations are drawn from the works of researchers primarily involved in the field of aging. Sadly but probably necessarily, most researchers work in disciplinary areas where there is great emphasis on depth of detail but where there is little time to encompass or integrate in discoveries from other disciplines. I believe the blog has been able to surface a number of important original insights by bringing together and interpreting discoveries drawn from different disciplines in new contexts.
I continue to see the value of this treatise mainly as a source document for somebody who wants to begin the process of learning about aging and longevity research, and who is concerned with practical steps, implementable today, that may be likely to extend their healthy lifespans.
If you want to learn about the forefront areas of the health and aging sciences, I suggest reading the blog entries.
What’s new July 3, 2014: Recent substantive blog postings include: * Anacardic acid - Ayurvedic medicine, old industrial phytochemical with newly discovered molecular actions and health properties, * Trehalose - a natural sugar that could possibly be consumed for health and longevity, * Glucosamine for longevity, * FIVE-YEAR PROGRESS REPORT ON MAJOR TRENDS IMPACTING ON LONGEVITY, * PRECONDITIONING - Adaptive Response In Biology And Medicine - report on the 2014 annual meeting of the International Dose Response Society , * Nuclear Aging: The View from the Telomere end of the Chromosome- Part 3 - Telomere Molecular Biology and GUT implications- The two faces of P53, * Shedding new light on circadian rhythms, * A proposed initiative to facilitate retirement transitions , * The evolving narrative and social transformation of aging - Part 3: major initiatives and activities that are reflecting and driving the changes in narratives of aging, * The evolving narrative and social transformation of aging - Part 2: Narratives of Aging, * The evolving narrative and social transformation of aging - Part -: Important issues confronting the world associated with aging populations</em>, * Update on C60 fullerenes in olive oil, * Nuclear Aging: The View from the Telomere end of the Chromosome - Part 2 - Telomere Molecular Biology, * Nuclear Aging: The View from the Telomere end of the Chromosome Part 1 - context, history, and about telomere lengths, * Jim Watsons Top 12 List of Things I Learned about Aging in 2013, * Editorial: 13 personal health and longevity science headlines for 2013, * ACE and Angiotensin II: The Double Agents that Play Multiple Roles in the Molecular Story of Life, * Nuts over Nuts, * Prospectus for a Grand Unified theory of Biology, Health and Aging, * The Master Regulator of Aging? Redox, Glutatione and Cysteine, Part 1, * Further extensions to and implications of the Xenohormetic live food hypothesis, * Genetic and epigenetic factors in cancer, cellular senescence and the light and dark sides of exosome communications in cancer, * Circular RNA - The RNA Story is coming Full Circle -Exon Skippingexplains Atherosclerosis and possibly aging, * More on the xenohormetic live food hypothesis - synergies among polyphenols, additional post-harvest plant stressors and stress responses, plant polyphenol transcription factors, * Health through stressing fruits and vegetables - the Xenohormetic Live Food Hypothesis (updated), * Quorum Sensing Part 2 - Intra and inter-species molecular communications, * Quorum sensing Part 1: quorum sensing inhibition via phytochemicals a new approach against infectious diseases, * THE HORMESIS BARS, * PART 3: Slaying Two Dragons with the Sound of Silence: How to Keep Your Repetitive DNA Turned Off with 3 Songs: Sirtuins, Polycomb Proteins, and DNMT3. And a Master List of Drugs and Natural Compounds for Cancer Chemoprevention, * PART 2: Slaying Two Dragons with One Hail of Stones: The Silencing Of Good Genes In Aging And Cancer And How Polyphenols Can Prevent That, * PART 1: Slaying TwoDragons with One Stone How to Prevent Cancer and Aging with the Same Strategy,
Posts earier than June2013 include:* Response to Jim Watson's wager challenge, * Autophagy - the housekeeper in every cell that fights aging, * Aging science wager challenges and prizes open to readers, * The Prospects that Emerging Science Offers Us for Longer Healthy Lifespans, * Announcement - Vivace Associates, * Multifactorial hormesis II - Powerpoint presentation, * Sarcopenia - the Age-related Los of Muscle Mass and Function - Part I: Pathways and factors, * Mitochondria Part 2: Mitochondrial Responses to Stress: Mitochondrial Signaling: Survival and Death Pathways, * Microtubules, the intra-cellular transport system, health and longevity, * Multifactorial hormesis - the theory and practice of maintaining health and longevity, * Mitochondria in health and aging, and possibilities for life prolongation Part 1:basics, * Buckyballs, health and longevity - state of knowledge, * Plant polyphenols - six epigenetic knockout punches against cancers, * The Hormetic Wild Animal Zoo and Their Zookeepers, * Editorial - Bridging the Great Divide, * Mitohormesis, * Radiation hormesis, * Adaptogens Part 2: - focus on rhodiola - video blog, * Adaptogens Part 1 - video blog, * Phytosubstances - focus on Andrographis, an old medicine with many possible new applications, * Observations on the evolution of evolution, * A stem cell cure for Parkinsons Disease - so close and yet so far away, * Insights into the epigenetics and rejuvenation of adult stem cells - Improving prospects for extraordinary longevity, * Guest commentary - Robert Pappas on de Grey - Blakemore Oxford University debate on defeating aging, * Telomerase update arguments for and against using telomere extender supplements, * Important recent research on cancer stem cells in lung cancers, * Prostate cancer - epigenetic factors, the role of Nrf2, cancer stem cells and actions of phytochemicals, * Chronic rhinosinusitis, MRSA, biofilms and manuka honey, * New, emerging and potential treatments for cancers: Part 3 - selected less-known phytochemicals that have long been used in traditional Chinese medicine - focus on gambogic and gambogenic acids, * New, emerging and potential treatments for cancers: Part 2 - focus on anti-cancer interventions that simultaneously address multiple growth pathways, * New, emerging and potential treatments for cancers: Part 1 - focus on the mTOR pathway, * Focus on phytosubstances - amazing properties of epimedium and icariin, * Epigenetic Mechanisms of Long-term Memory, * Blue light, sleep, mental alertness and health, * Gut microbiota, probiotics, prebiotics and synbiotics - keys to health and longevity
What’s new February 15, 2012: I have just rewritten the section on the Oxidative Damage theory of aging to reflect my research on the topic as reported in blog entries. Recent substantive blog postings include: * The pivotal role of Nrf2. Part 3: Part 3 - Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension?, * The pivotal role of Nrf2: Part 2 - foods, phyto-substances and other substances that turn on Nrf2, * The pivotal role of Nrf2: Part 1 - a new view on the control of oxidative damage and generation of hormetic effects, * Circadian Regulation, NMN, Preventing Diabetes, and Longevity, * Alternate-day Fasting - a better alternative, * Dietary factors and dementia - Part 3: plant-derived substances that can make a difference, * Dietary factors and dementia - Part 2: possible interventions, * Dietary factors and dementia - Part 1: important recent research, * Focus on phytosubstances - Danshen root - amazing properties of salvia miltiorrhiza Bunge, * History and future directions for this blog - invitation for associate researchers/writers, * More about Klotho - spinner of the thread of life, * CAR adoptive stem cell immunotherapy an emerging new weapon against cancers and other incurable diseases, * Mechanisms and Effects of Dietary Restriction, * Latest p16(Ink4a) senescence-reversing research - an important but not game-changing contribution, * Key roles of glia and microglia in age-related neurodegenerative diseases, * In-vivo cell reprogramming for longer lives, * Progress update on induced pluripotent stem cells, * Not-So-Disposable Somas: Proof of Concept Studies for Increasing Lifespan, * Phytosubstances focus on cats claw.
I have moved older What’s New items, those prior to September 24, 2011, to the end of this document to reduce up-front clutter. They can be found here, a history of what I have done to the treatise over time and past blog entries.
There are several major theories about the underlying causes of what we call aging and age-related causes of death, each with its own school of proponents. This treatise outlines fourteen such theories and comments on how each theory relates to primary diseases of aging such as cancers, cardiovascular diseases and Alzheimer’s disease. It then goes on to suggest a practical protective “firewall” against the biochemical processes underlying each aging theory through dietary supplementation and lifestyle modifications. The idea is that each theory of aging points to certain underlying biological processes. Through slowing, preventing or even reversing these processes, it may be possible to slow, prevent or even partially reverse aging. The practical objective is not only living longer but also living free of age-related problems and diseases.
Longevity sciences are far from static, and the same is true for this treatise. My thoughts and opinions about the theories of aging have evolved significantly since I published the first online version of this treatise in May of 2008. I continue to follow multiple streams of longevity-related research keeping my mind as open as I can. My blog has become my main vehicle for communicating what I have been learning but it is important for me to keep this treatise relevant. So, I continue to update it frequently. I hyperlink to blog entries that provide much more thorough treatments than I can lay out here. Typically, I include a number of minor corrections and modifications with each update of this treatise. From time to time I have updated entire sections of this treatise.
The theories and major causes of age-related death I treat are:
With aging, people tend to become more and more vulnerable to certain diseases and disorders related to aging. Sooner or later one of these diseases or disorders leads to death. Nobody dies of “old age” per se, but up to this point everybody dies before reaching the age of 123. The theories are concerned with the why and how of death coming so certainly in this fixed time frame. I first outline how each of the theories characterizes increasing susceptibility to key diseases and disorders with increasing age. Then I describe the corresponding protective “firewalls” that I have identified and personally employ.
There is much research evidence behind each of these theories and bodies of disease knowledge. Each appears to have its strong basis for validity. Since I first drafted this treatise I have added an additional six candidate theories of aging which are described later in this treatise here. And, yet-other theories of aging are described in various blog entries. These theories overlap each other in complex ways. Which one is correct? Probably all of them. They are like the different descriptions of an elephant given by blind men who each feel only a different part of the beast. I prefer to view them not as competitors but as synergistic, as parts of a larger systems perspective on aging yet to be developed. As time goes on more and more links among these theories are becoming known. I report on many of these links in my blog and mention some in updated discussions in this treatise.
Suceptablity to disease is a function of genetic background, constitutional history and environmental factors. How these factors interplay to create most diseases and degenerative conditions of old age is in many cases only poorly understood. The firewalls described here cannot be guaranteed to prevent or cure any disease. Nontheless, for healthy people with good genes, I believe the firewalls significantly decrease the probabilities of contracting or becoming debilitated from most of the worst diseases associated with aging at any period of age. Of course, sooner or later, one or the other of the disease and deterioriation processes will get everybody. My objective is to make that time later. So, one of my purposes here is to explain and justify some practical approaches that I have been using in an effort to retard my aging, not to provide medical advice.
The human body is extremely complicated and still mostly unknown territory. Even for what is known, I can't cover any individual topic in real depth. Fortunately, the state of knowledge in the areas I touch on here is rapidly developing. I have been updating this on-line treatise at least every few weeks since the first web draft in May 2008. In that time frame I have added two new theories of aging to the original twelve and have identified several additional firewall supplements. I have added a large number of comments, clarificatory explanations and literature references. I have also created the blog counterpart to this treatise and generally add new postings to the blog weekly. And, following current research frontiers, I have identified six additional candidate theories of aging. I discuss these in a final section of this treatise.
I briefly characterize each of the above-mentioned theories of aging and age-related death, and in some cases touch on how they are related one to another. Further, I outline how these theories explain the processes underlying the most serious diseases that eventually kill older people.
(Latest revision, February 2012) The most classical theory of aging is that it is the result of accumulative damage to tissues due to oxidation. This theory, dating back to the 1950s, is also known as the free radical theory of aging. However now, accumulating evidence suggests that the original formulation theory is probably invalid. I first outline the theory as I did in the earlier drafts of this treatise. Then I refer to the evidence to the effect that the oxidative damage theory of aging represents an obsolete and probably-invalid paradigm. Then I restate the theory in a more contemporary form.
Free radicals (ROS or Reactive Oxygen Species) are produced as a result of natural metabolism, by exposure to UV and X-rays, by exposure to certain toxic chemicals including heavy metals, and by consuming certain foods. ROS ions steal electrons from lipids in cell membranes, a process called lipid peroxidation. A chain of damaging events can be let lose from a single ROS molecule as unstable fatty acid radicals propagating in tissues and within cells produce other unstable radicals. The result can be cell death, damage to DNA or mitochondrial DNA, mangled chromosomes, protein cross-linking, cell apoptosis (suicide), genetic mutations, mutated germ cells and other forms of cell havoc. The damage can show up in many ways including skin erythema, hair loss, atherosclerosis and other forms of vascular damage, internal bleeding, cataracts, cancers, hypertension, type 2 diabetes, weakened immune systems, sterility, mutations in offspring, cancers, Alzheimer's disease, premature aging and death. Up to a few years ago, most students of aging thought that oxidative damage was the primary cause of aging. The newer theories of aging continue to see oxidative damage as very important in the aging process, but part of a larger picture. For example, oxidation is now seen to play a role in inhibiting the rate of renewal of neural cells. The biological pathways impacted by oxidative damage are becoming better understood, such as its effect on chromatin remodeling and pro-inflammatory signal transduction(ref) (ref).
The case against the original free radical theory of aging is put forward centrally and documented by multiple current research citations in Victor's Septermber 2011 blog entry End of the free radical theory of aging and negative consequences of indiscriminante antioxidant supplementation. And the paradigm shift associated with letting go of that theory is discussed in my blog entry Editorial - A shift in a key aging sciences paradigm. Essentially, radicals plan key roles in cellular processes and the body has its own sophisticated organ-specific processes for utilizing radicals and, when appropriate, for antioxidant defense. "Research in recent years has revealed that, in addition to cellular energy production, radicals play a crucial roles in many important physiological processes, including signal transduction, cell-cycle regulation, and immune function. -- to date, despite decades of intense research, and thousands of studies, with extremely few exceptions, like radiation sickness, conclusive evidence has not been found that radical formation is a causative factor in the pathogenesis of diseases. -- On the contrary, evidence indicates that, in most cases, radical formation results from, but does not cause disease processes (ref), (ref). Radical formation results from tissue injury, and is a necessary step in healing processes (ref). As discussed in references cited below, radicals play a crucial role in developmental, metabolic, immunological, and other physiological functions. Without them we would not be able to produce energy, develop properly, repair injury; nor would we be able to destroy pathogens or infected and malignant cells. In rare cases, radicals may cause DNA damage possibly leading to cancer; however, on a regular, widespread basis, radicals are involved in the destruction of malignant cells, protecting us from cancer."
We now know that we could not live without free radicals and stamping them out would also kill us. Further, the body has its own complex antioxidant defense system for protection against unwanted free radicals. Recent research suggests taking antioxidant supplements could both interfere with free radicals when and where they are needed and sabotage the body’s own natural antioxidant defense system. So, the whole idea of taking antioxidant supplements in the interest of longevity is challenged.
Other earlier blog entries telegraphed problems with the free radical theory of aging. These posts include The free radical theory of aging. Is it really a theory of aging?, The anti-antioxidant side of the story and Another possible negative for antioxidants.
However, discovery of the Keap1-Nrf2 pathway has provided an entirely new perspective on both the theory of aging and taking antioxidant supplements. A new free radical theory of aging in which Nrf2 gene activation is key is alive and thriving. The pathway acts on dozens or hundreds of genes activating the body’s own antioxidant defense system, stress-protective genes and inhibits the expression of NF-kappaB and consequent inflammation. The “antioxidants” that do provide demonstrable health benefits, like curcumin, green tea, fish oil and resveratrol, do so not by direct chemical antioxidant action as once thought. Instead, they act primarily by activating the Keap1-Nrf2 pathway and exercise their actions by activating multiple genes and associated pathways.
Among the pathways the appear to be involved are Keap1-Nrf2, AMPK, P13-kinase, AKT, P53, mTOR, MAPK, PPAR-gamma, FOXO/DAF-16, the GH-IGF axis, P16(Ink4a), SIRT1, telomerase, Klotho and NF-lappaB. Nrf2 has attracted great research interest as being a possible gateway for prevention or cure of multiple diseases ranging from neurological and cardiovascular disorders to cancers, with Pubmed.org showing 2,371 Nrf2-related publications in recent years. The author has recently (March 2012) published three extensive review-type blog articles on Nrf2 providing details * The pivotal role of Nrf2. Part 3: Part 3 - Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension?, * The pivotal role of Nrf2: Part 2 - foods, phyto-substances and other substances that turn on Nrf2, * The pivotal role of Nrf2: Part 1 - a new view on the control of oxidative damage and generation of hormetic effects.
Cell mutations can cause or lead to age-related deaths. An important form of oxidative damage can be in the DNA of cells. Environmental toxins, cigarette smoke and even some antibiotics and anti-inflammatory medications can also contribute to DNA damage. There are multiple kinds of DNA damage including single-strand breaks and double-strand breaks (ref) (ref). Even without extraordinary exposure, in the course of a normal good day a person may have a million or more events of DNA damage occur in his or her body. Consequences can include cell apoptosis, failure to reproduce, abnormal tissue reproduction, reproductive errors leading to cancers, and premature cell senescence. The list of age-related maladies resulting from genetic damage is long including immunodeficiency, rheumatoid arthritis, cancers of all kinds, arteriosclerosis, and chronic diseases such as chronic fatigue. It appears that DNA damage is also the source of a number of neuro-degenerative diseases including Parkinson’s disease and Alzheimer's disease. Since an important form of DNA damage is oxidative damage, the DNA mutation theory of aging is not independent from the oxidative damage theory, and in fact it is closely related to several of the other theories as well.
In response to this challenge, cells have evolved numerous repair strategies. Some such strategies are very clever and some still are being discovered. I discussed one such line of defense against an important form of DNA damage, double-strand breaks, in my March 2010 blog entry DNA repair cleanup failure - a root cause for cancers? I discuss four more strategies used by the body for DNA repair in the subsequent blog entry More on DNA repair strategies. The blog entry The Nuclear DNA Damage/Mutation Theory of Aging , guest-written by Brendan Hussey, offers a clear presentation of this theory and also provides a number of relevant insights into the cell biology of aging.
Mitochondria are tiny organelles within cells responsible for producing the cell’s source of chemical energy known as adenosine triphosphate (ATP). Many researchers believe that decline in the integrity of mitochondrial DNA is a root cause of aging and that maintaining mitochondrial health is central for longevity. Mitochondria, have their own DNA which is extremely subject to mutation such as resulting from attack by ROS. At least 40 diseases have been identified that involve pathology of mitochondrial functioning. They can affect brain and other nerve cells, kidneys, eyes, ears, the pancreas, and the liver. Also, damage to mitochondrial DNA can come about through insufficiency of certain micronutrients like zink and copper, and deficiencies of Vitamin D, C, E, B12, B6, niacin, and folic acid(ref). See also the candidate theory of aging based on micronutrient triage.
Cells have mechanisms for repair of damaged DNA and mitochondrial DNA, but these have their own side effects. There is a DNA repair enzyme known as NADH. However, repair results in depletion of NADH and of ATP. ATP depletion is believed to be one of the most critical factors leading to necrosis or cell apoptosis.
Mitochondria play additional critical roles in the cell life and reproductive cycle including roles involving cell signaling, growth, differentiation and death. They can be the sources of many important signals relating to cancers, neurological diseases such as Parkinson’s, cardiovascular diseases, type 2 diabetes, and optical neurological problems. Presence of oxidative conditions in a cell can signal the mitochondria to generate signals to other parts of the cell leading to cell apoptosis. It is thought that selective inhibition of this chain could be one means of retarding aging. The signaling relationships between mitochondrial DNA and regular cellular DNA is one example of the systems relationships between the various theories of aging. And it points out how addressing one “cause” of aging can sometimes also mitigate several others as well. The blog entry Mitohormesis discusses a number of processes that go on in mitochondria and the complex pathways through which they play their key role in energy metabolism. Two 2012-2013 blog entries offer in-depth explorations of mitochondrial molecular pathways and their relationships to health and longevity: Mitochondria in health and aging, and possibilities for life prolongation - Part 1:basics, and Mitochondria Part 2: Mitochondrial Responses to Stress: Mitochondrial Signaling: Survival and Death Pathways, Written by James P Watson.
Exponents of the glycation theory of aging believe that mitigation of tissue glycation (cross linking of tissue proteins with sugars) could contribute to raising the effective upper limit of human life spans. Glycation is a process involving a sugar molecule such as fructose or glucose bonding to a protein or lipid molecule without the involvement of an enzyme. Glycation may occur either inside the body or be present in foods consumed such as in browned meats, baked goods or french fries. Cross-linking compounds can also be introduced into the body by smoking or chewing cured tobacco. Known as the Maillard reaction, glycation leads to molecular cross-linking and polymerization and the development of brown-color products known as Advanced Glycation Endproducts (AGEs). The brown of toast and burnt crusts on roasted meat are examples of AGEs. A simplistic way of thinking about it is that glycation cooks tissues in an older person’s body rendering them dysfunctional and dangerous to their neighboring tissues.
Body levels of AGEs increase with age and depend on the kinds of food eaten as well as internal bodily processes that eliminate them. The result of AGEs can be self-propagating systemic or "silent" tissue inflammation. AGEs are recognized by cell RAGE receptors which result in the production of cytokine chemicals that can induce unwanted and potentially deadly inflammation in blood vessels, nerve, liver and other tissues. Atherosclerosis can be a consequence. AGEs are responsible for much bodily mischief related to aging leading to deterioration of function and structure of organs. They play important roles in diabetes, atherosclerosis, vascular disease, kidney failure, and neuropathy including Alzheimer's disease.
The presence of AGEs also appears to negatively impact on immune system functioning. Diabetes in particular appears to have its roots due to glycation and people with high blood sugar levels are particularly susceptible to glycation. Glycation and associated inflammation is believed to be a major contributor to microangiopathy. Glycation and oxidation seem to some extent to go hand in hand and there is evidence that the presence of one increases the susceptibility to the other. The presence of AGEs in swollen lysomes in a glycated tissue can result in a multifold increase in the rate of production of free radicals compared to that in an unclycated tissue. Moreover, glycation and oxidation can conspire with each other to produce disease effects such as renal failure.
To the Tissue Glycation Firewall
Control of levels of lipofuscin is another important component of an anti-aging regime. Lipofuscin is a yellow-brown byproduct of metabolism that tends to accumulate in cells with age, granules resulting from lysomal digestion. It is a marker of aging found in many different cells including ganglia, heart, muscle, kidney, adrenal and nerve cells. Brown “liver spots” seen on the hands and faces of aged people are lipofuscin deposits. While lipofuscin is not toxic, accumulations of it can impair normal cell functioning. These accumulations can be thought of as piles of uncollected garbage clogging up the insides of cells. Lipofuscin deposits, like AGEs, are not wanted. Lipofuscin accumulation is particularly a problem in post-mitotic (non-dividing) cells, such as most nerve. brain and muscle cells and cardiac myocytes. Accumulation in brain cells appears to be an important issue connected with heavy consumption of alcohol. Hearts with heavy accumulations of lipofuscin may appear to be black when surgery is performed on them.
Lipofuscin accumulation is implicated as a major risk factor in a number of age-related disease processes including macular degeneration and vision loss, Alzheimer's, Batten and Parkinson diseases, melanosis coli, denervation atrophy and chronic obstructive pulmonary disease, to name a few.
Readers who wish to learn more about this theory can view my June 27 2009 blog post that greatly expands on the above information and cites multiple research references: Research Roundup on the Lipofuscin Theory of Aging.
Excess or chronic inflammation appears to be a core condition underlying many if not most age-related disease processes Inflammation is a natural process, the response of circulatory system tissues to stimuli perceived to be harmful, such as, damaged cells, irritants or infectious pathogens. Inflammation is an automatic approach to eliminating injurious stimuli and to starting healing - a protective attempt by the body to remove the injurious stimuli as well as initiate the healing process for the tissue. Excessive or chronic inflammation, on the other hand, is an inappropriate response that can lead to all kinds of damage including potentially fatal conditions. It can be initiated by multiple inter-cellular signaling pathways and may be due to multiple causes including oxidative damage and the presence of AGEs as mentioned above.
In a condition of chronic inflammation there is a continuing release of pro-inflammatory signaling molecules including autocoids and cytokines. The impressive list of inflammatory disorders includes congestive heart disease, stroke, rheumatoid arthritis, chronic inflammation, tendonitis, pelvic inflammatory disease, vasculitis, auto immune diseases, asthma, other allergies, inflammatory bowel disease, and glomerulonephritis. It is also the active element in acute appendicitis, acute dermatitis, and acute meningitis. Inflammation contributes to the growth of many cancers affecting the micro environment around tumors. It can contributes to tumor proliferation, survival and migration. Many cancer cells secrete substances that promote inflammation, called selectins and chemokines, to contribute to their capability to grow, penetrate surrounding tissues and metastasize. Chronic inflammation such as connected with arthritis can affect joints and lead to orthopedic joint degeneration.
Immune systems tend to weaken with age – often to the point where common diseases become fatal. Immune system compromise may result from a hereditary condition (such as inheriting genes for lupus or rheumatoid arthritis), from a disease process such as AIDS, or simply from normal aging. Changes in hormones and hormone-like substances may contribute to immune system weakening with age. The production of important hormones that impact on immune system functioning like melatonin, DHEA and HGH decreases with age. In older adults, important immune cells may be inhibited from doing their jobs by an increase in certain prostaglandins that tend to regulate important body processes such as body temperature and metabolism. In elderly adults infection-fighting cells (lymphocytes) mobilized in response to an infection are likely to be less responsive and less effective than those found in younger adults. In aged people compared to younger ones, fewer antibodies are produced, they are less vigorous and the duration of their response is shorter. So, the immune system of an older adults -- including lymphocytes and other types of cells -- typically reacts more slowly and weakly.
I have already mentioned how tissue glycation can contribute to immune system disfunction, and how tissue glycation is correlated with oxidative damage and inflammation - another example of the multiple cross-links between the theories of aging.
The bottom line is that older people become more susceptible to infectious diseases with age. A viral infection or pneumonia infection that a young person could shake off in a week might kill his great-grandparent in a nursing home. Also, susceptibility to auto-immune diseases like fibromyalgia, lupus, scleroderma and arthritis increases with age. Old folks in their 70s and beyond are more likely to produce autoantibodies which attack parts of the body itself instead of infections. These autoantibodies contribute to causing atherosclerosis, rheumatoid arthritis and other pathological conditions.
Autoimmune diseases like rheumatoid arthritis and Lupus often co-exist with certain cancers. I have written a series of three blog postings on Autoimmune diseases and lymphoma: Part I: focus on Lupus, Part II: focus on inflammation, and Part III: focus on lymphomas. Other blog entries relevant to immune systems functioning include Immunosenescence - No thanks for the memories.
Neurological degeneration can take many forms which become increasingly manifest with age. It is often closely related to immune system compromise, decline in hormone levels and other already-conditions which tend to compromise nerve cells and tissues. I have already mentioned Alzheimer’s disease, Parkinson’s disease and macular degeneration as examples of age-related neurological diseases. All forms of memory loss and senile dementia fall in this category as well as increased stimulus response times which can make driving and even walking dangerous. Degeneration of neuron systems in the inner ear can make it difficult for older people to maintain their balance. They frequently fall and hurt themselves. Orthopedic injuries associated with falling constitute one of the major maladies of the aged leading to loss of normal functionality and nursing home occupancy.
The nervous system consists of much more than interlinked neurons. Glial cells like Schwann cells and oligodenadrocytes manufacture myelin, an insulating substance, and wraps it around the axons connecting neurons. Astrocytes are other glial cells that regulate the wrapping process. It is thought that health and longevity of those cells is as important as that of neurons for mental health maintenance. Multiple sclerosis and cerebral palsy, for example are known to be diseases associated with malfunctioning glial cells. And improper myelin formation possibly contributes to several other mental illnesses such as autism, schizophrenoa and bipolar disease. The blog entry Spinal cord injury pain - a personal story and a new paradigm deals with the key roles of microglia in chronic neuropathic pain. The blog post Alzheimers Disease Update March 2011 is the most recent update on Alzheimer's Disease research. The blog post New views of Alzheimer's disease and new approaches to treating it describes how senesence of microglia may be a root cause of Alzheimer's dementia. The blog post BDNF gene - personality, mental balance, dementia, aging and epigenomic imprinting relates to the importance of healthy functioning of the BDNF (brain derived neurotrophic factor) gene for maintaining mental balance and averting dementia. Other blog posts related to Alzheimer's disease include Alzheimers disease studies validate anti-aging firewalls suggestions, Alzheimer's Disease research update, The social cost of Alzheimer's disease and late-life dementia, and a short post Deconstructing Alzheimer's Disease - role of mitochondria.
The June 2012 blog entry A stem cell cure for Parkinson's Disease - so close and yet so far away discusses how stem cell therapy may offer what is close to a cure for PD based an experiment with mice, but how formidable obstacles must be overcome before such a cure can be available in the clinic.
Increasing research evidence suggests that maintaining a sufficient and consistent rate of neurogenesis in the brain, particularly in the hippocampus, is important for the maintenance of cognitive health. Insufficient or irregular neurogenesis is thought to be a causative factor in bipolar disease and other mood disorders. Neurogenesis takes place throughout the life of a mammal in two major brain structures: the dentate gyrus of the hippocampus and the subventricular zone of the forebrain. In these regions neural progenitor cells continuously divide and give birth to new neurons and glial cells. In the mammalian brain neural progenitor cells are multipotent. They can differentiate into neurons, astrocytes or oligodendrocytes, though the factors that determine differentiation are poorly understood. The rate of neurogenesis tends to decline with advancing age in old mammals, as well as the does the number of functional neurons.
Hippocampal neurogenesis is affected by environmental factors, body stress factors like radiation, integrity of circadian gene expression, emotional states and hormonal signals. Further, neurogenesis is tied to circadian rhythms and time-of-day dependent. Neurogenesis is positively affected by learning, voluntary exercise, good physical environment, regular daily rhythms and by ingesting certain mood-stabilizing agents including lithium and, fluoxetine (Prozac). It is negatively affected by involuntary stress, radiation, toxicity and several types of chemotherapy. An oxidative environment inhibits neurogenes while an antioxidant-rich environment promotes it. Also, an oxidative environment favors the production of astrocytes over the production of neurons. (ref). How all these factors interact is a matter of continuing exploration.
A number of substances in the combined anti-aging firewall promote neurogenesis, as described in the Firewall Section for the Neurological Degeneration theory of aging.
The cell-cycle of neurogenesis appears to be tied to daily light-related circadian cycles, with neural progenitor cells entering the cell cycle continually, but passing through into the M phase and generating new neurons mainly at night (at least in rats). It is speculated that irregularities in daily cycles and disrupted sleep may interfere with neurogenesis resulting in mood swings and possibly bipolar events. It is interesting that taking mood stabilizers like fluoxetine may not only inhibit serotonin uptake but also result in accelerated neurogenesis.
Researchers are actively exploring the genetic and cell-biology bases of neurogenesis. It appears that the Bcl-2 gene functions to regulate development and survival of neurons in the central nervous system and is very important for neurogenesis. Also, it appears that expression of a cell nuclear factor, NF-kappaB, is important for neurogenesis. A discussion of the relationship of NF-kappaB to neurogenesis is included later in this paper. Unfortunately there is a paradox in that the same mechanisms that promote neurogenesis, like expression of Bcl-2 and NF-kappaB, can also promote carcinogenesis(ref). The Ink4a proteins which are increaingly active with age suppress those mechanisms leading to increased protection against cancers with age, but at the cost of decreased neurogenesis and decreased proliferation of other somatic stem cell types. Sorting out the differences between the biomolecular programs that promote stem cell expression and the programs that promote cancers, assuming there are some differences, is a major challenge that must be overcome if substantial life extension is to be made possible.
The interdependence of these theories of aging should be becoming clear at this point. Neurological degeneration could be triggered by oxidative damage, lipofuscin accumulation, inflammation, faulty mitochondrial signaling or defects in energy production for example. And problems could originate in neurons, glial cells or in their association. The production of new neurons from neural stem and progenitor cells is important, and the cell-cycle factor NF-kappaB enters criticaly into the picture. Finally, there is an issue of how to promote neurogenesis without encouraging the formation of cancers. A number of blog entries deal with these and related issues increasingly, as time progresses, from the viewpoint of epigenetics. See for example the blog entry Epigenetic Mechanisms of Long-term Memory.
Many affects of aging are related to declines in hormone levels with age and the resulting negative impacts on immune system functioning. The declines appear to start around age 20 and affect just about every major hormone including Human Growth Hormone (HGH), DHEA, pregnenalone, testosterone and melatonin. Typically HGH declines about 80% from age 20 to 60. Some researchers have suggested that these declines constitute a major cause of aging.
As the hormones run down, so do all of the body systems which they regulate. Many body systems are re-regulated or affected by declining hormone levels including the immune system as already mentioned. The transcription of many genes is affected by the changing hormone mix. Impacts are thought to exist in many spheres including energy level, metabolism and weight, endurance, sexual drive, mental acuity, ability to sleep, age-related bone loss, and disease resistance. Specific diseases are associated with various hormone deficiencies. For example, incidences of testicular cancer and exotic-sounding diseases like cryptorchidism and hypospadias appear to be correlated with testosterone deficiency. Hormone levels appear to cause changes in male and female characteristics with age. Also, certain prostaglandins, hormone-like acids that affect important body processes such as body temperature and metabolism, tend to increase in old age and inhibit important immune cells from doing their jobs. Older adults appear to be more sensitive to the action of prostaglandins than younger adults. And some researchers think this could be a major cause of immune deficiency in elderly people.
Decline in bone density and osteoporosis are also attributable to shifts in hormone levels with age. Inadequate bone growth and mineral density is responsible for many older people sustaining serious injuries from falls, losing their capabilities to move freely, or even to walk.
Along with declines in levels of critical hormones, insulin resistance is another frequent hormone-related hallmark of aging, leading to hyperinsulinemia. Hyperinsulinemia shows up as a major risk factor for many age-related diseases, including cardiovascular diseases, Alzheimer's disease, and stroke.
While not properly a causal theory of aging, the danger of cancer pathology increases radically with aging and is the second major cause of age-associated mortality. Cancer is therefore worth separate treatment in this essay and cancers requires their own firewall for longevity. Age-related susceptibility to cancers is associated with multiple genetic changes in tissues probably due to causes basic to the other theories of aging already mentioned. There are many different cancers each with their individual properties but all come about through a combination of genetic changes. Genes related to cell differentiation, proliferation, apoptosis and angiogenesis can affect ability of cancers to come about, survive and grow. A tissue becoming cancerous may entail simultaneous mutation, activation or inhibition of hundreds of genes. Cancers may be initiated due to oxidative DNA or mitochondrial DNA damage or cell senescence. Inflammation both supports cancer growth and is often caused by it. And a healthy immune system, one that detects and wipes out cancer cells, is key to defense against many kinds of cancers.
The genetic pathways associated with the various kinds of cancer are much more complex than previously thought. They are the subject of much research throughout the world and are slowly being decoded. As this happens science is replacing trial-and-error and in coming decades we can expect to see constantly improved cancer treatments going beyond the traditional brute-force ones: surgery, burning with radiation, and poisoning with chemotherapy. Already, these treatments are being augmented by new science-based approaches. Tumor angiogenesis (blood vessel proliferation) inhibition is an approach only available in the last two years, yet it is already in widespread use. Tumor telomerase inhibition is among other research-based approaches that are likely to become available soon. Among the blog entries relating to new insights about cancers or new treatments for them are DNA demethylation - a new way of coming at cancers, Trojan-horse stem cells might offer an important new cancer therapy, On the TRAIL of a selective cancer treatment, On cancer stem cells, Update on cancer stem cells, Autoimmune diseases and lymphoma – Part III: focus on lymphomas, Dendritic cell cancer immunotherapy, Cordyceps militaris and cancer, Progress on fighting glioblastoma, Big pharma is targeting cancer stem cells, Nrf2 and cancer chemoprevention by phytochemicals, New-science approaches to detecting, preventing and curing cancers, News on disabling cancer stem cells, The NRG1 Gene - an important new tumor suppressor gene?, Progress in genetically profiling cancers, * Turning P53 on in cancer cells, * Melanoma research update, * Skin Cancer immunotherapies , * Curcumin, cancer and longevity, * HSP70 to the rescue - But, no, no! That's not what we want for cancer cells, * Another guided-missile cancer therapy - that works, * Cancer, epigenetics and dietary substances, and * CAR adoptive stem cell immunotherapy - an emerging new weapon against cancers and other incurable diseases. Three substantial blog entries published in March 2012 are New, emerging and potential treatments for cancers: Part 3 - selected less-known phytochemicals that have long been used in traditional Chinese medicine - focus on gambogic and gambogenic acids, New, emerging and potential treatments for cancers: Part 2 - focus on anti-cancer interventions that simultaneously address multiple growth pathways, and New, emerging and potential treatments for cancers: Part 1 - focus on the mTOR pathway. Also, the April 2012 blog entry Prostate cancer - epigenetic factors, the role of Nrf2, cancer stem cells and actions of phytochemicals looks in-depth at the factors in inerplay in one type of deadly cancer. For the present, I suspect that it is possible for people without genetic pre-dispositions to cancer or exposed to cancer hazards to construct a quite robust firewall against cancer. I do not expect to experience a serious cancer problem in my life.
Cardiovascular diseases are the biggest killers of old people. These comprise a host of maladies including cardiovascular stroke, heart attacks, ischemia (inadequate blood flow), congestive heart disease and atherosclerosis. So again, while cardiovascular diseases are not properly a causal theory of aging, they are worth discussion here. And it is important to create an effective firewall against these diseases. As for cancers, age-related susceptibility to cardiovascular diseases is attributable to multiple causes which are basic to the other theories of aging already mentioned. For example myocardial cell membranes become remodeled with advanced age possibly due to stress and oxidative damage, and this remodeling impacts negatively on mitochondrial function which is critical for sustaining energy production in cardiac membranes. The age-related remodeling appears to involve an imbalance between omega-3 and omega-6 fatty acids in these membranes as well as dysfunctional Ca2+ metabolism. The mechanisms of buildup of arterial plaque are related to over-eating, poor eating, overweight, stress, high blood pressure, conditions such as diabetes, immune fatigue and lack of exercise. Chronic inflammation is at the head of the list, and also implicated are tissue glycation, oxidative stress, declining immune functions, and changes in hormone levels. Insulin resistance is also highly implicated in the creation of heart disease risk as well, of course, in diabetes. A vicious cycle ensues for people who are genetically susceptible to insulin resistance when they eat a high glycemic-index diet and are sedentary. They gain weight and become obese. Insulin resistance worsens with the increase in weight and the result is gaining even more weight making themselves increasingly susceptible to cardiovascular diseases, diabetes and other serious conditions. The biology and molecular dynamics of diabetes are discussed in this blog post.
The Queen of existing theories of aging is that most of the diseases of old age come about through cell senescence due to telomere loss. Telomeres are the “caps” found on the end of chromosomes in somatic cells. They consist of long repeated strings of what appears to be otherwise inert DNA, much like the ends of shoelaces. Telomeres do not encode genetic information. Their role is to preserve the integrity of the information encoded in chromosomes during the process of cell division. When a cell divides, enzymes that duplicate the chromosome and its DNA can only produce a slightly shorter chromosome, with a little missing from each end. The telomeres become a bit shorter in the daughter cells but this does not matter because all genetic information is preserved. This works for a large number of cell replications – perhaps 50 or 70 – but after that point the telomeres are too short for reliable chromosome duplication. And at that point reliable cell duplication is no longer insured. It has long been known that a culture of somatic cells will live through a certain number of cell divisions and then reach the “Hayflick limit” and die. The telomere theory explains why this is so.
Telomere shortening can be observed in mitotic (dividing) human cells during aging. Further, almost all chronic diseases increase the rate of cell turnover and therefore telomere shortening. In body organs, cells with depleted telomeres may settle into bad-neighbor senescence sending out noxious signals to their neighbors, commit apoptosis, or reproduce with genetic errors in the chromosomes. Cancers and other pathological situations can result. It appears that cellular senescence initiates a self-amplifying cycle between mitochondrial and telomeric DNA damage. The telomere shortening theory of aging suggests that when a substantial number of cells in an organ approach the Hayflick limit and cell senescence, integrity of that organ can no longer be assured and that virtually all of the conditions and diseases of old age are thus traceable to cell senescence. Telomeres are the “clocks” that determine life spans in humans according to this theory. There is much experimental evidence related to telomere lengths and their significance. The blog entry Smurf2 in senescence, aging and diseases relates to a protein, Smurf2, that sends cells into a senescent state when telomere attrition happens.
Cell senescence explains why the diseases of old age become so extreme with old age. As the clocks start to run out there is a mounting tide of problems and diseases and it appears that there is an age limit of about 120 years that is insurmountable unless a way can be found to extend telomeres or keep them long. The research evidence implicating telomere shortening in the degenerative diseases of aging continues to build up (ref) (ref) and is no longer questioned.
There are tests that can measure telomere lengths, and average telomere length is often used to estimate biological age and remaining life span of an organism. It is known that individuals exposed to disease or oxidative stress have significantly shorter average telomere lengths than control groups. Minimization of stress, good rest, good diet and good mental attitude can result in longer average telomere lengths. So can regularly taking antioxidants and viatamins. Experienced stress of all kinds tend to reduce telomere lengths. A bout of radiation therapy or chemotherapy can significantly reduce average telomere length. A recent study measured telomere lengths of long-term family care givers, people who attend to chronically sick children, and compared these to telomere lengths of non-caregivers of comparable ages. The care givers had shorter telomeres and appeared to be biologically 4-5 years older than the non-caregivers. One recent study indicates that a history of childhood emotional trauma such as having been beaten or sexually abused is stongly correlated with shorter telomere lengths in grown adults(ref). Telomere length is often used as a surrogate in laboratory experiments to assess the impact of experimental biochemical processes on life spans.
A November 2009 Blog entry describes a breakthrough telomere research finding linking telomere shortening to another of the key theories of aging, Programmed Epigenomic Changes. "Telomeric shortening at some point induces DNA damage which lets loose signaling which changes the epigenome disrupting epigenetic silencing and resulting in pro-aging global DNA expression."
There is more to the the theory since germ-line cells and most cancer cells seem to be able to reproduce indefinitely. Their telomeres do not get shorter with reproduction. In 1980, two women researchers, Elizabeth Blackburn and Joan Steitz, discovered that cells contain a gene for a substance called telomerase that can paste telomere ends back on again after cell division. If telomerase is added to a human cell culture in a lab, it can reproduce indefinitely. When the telomerase gene is activated in a germ or cancer cell line, that cell line becomes essentially immortal. Dolly, the first cloned sheep, died prematurely from old age because the telomeres in the cells used to make the clone were already short because they came from a mature sheep.
In the caregiver stress study, the level of telomerase activity was significantly less in the higher-stressed group(ref). There seems to be a strong positive correlation between high levels of stress hormones and free-radical damage, and both of these correlate negatively with level of telomerase expression. Also interestingly, in an experiment when volunteers with high levels and low levels of telomerase expression were subjected to psychological stress, measurable cardiovascular reactions such as heart rate and pulse pressure were significantly milder in the high-telomerase-expression group(ref). So, the relationship between experienced stress and low level of telomerase expression appears to be a two-way street.
One explanation for the decline in immune function with old age is cell senescence – immune cells dying or losing functional capacity because they have duplicated too many times. The same result occurs when immune system cells duplicate at a high rate to fight infections. At one time it was fashionable to talk about an immune system becoming “worn out” because of too many challenges to it due to sickness or age. Now it is more fashionable to say that the immune system T cells telomeres are too short.
Research reported by Rita Effros of UCLA and her colleagues(ref) indicates that cortisol inhibits the expression of telomerase in immune system cells, This explains why people subject to considerable stress tend to have shorter telomeres. Of course, cortisol is produced in the body in response to stress.
A therapy that enhanced expression of telomerase in immune system CD4 and CD8 cells could offer many health and longevity benefits by delaying or preventing senescence of these cells. Benefits could include less bone loss, avoidance of release of inflammatory cytokines, maintenance of strong anti-viral capability, better capability of dealing with stress, and prevention of HIV infections resulting in AIDS. A collection of studies co-authored by Rita Effros relating cell senescence to HIV pathology can be found here.
One benefit of enhancing telomerase expression in immune cells could be for patients with systemic lupus erythematosus (SLE). Many T cells divide continuously in patients with SLE, Although the natural level of expression of telomerase in CD4(+) and CD8(+) cells is high in SLE patients, it is still insufficient to prevent telomere shortening in these cells. Prevention of this shortening by telomerase activation could prevent premature senescence of these cells, and could possibly prevent some of the pathological consequences of SLE.
It is interesting that all of the major risk factors associated with cardiovascular disease (obesity, smoking, poor lipid profile, high blood pressure, diabetes and psychological stress) are associated with key markers of cellular aging (shorter telomere lengths, reduced telomerase activity and higher oxidative index)(ref). So the Telomere Shortening theory of aging impacts directly on the Suceptibility to Cardiovascular Disease theory.
In patients infected with HIV there is typically an initial period of several years during which the immune system is capable of controlling the disease before it finally breaks out into being full AIDS. There is evidence that during this period CD4 and CD8 cells reproduce at an abnormally high rate to keep up their battle with the infection. When these cell lines approach senescence and can no longer reliably reproduce because their telomeres are too short, they can no longer control the spread of the HIV virus and full AIDS finally breaks out. It is thought that enhanced activation of telomerase in these immune cells could make them essentially immortal and continuously capable of fighting off AIDS. Research progress towards this objective was reported recently by a UCLA/Geron team headed by Dr. Effros(ref). "The present study shows that exposure of CD8(+) T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) modestly retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity." Study of the Geron patent and literature references indicate that TAT-2 is cycloastragenol, a substance that can be derived through purification of astragaloside IV, itself a component of astragalus root. ""In this study, we demonstrate that TAT2 can transiently activate telomerase, slow telomere loss, increase replicative capacity, and, importantly, enhance immune function in CD8+ T lymphocytes from HIV-1-infected persons. These data suggest a possible novel immune-based strategy to complement current treatments, which are primarily directed at the virus(ref)."
An evolving perspective on the Telomere shortening theory of aging (Update of March 26, 2011)
I continue to see telomeres and telomerase as extremely important topics from a longevity perspective, but I no longer see taking a telomerase extender like astragenol as likely to be a useful anti-aging intervention. Instead, I believe there is ample research supporting the pursuit of certain conventional-wisdom lifestyle and dietary patterns as ways of keeping telomeres long. My thoughts are expressed in a series of blog entries, particularly The epigenetic regulation of telomeres and Lifestyle, dietary, and other factors associated with telomere shortening and lengthening. See below how my perspective has evolved from that 15 months earlier.
An evolving perspective on the Telomere shortening theory of aging (Update of January 24, 2010)
Twelve years ago, if I were asked about the prospectus for radical life extension to well beyond 110-120 years of age I would have bet most of my chips on telomerase. I would have responded that such life extension will likely depend on our discovering ways to keep the telomeres in our somatic cells from getting to be too short. This would prevent replicative cell senescence and avert the consequent ravages of old age.
Now, based on what is being discovered and given that I am personally pursuing an initial approach to keeping my telomeres long, I see this Telomere shortening theory of aging in a much more nuanced perspective. Essentially everything I have written above still remains valid. But there are several additional factors to take into account:
The January 2010 blog post Vitamins, supplements and telomerase - upregulation or downregulation? points to a different study in which telomere lengthening was observed over a long period of time for a sizeable portion of the population studied. Also, it appears that taking a number of popular supplements in the anti-aging firewalls supplement regimen like Vitamin E, fish oils, Vitamin D3 and resveratrol can lead to telomeres being longer than they otherwise might be, possibly because they induce the production of telomerase, possibly for other reasons. And, several of these supplements actually turn off telomerase in cancer cells.
These results suggests to me that telomere shortening is a complex process involving a balance of shortening due to cell division, lengthening due to natural telomerase expression and perhaps cell replacement due to differentiation of stem cells. And these in turn are affected by many lifestyle and dietary factors and moderated by cell-signaling feedback loops.
My current bottom-line with respect to the Telomere-shortening theory of aging is:
An interesting lecture presentation on telomeres and telomerase by Professor Elizabeth Blackburn, one of the co-discoverers of telomerase, can be viewed by clicking here. Three October 2010 blog updates on telomere length research are Part 1: Telomere lengths, cancers and disease processes, Part 2: Lifestyle, dietary, and other factors associated with telomere shortening and lengthening, and Part 3: Selected current research on telomere-related signaling. Finally a telomerase gene-manipulation mouse experiment producing what appears to be actual age reversal is reported in the November 2010 blog entry Mouse age reversal - very interesting but misrepresented research.
In its most basic form this theory holds that aging is not just the result of accumulation of damage, as many of the aforementioned theories do, but is the result of some kind of program that unfolds through life from conception to death. This is a relatively old theory, but one with strong new supporting evidence. A classical argument for this theory is based on the theory of evolution. It holds that survival of a species requires individual survival only long enough for reproduction and care of offspring until they achieve independence. Young vital individuals are best suited for survival, and older members of the species are best gotten rid of. They should be put out of the way when their turn comes so that they do not compete with younger members of the species for resources. Therefore, the argument goes, evolution would set it up so that older individuals surely die off at a certain point, not just by accumulation of accidental damage but also by a programmed mechanism that is guaranteed to clear the deck. For a long time the concept stopped with this idea. There was no biological evidence of a process of programmed aging, so the theory remained as just an academic possibility. Genetics research empowered by gene chips and computational genetics are now starting to produce such evidence.
In the last two or three years, genetics research, particularly computational genetics, has been revealing the possible existence of complex additional genetic switching mechanisms that could contribute to or be part of an overall program of aging. The emerging concept is that hundreds of genes are involved in what we call aging, and that there is one or several master programs according to which these genes are switched on and off through a lifetime in an intricate pattern to produce early growth, maturation and, finally, assured death.
Epigenomics provides a general framework for explaining aging as a programmed phenomenon. Epigenetics is concerned with both heritable and non-heritable changes in gene expression and activity and also stable, long-term alterations in the gene transcriptional potential of a cell. Epigenetic information is based on the experience of a cell, is stored via DNA methylation and histone actylation patterns, may be passed on in the process of cell division, and may be accumulated over the lifetimes of a cell and all of its ancestors. While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome. So, the epigenomic profile of an organism changes continuously over the lifetime of that organism and that set of changes defines what we call aging. I outline three current chains of research that partially support the idea of programmed genetic changes of aging leading to death.
From my perspective in February 2011, almost three years after writing the original draft of this treatise, I am coming to see how epigenetics and epigenomics provide a basic-science framework of understanding that integrates across the other theories of aging discussed here. The February 2011 blog entry JDP2 - linking epigenetic modifications, stem cell differentiation, cell senescence, cell stress response, and aging provides a discussion of how this works. An updated review discussion of the related roles of genomics and epigenomics in aging and disease processes is given in the June 2011 blog post Aging as a genomic-epigenomic dance. Epigenetics is showing up in almost all areas of research related to aging. For example the roles of epigenetic mechanisms in regulating circadian body clocks is discussed in the January 2012 blog entry Circadian Regulation, NMN, Preventing Diabetes, and Longevity.
The first possible mechanism of programmed aging to come along in the 1990s was the telomere shortening theory already treated above (the 12th theory of aging). The genetic program in this case is simple: telomeres in somatic cells become shorter each time the cell divides until the point where genomic instability and cell senescence sets in. I will discuss two additional llines of research related to programmed epigenomic changes: b) changes in DNA methylation and histone acetylation, and c) changes in expression of a key cell nuclear factor NF-kappaB . Prior to revision of this discussion on May 7 2010, b) was listed as a separate candidate theory of aging.
According to this theory of longevity, an important mechanism is DNA methylation, a process by means of which sites adjacent to genes on chromosomes (promoter regions) are chemically methylated after a cycle of DNA replication(ref). The methylation is passed on in the course of cell divisions and through generations of people. The methylation pattern captures the ancesteral history of the cell that is not in the genes themselves and is unique to every cell. DNA methylation is thought to be one of the main ways epigenetic information is captured and passed on. Histone acetylation, another important mechanism of epigenomic change, relates to folding of histones, the protein spindles around which DNA is wrapped. Patterns of histone acetylation are also part of epigenomic memory. See the blog post Epigenetics, Epigenomics and Aging.
The DNA methylation profiles of individuals are unique, change with aging, and include valuable clues to disease and treatment progress. For example, DNA methylation of tumor suppressor genes predicts the relapse risk in acute myeloid leukemia for patients in clinical remission(ref). So, research groups throughout the world are building databases of DNA methylation epigenomic information, in part to establish methylation markers that are “normal” and other markers that indicate diseases, susceptibility to particular disease conditions and associated information . See the blog entry Epigenetics, Epigenomics and Aging.
DNA methylation is impacted by aging and impacts on aging(ref). The suggested theory of human aging here is that DNA methylation and histone actylation patterns in cells define the biological age of an organism. They tell the body how old we are and drive the symptoms and signs of aging.
Methylation in the promoter region of genes is thought generally to be associated with gene silencing. Longevity-related and health-promoting genes may be turned off in the process of aging due to progressive methylation. The P66Shc gene for example, associated with longevity in mammals, appears to be silenced through some combination of histone deactylation (resulting in protein folding) and cytosine methylation(ref). Little is known yet about how to go about DNA demethylation, but demethylation appears to be necessary for epigenetic cell reprogramming(ref). The intriguing possibility is that through selective demethylation of aging markers it might some day become possible to restore cells, organs and organisms to earler age states. As of now relatively little is known yet about how DNA methylation plays out in aging, yet alone how to work with DNA demethylation in order to stop or reverse aging. Again, it appears that the more we discover, the more there is that we know we don’t know.
An important line of epigenomic research relates to NF-kappaB signaling. NF-kappaB is a nuclear transcription factor involved in cell signaling, i.e. a protein that binds to a specific sequence of DNA. It is present in a latent (non-activated) form in many cell types. On the one hand, expression of NF-kB appears to be one of the body’s regulatory means for handling situations of stress, cancer, damage or disease. In eukaryotic cells NF-kB is an important regulator of genes that control cell proliferation and cell survival. NF-kB regulates anti-apoptotic genes that protect healthy cells from cell death and activates the expression of genes that keep cells proliferating. On the other hand, activated NF-kB binding to genes has long been known to play a central role in promoting runaway inflammation and inflammation’s negative consequences. Oxidative damage, the first theory of aging, is strongly implicated. Free radicals initiate changes that unbind NF-kappaB in the cytoplasm of cells, so that it translocates to the cell's nucleus where it binds to the DNA and initiates inflammatory responses. These consequences are characterized under the sixth theory of aging described above. They include promotion of angiogenesis, proliferation, metastasis and invasiveness in cancer tumors, autoimmune diseases, neurodegenerative diseases and contributing to the activation of human immunodeficiency virus (HIV) leading to AIDS.
There appears to be increasing evidence that inhibition of expression of NF-kB could be a key approach for fighting cancers, controlling inflammatory diseases, AIDS, neurodegenerative conditions like Parkinson’s Disease and a number of other significant age-related maladies.
Recent studies position NF-kB even more centrally with respect to longevity. It is likely that NF-kB expression is central to a programmed set of changes which we call aging. One study(ref1) confirms that that in multiple mammalian tissues (including skin fibroblasts, kidney, cortex, kidney medulla, abdominal muscle, skeletal muscle, and brain), aging involves continuing changes in expression of hundreds of genes. And, further, NF-kB signaling appears to be a major regulator of gene expression related to the aging progress. In fact, by inhibiting NF-kB cell signaling the researchers were able to cause the epidermal tissue of old mice to revert to the state of very young mouse tissue, both in observable characteristics and in genetic expression profile. The authors show that NF-kB cell signaling is a meta-factor for determining aging of nine other key cell types as well, and they argue that the results should apply equally to humans and other mammals.
A very recent study(ref) has to do with the role of Tumor Necrosis Factor (TNF) activating the expression of NF-kappaB in Muscle Progenitor Cells (MPC). This study is also relevant to the fourteenth theory of aging, Deterioration of the Stem Cell Supply Chaiin. TNF acts via a number of pathways in a complicated manner, including activation of NF-kappaB, to produce a variety of effects including induction of apoptosis (cell suicide). This apoptosis is useful when cancers are concerned but is also potentially destructive of healthy cells. It appears that in MPC cells at least, TNF-alpha activates NF-kappaB more in older animals than in younger ones. So, TNF activation of NF-kappaB in older animals can lead to apoptotic signaling and death of otherwise-healthy MPC. The problem is thought to be a decline with age of effective cellular mechanisms for keeping NF-kappaB inactive. Fortunately, as listed in the firewall section for this theory, several dietary substances are capable of restraining the expression of NF-kappaB.
Another study reported in January 2009(ref) adds an additional key piece to the puzzle. It appears that the sirtuin protein SIRT6 is important in limiting the expression of NF-kappaB and thereby restraining aging. The sirtuins are known to be implicated in longevity, but most emphasis so far has been on SIRT1 which is stimulated by resveratrol.
These and related recent studies are important in that they suggest that aging is programmed rather than the result of accumulated damage, and that the program can potentially be reversed. A number of blog posts treating topics of epigenomics are listed in a November 2010 blog entry Past blog postings on stem cells and epigenomics.
This theory holds that aging is due in large or major part to a breakdown in the healthy functioning of the stem cell supply chain. This breakdown may be due to problems in replication or differentiation of critical stem cell populations, depletions of such populations due to aging or pathological conditions, or age-related shutdown of key parts of the supply chain. This theory includes and is more general than and the former 14th theory of aging, Decline in Adult Stem Cell Differentiation. This expanded treatment is more comprehensive and details additional ways in which the stem cell supply chain can be implicated in aging.
This discussion represents a major evolution in my thinking and much of the new material is adopted from blog entries I have generated in the last nine months. It is significantly different than the other aging theories in another respect. This theory represents an original synthesis while the other 13 theories are largely characterized in the existing literature. Stem cell research is churning along at a ferocious rate and is revealing new discoveries almost daily. Therefore this discussion should be viewed as a work-in-progress subject to continuing refinement as more is learned.
The stem cell supply chain
To begin, I characterize the stem cell supply chain and recapitulate some key facts known about stem cells. In a simplified model, think of the 210 kinds of cells found in the human body as falling in five categories:
B. Relatively undifferentiated multipotent somatic stem cells, such as may exist in bone marrow or vascular walls (e.g. hematopoietic stem cells, mesenchymal stem cells and pericytes). These multipotent cells are each capable of differentiating into a variety of kinds of somatic cells.
C. More differentiated stem and progenitor cells (e.g. endothelial progenitor cells, myoblasts or satellite cells in muscle tissue). These are cells capable of differentiating only into specific somatic cell types.
E. Senescent cells, ones which no longer can divide.
The list is in order of increasing cell-type specificity
and decreasing potency to differentiate into other cell types. Starting
at conception and throughout life, all cells on this list except the senescent
ones will selectively reproduce and possibly differentiate into cells of types
further down in the list. In some cell lines there are actually
many more intermediate forms of progenitor cells, but a model of five categories
of cells is sufficient for this discussion.
In some cell lines there are actually many more intermediate forms of progenitor cells, but a model of five categories of cells is sufficient for this discussion.
Of course all the cells in an individual have the same genome but their DNA acquires additional epigenomic markers as they differentiate. So, looked at in terms of DNA, the differences between these kinds of cells is one of epigenomics, e.g. DNA methylation, histone acetylation and binding-site molecular folding.
Cells in all categories except Type E can divide to make new cells. They are all subject to mutation, cell damage, oncogenesis and, it is thought, are subject to replicative senescence due to telomere attrition. Cells of Type A in the early embryo progressively differentiate to make all cells of Types B, C or D. All cells of Type D result from differentiation of cells of Type A, B and/or C, possibly via intermediary progenitor and stem cell types. Some cells of Type B may differentiate through several intermediate forms before creating Type D cells. Hierarchy in differentiation is always preserved under natural conditions, although it may or may not necessarily be the case that intermediate stem cell types are involved depending on the kind of cell.
An early embryo consists of A-Type cells. This supply-chain process continues through life although in aging there will be more and more cells of Types D and E and fewer and fewer active cells of Types B and C. and virtually no active Type A cells left. Healthy normal aging is thus a matter or cellular supply chain management. The body must assure that there are not too many Type E cells around for they create havoc. Type D cells are the workhorses of day-to-day functioning and the key factors involved are insuring a good supply of them by avoiding damage-related or replicative senescence, taking care of their need for nutrition and a healthy intra-cellular environment, and making sure that damaged or proto-cancerous cells are eliminated through proper apoptosis. Also, it is important to assure that Type B and C cells are able to differentiate properly to provide a reliable continuing source of replacements for the Type D cells.
The issues for Types B and C cells include seeing that they are in sufficient supply and health so as to be able to differentiate into Type D cells and making sure that the differentiating option is readily available when needed. Other issues for Types B and C cells are similar to those for Type D cells - preventing damage-related or replicative senescence, and preventing oncogenesis. It appears that in aged individuals there are few if an active Type A cells around to replace Type B and C cells as they are lost, a possible major reason for aging.
About stem cells and stem cell niches
Before looking further at anti-aging interventions given this new perspective, I review some of the recent relevant research findings and perspectives. Stem cell research is still at an early stage and proceeding at mighty pace. So, this list represents current views which are likely to evolve and be augmented as the months pass.
· The supply chain mechanisms appears to be operable throughout life. For example, it is known that there are some ways Type A ESCs and iPSCs can be introduced into mature adults so that they eventually differentiate into mature healthy Type D cells. The machinery of A to E is always there although later in life there may be no Type A cells left for the machinery to work with.
· The balance of cell Types is highly dependent on the stage of development of the organism, favoring gradual shift to the more-differentiated cell types further down in the list. A human embryo starts out all Type A cells while an aged individual may have virtually no Type A cells left, depleted stocks of Type B and Type C cells and too many Type E cells.
· Even so, health for older people requires continuing operation of the supply chain at some levels throughout life. If an injury is sustained, mesenchymal stem cells must make new tissue cells. If there is loss of blood, hematopoietic stem cells must make new blood cells. And cells that die of attrition trauma or apoptosis must be replaced by new ones. “Hematopoietic stem cells (HSCs) are responsible for blood cell production throughout the lifetime of an individual(ref),” and the same is true for other Type B and Type C stem cells. A new concept is emerging: that age-related changes in the stem cells in many body organs may be responsible for deterioration and decline in functionality of those organs. As a simple example, new research suggests that gray or white hair is due to age-related depletion of melanocytes which is a direct result of depletion of melanocyte stem-cells(MSCs) which in turn is the result of DNA damage. It has been known for some time that " - hair graying is caused by defective self-maintenance of MSCs(ref)." These stem cells, living in hair follicles, can normally both reproduce making new stem cells and differentiate into mature color-producing melanocytes. The new research based on experimentation with mice suggests that DNA damage to MSCs causes them to stop reproducing and instead terminally differentiate into melanocytes. As the melanocytes in hair follicles die off, there are no new melanocytes to replace them because there are no more MSCs to make them.
· Adult stem cells live in niches - stem cell microenvironments and the health of the stem cells and their ability to reproduce or differentiate both depend upon and condition the states of their niches. The behavior of stem cells can be expected to be very different within and without their niches. “Interaction of HSCs with their particular microenvironments, known as stem cell niches, is critical for maintaining stem cell properties, including self-renewal capability and ability for differentiation into single and multiple lineages. In the niche, the niche cells produce signaling molecules, extracellular matrix, and cell adhesion molecules and regulate stem cell fates(ref).” “Various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding microenvironment actively signals to stem cells to either promote self renewal or differentiation to form new tissues(ref).” For example, “Haematopoietic stem-progenitor cells (HSPCs) reside in the bone marrow niche, where interactions with osteoblasts provide essential cues for their proliferation and survival(ref).” Among the other places where niches of Type B cells can be found are hair follicles (see the blog entry Hair stem cells) and in dental pulp (see the blog entry Dental pulp stem cells).
· Both proliferation and differentiation of Type A, B, and C stem and progenitor cells decreases with aging. This is attributed to properties of aged niches which reduce stem cell regenerative potential. “Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches(ref).” In other words, the very existence of differentiated cells in their niches acts to inhibit the proliferation and differentiation of stem cells. This appears to be a form of age-related epigenomic programming.
· Although the mobilization responsiveness of Type C stem cells declines with age, it appears that their regenerative capability can be restored through environmental messages or induction of Notch activity. “In adult skeletal muscle, where the resident dedicated stem cells (”satellite cells”) are capable of rapid and highly effective regeneration in response to injury, there is just such a loss of regenerative potential with age. Satellite cell activation and cell fate determination are controlled by the Notch signaling pathway that is initiated by the rapid increase in expression of the Notch ligand, Delta, following injury. In old muscle, this upregulation of Delta is blunted and thus satellite cell activation is markedly diminished. However, by indirectly inducing Notch activity, the regenerative potential of aged satellite cells can be restored. Furthermore, exposure of aged satellite cells to serum from young mice, either in vivo by heterochronic parabiotic pairings or in vitro, rejuvenates the satellite cell response. This restorative potential suggests that tissue-specific stem cells do not lose their ability to participate in tissue maintenance and repair. Therefore, it may be that even very old stem cells may be capable of maintaining and repairing aged tissues if provided with optimal environmental cues (ref).”
· The gene expression profiles in Type A human embryonic stem cells offer regenerative anti-aging potential not found in more mature stem cells. “Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo (ref).” This gene expression is driven by age-related epigenomic factors
· Very likely, iPS cells can be induced to do all the jobs done by hES cells. See the March 2009 blog post Rebooting cells and longevity and the June 2009 Update on induced pluripotent stem cells. Finally, there is a relevant July 2009 post on Embryonic Stem cell research news. There is ongoing research progress in generating iPSCs that are free of transfer virus DNA or genetic aberrations. The blog entry Chimeras cites “reports from Chinese researchers of making chimeric mice using induced pluripotent stem cells (iPSCs).” The mice were made by taking skin cells from mice, reverting these cells to iPSC status where they become virtually identical to embryonic stem cells, and injecting them back into into early-stage mouse embryos.” “Here we report the generation of several iPS cell lines that are capable of generating viable, fertile live-born progeny by tetraploid complementation(ref).” This work is important in that it established the true pluripotency of the iPSCs used. If a whole living mouse can be made out of them, they must be capable of differentiating into any mouse tissue. “The generally accepted “gold standard” for determining whether a mouse iPSC line has been fully reprogrammed is to show that when injected into an early embryo (or blastocyst), the iPSCs can contribute to many different tissues in the resulting chimeric mouse, including the germline(ref). ” Recent reports indicate that mice so-created have reproduced normally and second and third-degeneration descendents of them appear to be normal.
cell research reported in July 2007 and indicates that the gene expression profiles of iPSCs and eSCs are
different. The study compared eSCs and
iPSCs made by reprogramming skin cells. “The data from the study suggest that
embryonic stem cells and the reprogrammed cells, known as induced pluripotent
stem (iPS) cells, have overlapping but still distinct
gene expression signatures. The differing signatures were evident regardless
of where the cell lines were generated, the methods by which they were derived
or the species from which they were isolated(ref).”
The researchers do not know what the practical implications of this finding
are. Whatever they are, they seem to be not enough to get in the way
of making whole living chimeric mice capable of
having children and grandchildren mice.
· September 2009 news reports development of "a safe strategy for reprogramming cells to a pluripotent state without use of viral vectors or genomic insertions. Their studies reveal that these induced pluripotent stem cells (iPSCs) are very similar to human embryonic stem cells, yet maintain a "transcriptional signature." In essence, these cells retain some memory of the donor cells they once were." -- ""Working with neural stem cells, we discovered that a single factor can be used to re-program a human cell into a pluripotent state, one with the ability to differentiate into any type of cell in the body" said Muotri. Traditionally, a combination of four factors was used to create iPSCs, in a technology using viral vectors – viruses with the potential to affect the transcriptional profile of cells, sometimes inducing cell death or tumors(ref)."
· Being capable of doing everything an embryonic stem cell can do, induced pluripotent stem cells (iPSCs) are likely to be more and more used in future therapeutic applications. They are fully pluripotent, can be made by resetting any normal somatic cell like a skin cell to ground zero state and, unlike cells from other donors, do not invite immune system rejection. Also, newer and faster ways are being discovered to make iPSCs, including generating them wholesale from body fat extracted by liposuction(ref).
· More is being learned about the relationships between stem cells and their niches and environmental messaging relating to stem cell division and differentiation. For example, “With the expanding knowledge of HSC physiology, a new paradigm emerges in which HSCs and haematopoietic progenitor cells (HPCs) migrate to defined microenvironments within the bone marrow (BM) and to 'activated' or 'inducible' niches elsewhere(ref).” Also you can see ref, and ref. While there is intense ongoing study of the relationships of many kinds of adult stem cells to their niches (Types B and C), the literature reveals little as to whether there are niches of fully pluripotent Type A cells left in mature humans. It is known, however, that embryonic human Type A stem cells form their own niche when in-vitro(ref).
· Stem cells are subject to replicative senescence, although niche signaling and telomerase expression may have strong influences on their replicative lifespan. This 2008 study looked at replicative senescence of mesenchymal stem cells in vitro and found it to be “a continuous and organized process.” “Within 43 to 77 days of cultivation (7 to 12 passages), MSC demonstrated morphological abnormalities, enlargement, attenuated expression of specific surface markers, and ultimately proliferation arrest. Adipogenic differentiation potential decreased whereas the propensity for osteogenic differentiation increased. mRNA expression profiling revealed a consistent pattern of alterations in the global gene expression signature of MSC at different passages. These changes are not restricted to later passages, but are continuously acquired with increasing passages. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages.” This form of replicative senescence occurring at each reproduction cycle appears to be absence-of-niche related and not to be driven by telomere shortening, the usual cause of replicative senescence. It highlights the importance of understanding what is going on in stem cell niches. Proliferation and differentiation of stem cells involves a bimolecular dance with their niches.
· A lot is being learned across the whole stem cell spectrum. Several recent research findings related to Type A human embryonic stem cells (hESCs) can be found in my blog post Embryonic Stem cell research news. In particular, this post deals with the relationships among networks of transcription factors, pluripotency and genetic circuits that regulate diferentiation and self-renewal. Again, the point is made that differentiation involves epigenetic markers.
· Highlighting the importance of stem-cell environment signaling, a recent finding is that Co-Culture with Mesenchymal Stromal Cells Increases Proliferation and Maintenance of Hematopoietic Progenitor Cells. Stem cells seem to be very social animals.
· Buildup of levels of Ink4a/P16 associated with aging slows down the rate of differentiation of adult stem cells. “Recent evidence shows that loss of Bmi-1, a polycomb transcriptional repressor of theInk4a-Arf locus, results in progressive loss of HSCs in adult mice with subsequent failure of hematopoiesis.” – “ These results show that either both p16Ink4a and p19Arf can inhibit HSC self-renewal in a serial transplant setting, or that only p16Ink4a is necessary(ref).“ I expand on this point later
· Several proteins seem to play key roles in stem cell differentiation, survivin, an apoptosis inhibitor that is a target of cancer therapies, being a key one. “Our studies demonstrate that survivin is essential for steady-state hematopoiesis and survival of the adult, and further, that a high level of survivin expression is critical for proper erythroid differentiation(ref).” Survivin is an example of several factors involved in both stem cell differentiation and the proliferation of cancers(ref).
· This review article looks further at the links between cellular senescence, aging, and bone marrow-derived cells.
Autologous (patient-derived) stem cells are being modified to provide targeted
therapies for leukemias and other intractable cancers. See the November 2012
blog entry CAR
adoptive stem cell immunotherapy an emerging new weapon against cancers and
other incurable diseases.
· Autologous (patient-derived) stem cells are being modified to provide targeted therapies for leukemias and other intractable cancers. See the November 2012 blog entry CAR adoptive stem cell immunotherapy an emerging new weapon against cancers and other incurable diseases.
· I I have written many blog postings related to stem cells and a listing of them through November 12, 2010 can be found here.
The stem cell supply chain and aging
The operation of the supply chain changes with age and a number of things can happen that accelerate or even define aging. These include:
· Exhaustion of critical pools of healthy adult stem cells
· Slowdown in the rate of operation of the supply chain, e.g. decline in the rate of differentiation of adult stem cells
· Problems in stem cell niches
I touch on each of these.
Exhaustion of critical pools of healthy adult stem cells
Adult stem cells like other cells are subject to mutation, senescence, oncogenesis, damage, apoptosis and other causes of cell loss. Critical pools of stem cells may thus be compromised or lost resulting in loss of their repair, replacement and regenerative functions resulting in multiple symptoms of aging.
Several recent studies have been concerned with how mTOR signaling relates to the fate of an important pool of multipotent stem cells - hematopoietic stem cells (HCSs), the stem cells that give rise to the various blood cell types. Introductions to mTOR signaling and its relationship to longevity can be found in my blog entries Longevity genes, mTOR and lifespan, More mTOR links to aging theories, and Viva mTOR! Caveat mTOR! From an April 2008 publication mTORC1 signaling governs hematopoietic stem cell quiescence: “The stringent regulation of hematopoietic stem cell (HSC) quiescence versus cell cycle progression is essential for the preservation of a pool of long-term self-renewing cells and vital for sustaining an adequate supply of all blood lineages throughout life. Cell growth, the process that is mass increase, serves as a trigger for cell cycle progression and is regulated predominantly by mammalian target of rapamycin complex 1 (mTORC1) signaling. Emerging data from various mice models show deletion of several mTORC1 negative regulators, including PTEN, TSC1, PML and Fbxw7 result in similar HSC phenotypes characterized as HSC hyper-proliferation and subsequent exhaustion, and defective repopulating potential(ref).” In other words, unless the negative regulators of mTORC1 are working well, the growth factors loosened by mTORC1 will cause the hematopoietic stem cells to reproduce in an uncontrolled manner exhausting the pool of these valuable cells – a major disruption in the stem cell supply chain.
A second publication highlights the same point. “A balance between quiescence and proliferation of hematopoietic stem cells in interaction with the microenvironment is critical for sustaining long-term hematopoiesis and for protection against stress. — We demonstrated a pivotal role of two downstream effectors of the PI3K/Akt pathway, FoxO3a and mammalian target of rapamycin, as connectors in the SDF-1-/TGF–induced control of the cycling/quiescence switch and proposed a model integrating a dialogue between the two molecules in cell cycle progression(ref).” Essentially the same point is made by a third study report, the December 2008 publication mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. “TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis — Using hematopoietic stem cells (HSCs) as a model system, we demonstrate that somatic deletion of TSC1 produces striking stem cell and derivative effector cell phenotypes characterized by increased HSC cell cycling, mobilization, marked progressive depletion, defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. On the mechanistic level, we further establish that TSC1 regulation of HSC quiescence and long-term repopulating potential and hematopoietic lineage development is mediated through mTORC1 signaling(ref).”
The bottom line is that effective mTORC1 negative regulation is essential for keeping the stem cell supply chain working well, at least insofar as hematopoietic stem cells are concerned. FOXO transcription factors are also important. Foxo3a in particular appears to be "essential for maintenance of the hematopoietic dtem cell pool(ref).” “Hematopoietic development is regulated by a dynamic balance between HSC (hematopoietic stem cell) self-renewal and differentiation to mature effector cells. The balance between self-renewal and differentiation is of critical importance: too little self-renewal or too much differentiation may jeopardize the ability to sustain hematopoiesis throughout life, whereas excessive self-renewal and/or aberrant differentiation may result in leukemogenesis. The regulation of HSC self-renewal is not fully understood, but recent studies have underscored the importance of cell cycle, apoptosis, and oxidative stress response in HSC homeostasis. Recent data indicate that FoxO family members play a critical role in these physiologic processes in the HSC compartment and thereby regulate maintenance and integrity of HSCs(ref).”
There is no doubt that much more to be learned regarding the exhaustion of critical pools of healthy adult stem cells. In particular, in the Firewall Section for this theory of aging I speculate on approaches to maintaining or renewing the pools of adult stem cells.
Decline in the rate of differentiation of adult stem cells
This phenomenon of aging relates particularly to somatic stem cells (SSCs) of Type B described above and the role they play in continuing organ renewal. SSCs are capable of differentiation to produce normal somatic cells though they normally engage in cell division without cell differentiation. Unlike Type A stem cells, SSCs are specific to particular kinds of tissues but still may be capable of differentiating into several different cell types. They are capable of producing progenitor cells, Type C cells that can transform into regular somatic Type D cells in the course of additional rounds of cell division. For example, epithelial stem cells can differentiate into the various types of skin cells. Under conditions of signaled stress such as produced by a wound or burn, SSCs will produce progenitor replacement cells. The triggering of an SSC to produce a differentiated cell is due to cell signaling initiated by a shift in the pattern of gene expression, for example as initiated by organ damage. The cell signaling through which this process takes place is only now in the process of being discovered.
This matter of concern here is that aging is due to a slowing rate of organ regeneration due to declining SSC differentiation activity. This change in rate is thought to be associated with declines in numbers of or defects in aged SSCs, including shortened telomere lengths and replicative cell senescence, and is also due to the actions of certain proteins that accumulate in cells with age(ref, ref,ref,ref,ref)
When a SSC like a hematopoietic stem cell is triggered to produce a progenitor to a somatic cell of its type, such as a macrophage, basophil or eosinophil, a copy of the SSC is also produced along with the new more-differentiated progenitor cell. The number of SSCs stays the same but they age because of telomere shortening in the process of mitosis or telomeric DNA breaks and become less active with age. SSCs tend to express more telomerase than their normal somatic cell counterparts but significantly less than embryonic stem cells. In the normal course of a lifetime, SSCs have telomeres that progressively shorten as do other somatic cells and like other somatic cells are subject to cell senescence due to too-short telomeres(ref). It appears that with advancing age SSCs become progressively less responsive to producing their counterpart progenitor somatic cells. Loss of adult stem cells via telomere attrition provides strong selection for senescent, cycle-arrested (Type E), abnormal and malignant somatic cells, producing vulnerability to the diseases of old age.
There is another cause for concern regarding the longevity of stem cells as mentioned previously. The culprit is thought to be increasing amounts in cells of certain tumor-suppressor proteins, p16Ink4a and p19Arf in particular(ref). For a plain-language discussion of the process, see this reference. A new line of research(ref) focuses on four genes known to be implicated in both cancer and stem cell activation: Ink4a, Arf, Hmga2 and let-7b. P16/Ink4a in particular, a tumor suppressor gene, appears to become increasingly active with age in mice, humans and other mammals. It is a known mediator of cell senescence and biomarker of aging as well as a possible promoter of mammalian aging. P16/Ink4a works together with the three other genes to articulate a process of simultaneously protecting against cancers and shutting down adult stem cell function and regenerative capacity in aging tissues. Expression of Ink4a and Arf in the absence of a protein Bmi1 results in loss of self-renewing stem cells. The four genes involved, appear to switch on and off in a coordinated fashion that depends on age. Older stem cells don’t wear out or die from damage according to this line of reasoning; they are shut down. Increasing cancer protection is paid for by accelerated aging. This research is based on neural tissues in mice and the extent to which it can be generalized to other human cell types is still to be discovered.
The research relating aging to processes going on in the stem cell supply chain is relatively new and still sketchy. Many more discoveries are yet to come and I expect they will be coming with increasing frequency.
I continue to follow stem cell research as it is applicable to aging and has generated a number of blog posts related to the rapidly changing state of that field. There are several blog postings relevant to use of somatic stem cells for tissue regeneration including a May 2009 item State of autologous stem cell therapies, a June 2009 item Simple but powerful non-invasive adult stem cell cures, and a June 2009 item Dental Pulp Stem Cells - the big needle vs the tooth fairy
A July 2009 study report , TAp63 Prevents Premature Aging by Promoting Adult Stem Cell Maintenance, provides another piece of evidence supporting the Decline in Adult Stem Cell Differentiation concern related to aging. The report indicates that “that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely.” “TAp63 / mice (mice with TAp63 knocked out) age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis.” – “These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging(ref).
Another recent research study points to another aspect of stem cell differentiation. The study indicates that nano-scale substrate surface topography (micro characteristics of the surface on which a cell culture is grown) can significantly affect stem cell differentiation. The study looked at human mesenchymal stem cells (hMSC) that can differentiate into a variety of cell types including chondrocytes, osteoblasts, myocytes, and adipocytes. It was discovered that when the surface consisted of relatively small nanotubes, hMSC adhered to the tubes without noticeable differentiation. Somewhat larger diameter nanotubes (≈70- to 100-nm diameter) “elicited a dramatic stem cell elongation (≈10-fold increased), which induced cytoskeletal stress and selective differentiation into osteoblast-like cells.”
Problems in stem cell niches
Since there is such a tight health-interdependency between stem cells and their niches, problems with niches such as due to trauma can have serious consequences on the corresponding stem cell populations. “Understanding how extrinsic factors (niche factors) control hESC self-renewal and differentiation will allow us to culture and differentiate these pluripotent cells with higher efficiency. This knowledge will be essential for clinical applications using human pluripotent cells in regenerative medicine(ref). One key role of niches is maintaining stocks of stem cells in a state of protected quiesence. For example, in the osteoblastic niche “Interaction of HSCs (hematopoietic stem cells) with OBs (osteoblastic cells ) through signaling and cell adhesion molecules maintains the balance in HSCs between cell division/proliferation and quiescence. In particular, the quiescent state is thought to be an essential mechanism to protect HSCs from stress and to sustain long-term hematopoiesis (ref) . We can expect a continuing stream of such research relating stem cells to their niches.
Again the message is that aging is associated with breakdown or deterioration of the supply chain for new somatic cells. It is appropriate to start focusing on what is happening to adult stem cells. The Firewall section for this theory of aging discusses lifestyle factors and possibly-helpful dietary supplements as usual. It also characterizes some current experimental practices, and speculations about the far-ranging future possibilities for halting and reversing aging by means of stem cell supply chain interventions.
Relationship to the Programmed Epigenomic Changes theory of aging and particularly to Epigenomic Changes In Dna Methylation And Histone Acetylation.
The Stem Cell Supply Chain Breakdown and the Programmed Epigenomic Changes theories of aging are completely compatible and complementary. As mentioned before, the differences between the Types A, B, C, D and E cells are to be found in the epigenome, not in the genome – the genes in all body cells are the same. As Type A cells begin to differentiate they acquire epigenomic histories such as are due to histone acetylation and DNA methylation modifications. See the discussion of Epigenomic Changes In DNA Methylation and Histone Acetylation.
at discovering exactly what the epigenomic modifications are when stem cells
differentiate is still at an early stage.
See for example the June 2009 publication Epigenetic
Landscaping During hESC Differentiation to Neural
Cells. It is known,
however, that when a mature Type D body cell is reverted to being a Type A iPSC cell, its epigenetic markers
are essentially erased. Turning to
another study, “The researchers found that Jmjd1a and Jmjd2c, which encode enzymes that
demethylate histone H3 lysine 9, regulate self-renewal in
mouse ES cells: Depletion of Jmjd1a and Jmjd2c promoted differentiation, at
the expense of self-renewal. Thus, these two histone modifying enzymes are
required for maintaining pluripotency of ES cells(ref).”
Self-renewal vs differentiation of ES cells thus appears to be a matter
of epigenetics. As long as Jmjd1a and Jmjd2c
are around, histone methylation is nipped in the bud and the cell acquires
no epigenetic history due to such methylation. Once methylation starts
to take place the cell starts acquiring history and is prone to differentiation. Stem cell gene
expression evolves with age reflecting changes in the epigenome. “In newborn mice,
blood-forming cells (haematopoeitic stem cells, HSCs) rely on a transcription
factor known as Sox17 for self-renewal, but adult HSCs rely on a different
transcription factor, Bmi-1(ref).”
Stem cell gene expression evolves with age reflecting changes in the epigenome. “In newborn mice, blood-forming cells (haematopoeitic stem cells, HSCs) rely on a transcription factor known as Sox17 for self-renewal, but adult HSCs rely on a different transcription factor, Bmi-1(ref).”
In the normal life cycle of an organism, the programmed epigenomic changes are exactly those that make for differentiation into the various cell types and are expressed by changes in DNA methylation and histone acetylation. So these three “theories” are in fact different but consistent viewpoints of aging. It is all starting to come together.
Thorough updated discussions can be found in the June 2011 blog posts Update on induced pluripotent stem cells and Longevity of stem cells and the roles of stem cells in aging..
The theories of aging I have outlined are neither complete, independent nor final. Aging is not a simple process and there is much signalling between systems in the body. So all of the theories of aging covered here are part of a more comprehensive systems-oriented theory yet to be clarified. The age-related epigenetic signaling involving changing hormone levels, oxidative damage, glycation and lipofuscin generation and removal is complex and not yet well understood. Signals originating in the mitochondria affect DNA expression and visa-versa. Cancer and inflammation have a close relationship as do oxidative damage and tissue glycation. There is without doubt much interplay between the programmed mechanisms of aging and the presence of cell damage. Of the theories mentioned, perhaps the four most fundamental are Programmed Epigenomic Changes, Mitochondrial DNA damage, Telomere shortening, and Stem cell supply chain breakdown. It may require 30 or more years for a fairly complete systems perspective of what constitutes aging and the diseases of aging to emerge. In the interim, selected pieces of the picture are becoming clear and it seems that every few days or weeks a new piece of the puzzle is revealed.
As a way of summary, here is a first cut of how the 14 theories of aging relate to each other. The most general theory is that aging is defined by Programmed Epigenomic Changes. The age-related changes include an accumulation of damage affecting DNA, proteins, membranes, and organelles and decline in maintenance and repair on the cell level. On the more macroscopic level these changes show up as the usual indicators of aging including decline in organ function, decline in hormone levels, loss of muscle mass and grey hair. To be more precise, aging is not a program in itself but is a consequence of the totality of biochemical programs that operate in an individual over that individual’s lifespan. Those programs are species-specific and define typical average and maximum lifespan for each species. We don’t yet understand what the main programs are for most species including humans. We are starting to understand some of the subroutines and sub-subroutines, however, mechanisms that regulate cell cycles and the roles of key genes and proteins. For example we know there is a family of proteins called Sirtuins that are closely implicated in aging processes. One pathway, known as the calorie-restriction pathway, operates in a wide variety of organisms and in humans involves the sirtuin protein SIR1. Activation of that pathway appears to make up to 30% life extension available across a variety of species. See, for example these blog posts that relate to SIRT1: ref, ref, and ref.
In the previous Section I discussed how the Stem Cell Supply Chain Breakdown, the Programmed Epigenomic Changes (Epigenomic Changes In DNA Methylation and Histone Acetylation) theories of aging are completely compatible and complementary.
The Telomere Shortening theory of aging fits in neatly as a component of the Aging as Programmed Epigenomic Changes theory. Other aging programs could involve age-related increases in NF-kappaB and P16. These and associated increases could lead to age-related Decline In Adult Stem Cell Differentiation, an aspect of the Stem Cell Supply Chain Breakdown theory of aging. The basis for regeneration of aging tissues is provided by adult stem cells. P16 protects against cancers but induces premature senescence in progenitor cells. Progenitor stem cells play important roles in the maintenance of homeostasis in cardiac and other tissues and organ maintenance and repair after injury.
In the traditional view,Oxidative Damage has been seen as an important driver of aging and implicated in the processes of several of the other theories of aging. We knew for example that Oxidative Damage leads to Telomere Shortening. It is also a major cause of Cell DNA Damage which in turn can lead to Susceptibility to Cancers. Mitochondrial Damage can be brought about through Oxidative Damage or via signaling pathways conditioned by Programmed Epigenomic Changes. In turn, faulty mitochondrial functioning can lead to a number of metabolic disease conditions and faulty mitochondrial signaling can lead to errors in apoptosis and a multiplicity of disease susceptibilities including Susceptibility to Cancers and Susceptibility to Cardiovascular Disease. Just about every cellular process involves the operation of multiple feedback loops. Whether and how much exposure to oxidative conditions actually leads to aging depends on numerous factors such as the availability of antioxidant defenses. Natural antioxidant defenses decline with aging, another aspect of the epigenomic aging program driven by changes in the chromatin of cells which accumulate with age. As pointed out in the blog entry End of the free radical theory of aging, however, the free radical theory of aging is itself in deep trouble and both free radicals and the use of antioxidant supplements have to be looked at in a much deeper manner.
The feedback loops between many body systems are so tightly interrelated that it is difficult to say where one theory leaves off and another one starts. Considering the Decline in hormone levels and the Neurological degeneration theories, for example, it has long been known that "the neuroendocrine and immune systems are intimately integrated into one system that provides a complex homeostatic network(ref)." And auto-immune diseases like lupus erythematosus and rheumatoid arthritis can involve Chronic inflammation.
A simplified example of how seven of the aging theories link together is that Oxidative Damage activates NF-kappaB (the Programmed Epigenomic Changes theory of aging) resulting in expression of pro-inflammatory genes leading to a chronic inflammatory response. The inflammatory response is a mechanism in turn deeply implicated in Susceptibility to Cancers and Susceptibility to Cardiovascular Diseases, and Neurological Degeneration. Nothing is really simple, however. Whether a cancer cell is subject to apoptosis or proliferates is dependent on other epigenomic considerations such as the availability of a strong P16 or P53 defense.
Chronic Inflammation is a part of an aging-related program that can be triggered by numerous stimuli, is generally mediated by a gene activation sequence triggered by overexpression of NF-kappaB and related factors, and is an entry portal to several other of the aging related conditions including Tissue Glycation, Susceptibility to Cardiovascular Disease, Neurological Degeneration, and Susceptibility to Cancers. Telomere Shortening and Damage leads in time to cell senescence, apoptosis and mutations which in turn generate a number of the epigenomic-mediated aging conditions including Immune System Deterioriation, Susceptibility To Cancers, Susceptibility to Cardiovascular Disease, Neurological Degeneration, and atrophy of hormone-producing organs leading to Declines in Hormone Levels. The later is an example of the feedback between cell-level and organ-level functioning showing how damage on one level can cause damage on the other level as well.
The pathways affecting aging are complex and multiply interconnected. And gene expression as well as activation of factors like NF-kappaB are themselves dependent on the state of the epigenome and are therefore functions of age.
During chronic diseases there is generally a decline in the functioning of adult stem cells, cells essential for organ repair and regeneration. The same happens in the process of aging. The survival of adult stem cells and their ability to differentiate depends on the presence of growth regulatory signals and NF-kappaB plays an important epigenomic role in this process. Also, Telomere Shortening and Damage in adult stem cells may be a major cause of age-related Decline In Adult Stem Cell Differentiation.
Telomere Shortening and Damage itself, on the other hand, appears to be not inexorable because long-term population studies show that for some individuals telomeres actually get longer over substantial time periods. Telomere shortening may be caused by stress and oxidation, but may be mitigated by effective expression of telomerase which in turn requires the availability of telomerase binding proteins which is dependent on the states of histone acetylation of the DNA binding sites for these proteins – e.g. on their epigenomic states. Another of the Sirtuins, SIR6, appears to play a key role in maintaining telomeric integrity by preventing telomere looping and other damaging conditions, another link between the Programmed Epigenomic Changes and the Telomere Shortening and Damage theories of aging.
On the surface it appears that the 14th theory of aging Stem Cell Supply Chain Breakdown is very different than the 12th theory Telomere Shortening. And these two theories seem to be different than the 2nd theory Cell DNA Damage. However, a number of recent studies show a growing web of relationships among these theories. For example, telomeric dysfunction may be at the heart of the decreasing capability of stem and progenitor cells to replicate and renew tissues with increasing age (ref,ref,ref,ref). The studies have looked at telomere shortening in hematopoietic stem cells (HSC), mesenchymal progenitor cells, osteoblasts and neural progenitor cells. One study suggests that proteins secreted from telomere-dysfunctional bone-marrow cells may provide accurate biomarkers of aging. As usual when it comes to aging, there are wheels within wheels. Among the many cellular proteins that influence telomere structure, function and enlongation are the telomerase binding factors TRF1 and TRF2 and less-directly shelterin-complex, PinX, Apollo and tankyrase(ref). TRF2seems to play a key role in the differentiation of neural stem cells( ) as well as in cancer proliferation. In a closely related front, telomerase expression and TRF2 seem to play key roles in maintenance of DNA repair mechanisms in neural cells and stem cells(ref).
Lipofuscin Accumulation is driven by a history of metabolic processes dependent on the mitochondria, facilitated by oxidative stress and conditioned by the availability of substances which pump lipofuscin out of cells which depend on the epigenomic states of the cells. Declines in Hormone Levels may be the result of some kind of epigenomic program as well as a consequence of hormone-producing organ deterioration. In fact hormones are intermediary epigenomic factors because they themselves lead to changes in gene expression that affect the production of other hormones as well as disease susceptibilities and other markers of aging.
Additional discussions of how the theories of aging link to one another are provided in the Note New evidence linking the aging theories and in the blog entry Linking up the theories of aging. The Note describes crossover links among at least four of the theories: Programmed genetic changes, Oxidative damage to tissues, Chronic inflammation, and Telomere shortening and damage. The blog entry describes a link between the Telomere shortening and damage, the Programmed epigenomic changes, the Susceptibility to cancers and the Decline in adult stem cell differentiation (later subsumed under Stem Cell Supply Chain Breakdown) theories. In November 2009 I added a blog post that identified another important link between two of the theories: Breakthrough telomere research finding. As telomeres become critically short, the gene expression in affected cells changes so as to induce senescence and at the same time to affect the maintenance of epigenomic memory and nuclear organization, thereby contributing to organismal aging on the whole-animal level. Critically short telomeres deregulate epigenomic control and alter gene expression so as to create the changes we know as “aging.” A more-recent February 2011 blog entry JDP2 - linking epigenetic modifications, stem cell differentiation, cell senescence, cell stress response, and aging demonstrates how epigenetics provides a powerful integrative framework that applies across most if not all the other theories of aging.
The above is just a starting sampler of known links among the theories of aging. It seems that research revealing a new link or shedding new light on existing ones is reported almost every week. As this happens, we are getting closer to understanding aging and what can be done about it. While we are not there yet we are getting closer to a unified theory of aging. Also it is already clear how an anti-aging firewall intervention intended to address aging according to one theory usually addresses aging according to several other of the theories as well. For example, a number of the anti-inflammatory phyto substances like curcumin inhibit the expression of NF-kappaB and addresses aging according in multiple other dimensions beyond control of inflammation. The same is essentially true of most of the supplements in the combined firewall, they being antioxidants and/or inhibitors of NF-kappaB.
My firewall approach to longevity is a simple and practical one. When I drafted the first version of this document in 2008, I saw this approach as appropriate for older people given the current state of knowledge and relative ignorance compared to what will be known in coming decades. And I still see it that way. However, my views have been far from static. As I have learned more about the sciences of longevity and the overall state of knowledge has expanded, I have continued to revise the firewalls regimens. For example, by November of 2010 there was more published knowledge about telomerase biology and telomerase and the depth of my personal knowledge about this field had increased considerably. Based on this knowledge I decided to discontinue use of cycloastragenol or any other specialized commercial "telomerase activator." See the March 2011 blog entry The epigenetic regulation of telomeres. Further, in September 2011 I published entries in my blog suggesting the end of the free radical theory of aging(ref)(ref), a radical shift that is likely to produce ongoing controversy.
I started working with primitive computers in 1951 and have spent much of my previous career in computer-related work. The science and practice of longevity seems to be now (2011) in about the same stage now as was the computer field back in 1958 - the same kind of excitement, the same rapid influx of new people into the field, the same competition among new ideas, the same rapidly increasing rate of knowledge and practical progress.
Given the mechanisms of aging characterized in each of the theories of aging, I lay out what I think can be done now to protect against those mechanisms. That is, for each theory of aging, I seek to identify a protective “firewall” that can be practically implemented today that will likely retard, stop or even reverse aging according to that theory. I am talking about lifestyle modifications and use of dietary supplements. In fact I am describing a highly personal matter – what I have been doing to prolong my life and live fully with a high quality of life while I am still alive. I have been studying this matter for 15 years now, and have gradually come to the program I am describing. This program is neither complete nor final nor guaranteed to work. I continue to modify it as new research findings come to my attention. It is quite different now than it was almost four years ago when I created the first version of this treatise. I mention the research bases for the firewalls and offer further caveats at the end of the treatise.
My general approach is to construct an in-depth defense (a firewall) against the causes of aging attributable to each theory of aging or cause of aging death, to the extent that is possible given current knowledge. A firewall can be compared to an infantry line of military defense. Rifles, machine guns, grenades, land mines, rocket launchers, fox holes and camouflage can be useful parts of such a line of defense. But it would not be wise to try to construct a defensive position using only one of these kinds of weapons, say only machine guns. Similarly an adequate defense against free radicals cannot be based on using only one antioxidant like vitamin C. Most of the supplements I suggest are pluripotent, i.e. are effective against many conditions. For example, in animal studies resveratrol has very strong positive effects on reducing heart inflammation, preventing cardiovascular disease, supporting bone structure and function, and maintaining loco-motor and balance activity. However, no one substance is a sure cure or preventative for a specific cause of death. Each substance works through its own biochemical mechanisms and has its own role in a protective firewall. I have attempted to construct practical firewalls that each contain multiple defensive measures, limited only by the state of research knowledge, by my own knowledge, and by the practical availability of firewall substances.
The traditional view is that anti-oxidants are highly effective in scavenging ROS and mitigating their damage. Therefore, taking antioxidant supplements has been seen as generally health-promoting if not life-extending. However, as we have developed much more sophisticated understanding of cellular processes, this view has become seriously challenged. "Long-lived organisms, like humans, have developed very sophisticated enzymatic systems for controlling and utilizing radicals. These natural antioxidant defenses are much more effective than crude antioxidant supplements which have not been shown to be effective at preventing aging, or any degenerative disease. Some clinical trials of antioxidant supplementation have even found harmful effects(ref)."
That taking antioxidants may actually create harm has been telegraphed in my earlier blog entries. Over a year ago I reported on a publication How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). “Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman’s free radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species (ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased stress resistance assumed to ultimately cause a long-term reduction of oxidative stress. This type of retrograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are essential signaling molecules which are required to promote health and longevity. "
Hormesis is a natural process, having to do with responses to stresses, disease resistance and longevity, a process that plays a critical role in all successful species, plant and animal, from the smallest bacteria to the biggest animals. Hormesis is a fundamental and universal process of biology. It is essential for both evolution and survival of individuals and species. Although hormesis was unknown to me when I drafted the first version of this treatise, I now (April 2013) see hormesis as extremely important. This importance is not only for understanding what is going on in health, diseases and aging, but also for suggesting practical health and longevity-enhancing interventions. For the reader unfamiliar with hormesis, I suggest, to start, viewing the presentations which can be downloaded from the recent blog entry Multifactorial hormesis - Powerpoint presentation. See also the blog entry Multifactorial hormesis.
One type of hormesis has to do with the body's natural response to oxidative stress whereby, up to a point, modest amounts of oxidative stress are good for you and confer a number of beneficial health effects. So, hormesis dictates that oxidative stress is bad for you and may contribute to aging only if it is beyond a threshold level. Below that level it is good for you. This is quite contrary to the original theory of oxidative stress which held that free radicals at any level are bad for you. The evidence is quite clear that, in a number of species, a modest level of oxidative stress and hormesis also contributes to longevity. Two of the more-recent (September 2012) blog entries go into depth on the topic of ROS hormesis are Mitohormesis, and Radiation hormesis. Earlier (2009) blog entries on the topic were Hormesis and age retardation and Stress and longevity. The benefits of regular exercise are realized via stress-induced hornesis, so such exercise is an extremely important part of the oxidative damage firewall. The central pathway involved in the induction of ROS hormesis involves the transcription factor Nrf2, discussed below.
Most of the supplements I have previously listed in this section as antioxidants are pluripotent in their biological activities, substances that act through a multiplicity of biological pathways to produce documented health benefits. Whether such a substance is an anti-oxidant or not may not may be of secondary or of no importance to the key biological activities of that substance which might include activation of Nrf2 and activation pecific pathways like SIRT1 and inhibition of others like of NF-kappaB, not to mention epigenomic impact on methylation or histone acetylation and siRNAs. etc. This applies to food substances such as olive oil and walnuts as well to many of the firewall supplements such as curcumin and resveratrol. What seemed simple becomes very complex and yet very exciting.
I have been asked by others and have asked myself "“How can you simultaneously warn against indiscriminant antioxidant supplementation and at the same time so enthusiastically endorse consuming foods which have strong antioxidant capabilities, ones like broccoli, coffee, olive oil, chocolate, garlic, green tea and blueberries? And, if antioxidants are bad for you, how can you continue to advocate taking so many antioxidant supplements like curcumin, alpha-lipoic acid, ashwagandha, boswellia, ginger and resveratrol?” The answer to that question is provided in detail in the three blog entries * The pivotal role of Nrf2: Part 1 - a new view on the control of oxidative damage and generation of hormetic effects, * The pivotal role of Nrf2: Part 2 - foods, phyto-substances and other substances that turn on Nrf2, and * The pivotal role of Nrf2. Part 3: Part 3 - Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension?
There are hundreds of antioxidant substances, that is substances whose molecules are chemically capable of inhibiting ROS from being formed, or capable neutralizing ROS. While many such substances in my suggested anti-aging firewall list are incidentally antioxidants, being an antioxidant was not the central reason for including them in the firewall list. They are on the list for other research-based reasons, for example in many cases that they activate the Keap1-Nrf2 pathway and inhibit the inflammatory activities of NF-kappaB. . Blueberries, for example are commonly touted as good for you because they are excellent anti-oxidants. Actually, they consist of complex phyto substances that act through a multiplicity of channels, and produce a myriad of documented positive health impacts(ref) (ref). In a series of blog entries I have looked at a number of such substances that are nominally antioxidants, citing research relating to their modes of action and health benefits resulting from taking them. Beside blueberries, in my blog I have looked explicitly at olive oil, walnuts, dark chocolate, hot peppers, ginger, curcumin, resveratrol, caffeic acid, rosmarinic acid, grape seed extract, and bitter melon. Similarly many other plant-based phyto-substances with documented positive health impacts happen also to be anti-oxidants like green tea, garlic, boswellia serrata, cat's claw and lycopene. And I have reported also on certain non-phyto supplement substances that are much more than antioxidants, like l-carnosine, and PQQ.
It is no longer a sweeping game where antioxidant = good and radicals = bad, but neither do I believe that the opposite is true. Rather. I am suggesting that direct chemical antioxidant properties of substances may be fairly irrelevant compared to other properties and each substance must be examined for its specific activities. Further, I believe that circumstances can exist in which taking a strong mix of antioxidant supplements is probably well-justified , such as when one has had or will have a major exposure to radiation(ref).
I will be continuing to revise this section. For the moment, what follows for historical purposes is the material originally included in this section of the treatise. It describes the argument for using antioxidant supplements to defend against oxidative damage. But remember, most of the suggested substances do their good work via gene activation and inhibition and via epigenetic actions, not by simple direct chemical antioxidant actions on free radicals.
Basically the program is to avoid circumstances that produce very large number of unnecessary free radicals (ROS) in the body. But the situation is not that simple. X-rays or other stressors that arein small enough doses to be in the hormetic response range might actually be good for you. Do not smoke and avoid breathing second-hand smoke. Use protective clothing, sunglasses and sunscreen under outdoors sunny conditions. Avoid exposure to heavy metals and toxic chemicals. For example, avoid handling arsenic-containing pressure-treated lumber without gloves or breathing the smoke of it burning. Adopt dietary habits featuring large amounts of fruits and vegetables, some fish, moderate consumption of meats and consciously limit eating foods that contain excessive omega-6 fatty and trans- fatty acids. Cook foods only at moderate temperatures and avoid browned food. Avoid fried foods, fast foods, hydrogenated oils and ones preserved with nitrites. Eat mercury-containing fish like tuna or swordfish only once a week. Use plenty of olive oil and drink ample amounts of green tea. Good foods include blueberries, sardines, and broccoli. Consume a moderate amount of dark chocolate daily – with 70% or greater cacao content. Consume alcohol in moderation stress. A small glass of red wine at dinner might help. Consult my blog entries on hormesis for more details.
Supplements for the oxidative damage firewall
When I started out writing this document five years ago, I thought that taking exogenous antioxidants like Vitamin C was the way to deal with free radicals and ROS damage. My thinking about that has changed direction by 180 degrees as I learned more. Now I believe that the body's own anti-oxidants are effective in scavenging ROS and mitigating their damage. Further, there is research that consuming large quantities of anti-oxidants like Vitamin C can interfere with the body's own antioxidant defense system and have negative health consequences. I see the appropriate role of dietary supplements is supporting the body's own anti-oxidant defense systemnot exercising chemical anti-oxidation as rust removers would. For most of the supplements suggested here, they work by activating the Keap1-Nrf2 pathway which in turn activates a large number of stress-protetive genes, including genes for our body's own antioxidant defenses. Different antioxidants have different properties with respect to the kinds of ROS ions they can neutralize, their fat solubility, the tissues they penetrate, their effective duration in the body and their biochemical mechanisms of operation.
The body uses several different antioxidants as part of its own ROS defense system and I prefer doing the same rather than on relying on only one or two. My current "antioxidant" regime includes phytosubstances that activate the Nrf2 pathway in the foods mentioned above and: Essential Fatty Acid oils (EFAs) focusing on Omega-3 oils, Vitamin D-3, the hormone melatonin and plant-derived substances (phytochemicals which might be known as flavinoids, carotenoids or polyphenols) including resveratrol, curcumin, boswellia, ashwagandah, pycnogenol, green tea extract, olive leaf extract, lycopene, allicin and OPC grape seed extract. While these are commonly refered to as "antioxidants." they are actually not that. These substances work through a number of different complicated channels to achieve their ROS-quenching and other health-producing impacts, particularly the Keap1-Nrf2 pathway.(ref) .
A basic tenant of my firewall philosophy is to use multiple different defense mechanisms whenever they are available. I summarize the supplements I take daily and dosages in a table at the end of this article.
I touch on the subject of poisoning due to heavy metals and certain substances such as PCBs here. Some of these poisons produce large quantities of ROS; some operate through additional channels of toxicity. For example, it appears that exposure to heavy metals and arsenic reduces serum concentrations of carotenoids, reducing the body’s natural anti-oxidant defenses. Such poisoning can lead to degeneration and premature aging according to a number of the age-related theories, including immune system deterioration, neurological degeneration, susceptibility to cancer and susceptibility to cardiovascular disease. While acute poisoning with excessive blood serum levels of PCBs, lead, arsenic, cadmium or mercury requires intravenous chelation and other aggressive treatments, supplements can play a role in ongoing control of serum levels of these substances in healthy individuals and on the biological impacts of the presence of such toxins. L-carnosine is an important element of my firewall defense against toxic heavy metals like cadmium, lead, and mercury since it has an ability to chelate them (literally, to grab on to and combine with the molecules of these metals so the kidney and liver can excrete them). Further, according to animal experiments, certain antioxidants already in this firewall, vitamin C, alpha tocopherol, melatonin and alpha-lipoic acid in particular, can play roles in reducing the toxicity of heavy metals and PCBs, in some cases reducing it dramatically. Other components of the firewall defense against toxic metals are mineral supplements that compete for absorption and compete metabolically with such metals. For example, copper and selenium antagonize mercury. Calcium helps reduce lead and zinc helps reduce cadmium. Magnesium also appears to be very important for protecting cells from heavy metals. Besides protecting cells from certain forms of ROS damage, magnesium appears to be important for the absorption and metabolism of other supplements in the anti-oxidant firewall, including vitamin C and E and the B vitamins.
Follow the basic advice I have already given above under the Oxidative Damages to Tissues firewall.
Supplements for the Cell DNA Damage firewall
The advice with respect to supplements is also the same. Curcumin, ashwagandha, resveratrol and green tea in particular appear to have important properties in regulating P53, P21, CASP9 and other genes which control apoptosis, inhibition of cell growth and cell cycle arrest so as to maintain a line of cells in a healthy state. These herbal substances act through complex biochemical and genetic pathways only now becoming understood, and are also important components of the firewall against cancers. Resveratrol, a polyphenol found in grape skins and red wine, activates an ancient life-extending chain of genetic reactions that works across species in plants as well as animals - Xenohormesis. It’s use can extend the life spans of small animals up to 30% and many researchers familiar with this substance take it regularly. OPC and other polyphenols may exercise similar effects. The firewall for the 13th theory of aging (Programmed Genetic Changes) and the ability of thirty-nine of the firwall substances to inhibit activation of the nuclear factor NF-kappaB is particularly relevant to DNA protection. Alpha-lipoic acid and many other of the combined firewall substances work to block the binding of NF-kappaB to cellular DNA. The results can be multifold, ranging from increased apoptosis of cancer cells to reduction of diabetes or atherosclerosis to a younger and less-wrinkled skin.
Again, follow the advice already given.
Supplements for the mitochondrial DNA mutation firewall
Certain supplements have the capability to penetrate into the mitochondria and prevent oxidative damage(ref). Acetyl-l-carnitine and alpha lipoic acid work synergistically(ref),(ref). This combination alone has been shown to extend the lives of some small animals by as much as 30% The R isomer of alpha lipoic acid can facilitate repair of mitochondrial DNA according to one study. It appears that the combination of Acetyl-l-carnitine and R-alpha lipoic acid can exert a preventative effect against Parkinson's disease according to a recent cell-level study(ref). Research on this relatively new combination of mitochondrial antioxidants continues and further interesting results can be expected.
Of course the previous list of supplements also applies, often in special ways. Resveratrol targets one of the enzymes that regulate the function of mitochondria, and has been shown to block high glucose–induced mitochondrial ROS production in certain animal cell lines. In the mitochondria. Coenzyme Q-10 is a key mediator for electron transfer and is a highly recommended supplement for people known to have a mitochondrial disease.
Telomerase activation via use of an astragaloside IV extract, as described in the firewall for the Telomere Shortening and Damage theory of aging, also provides mitochondrial protection and is part of this firewall. Telomerase expression does not always lengthen telomeres. When a cell is under stress, telomerase (actually its catalytic subunit TERT) migrates into the mitochondria. There TERT plays a DNA-protective role and improves mitochondrial functioning. Thia quote is from a study report entitled Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. “While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. This is because TERT is reversibly excluded from the nucleus under stress in a dose- and time-dependent manner. Extranuclear telomerase colocalises with mitochondria. In TERT-overexpressing cells, mtDNA is protected, mitochondrial membrane potential is increased and mitochondrial superoxide production and cell peroxide levels are decreased, all indicating improved mitochondrial function and diminished retrograde response. We propose protection of mitochondria under mild stress as a novel function of TERT.” Several other recent research reports supports this finding. For example, see the June 2009 publication Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Here is a May 2009 review study on the same issue.
Minimize eating substances having a high glycemic index, that is, sugars and substances your body converts to sugars. There are multiple reasons for this including and going beyond minimization of glycation within the body. Consuming low glycemic-index foods is very important for weight control, cardiovascular health and control of diabetes. High serum levels of simple sugars can contribute to the proliferation of cancers. Further, consuming high glycemic-index foods can lead to drastic changes in blood sugar levels affecting mental balance and one's sense of well being. It is a good idea to become familiar with the glycemic index so as to learn about the foods to avoid and other foods that can be substituted for them. For example,products containing corn syrup, soft drinks, sweetened breakfast cereals, white bread, refined-flour pastas and sugary deserts rank high on the glycemic scale, while whole-grain cereals, fruits, leafy vegetables and soybeans rank lower on the scale.
Specifically with respect to glycation, avoid eating large amounts of substances where glycation has occurred, including burned or browned meats and fast foods of all kinds. Eat foods cooked at lower temperature, avoiding those cooked by grilling, broiling and frying. Wear sunglasses to help protect against cataracts.
Some lifestyle adoptions offer longevity benefits that
cut across several of the theories of aging, including inflammation. A good example is the so-called Mediterranean
diet, which I am well aware of because I recently returned from two weeks
Supplements for the tissue glycation firewall
Two supplements are of particular interest. The first of these is l-carnosine. It acts both to prevent glycation in the body and to stimulate enzyme reactions that break up and eliminate already-formed AGEs. Carnosine is an effective scavenger of several unsaturated aldehydes (sugars) which induce DNA-protein and protein-protein cross-linking seen in ischemic-damaged cardiovascular tissues, in Alzheimer's disease and other neurodegenerative disorders, and in various inflammatory diseases. The other substance is a fat-soluble form of the vitamin B-1 known as benfotiamine. Benfotiamine inhibits the formation of AGEs. These firewall substances are particularly important for diabetics. They can mitigate or block the biochemical processes that lead to nerve, kidney, retinal and vascular damage associated with high blood sugar levels. Magnesium, another component of this as well as other firewalls, helps regulate blood sugar levels and prevent glycation. Other supplements in the overall list also contribute to this firewall, such as Vitamin C. Vitamin C is important for collagen metabolism; it is believed to increase the level of pro-collagen messenger RNA, and facilitates "hydroxylation," a process that facilitates collagen molecules to organize themselves in the best protective configuration to resist damage. There is much laboratory evidence that acetyl-l-carnitine helps to reduce glycation in eye lenses, the cause of cataracts. Phosphatidylcholine, previously a firewall substance, is a major constituent of cell membranes, and also plays a role in membrane-mediated cell signalling.
Protection against oxidative damage is a key strategy for minimizing the production of llipofuscin. So, see the firewall for the oxidative damage theory of aging. Ihave no particular additional advice in this regard except to emphasize the importance of wearing sunglasses in sunlight to protect the retina from buildup of lipofuscin and druzen that can lead to macular degeneration.
Supplements for the lipofuscin accumulation firewall
of the antioxidants already mentioned function so as to reduce levels of
lipofuscin accumulation in brain and other cells, including alpha-lipoic
acid, CoQ10 and curcumin. Piracetam, another firewall component, appears
to significantly decrease the formation of lipofuscin in neurons. I take
two supplements which have a capability to pump lipofuscin out of cells.
One is meclofenoxate (centrophenoxine) a ‘smart drug” used in
Follow the suggestions previously made with respect to dietary habits. The Mediterranean diet can be very helpful.
Supplements for the chronic inflammation firewall
Some of the antioxidants previously mentioned have anti-inflammatory properties. For example, Vitamin C assists in the breaking down of histamine, an inflammatory substance produced by many allergic reactions. Vitamin D-3 suppresses the production of cytokines (inflammation-producing messenger substances exuded by cells) and is an important component of the firewall. Several of the the plant-derived phytochemicals are powerful anti-inflammatories, including aswagandah and boswellia. These as well as green tea and use of green tea supplements are important components of the firewall against rheumatoid arthritis, osteoarthritis, tensovitis and other inflammatory diseases. Bromelain is another anti-inflammatory phyto-substance in the firewall shown to be effective against joint inflammation. Several of these plant-based substances including ginger and curcumin are COX-2 enzyme inhibitors but, being natural substances, tend not to have the side effects of drugs designed for that purpose.
There is increasing understanding of the genetic mechanisms underlying inflammation and how supplements in the firewall can intervene in inflammatory processes. An example is low-level chronic inflammation in obese individuals. Their adipocyte (fat cell) genes express cytokines (TNF-alpha, IL-1beta, IL-6 and COX-2) implicated in cardiovascular diseases, type 2 diabetes and other pathological conditions. Curcumin and resveratrol are among the phyto-substances able to inhibit TNFalpha-activated NF-kappaB signaling in adipocytes and as a result significantly reduce their inflammatory cytokine expression. In fact, some 39 substances in the combined firewall are inhibitors of NF-kappaB cell signalling and therefore work to inhibit inflammation. See the discussion under the Programmed Genetic Changes Firewall. .
Control of tissue glycation and production of AGEs is important for control of inflammation. As saturation of tissues with AGEs begins to reach an advanced stage in older individuals, aggressive use of supplements to reduce them can be necessary to control the source of inflammation. See the tissue glycation firewall.
Also, potassium is part of this firewall. It can help the management of inflammation and some researchers believe it is very important for controlling arthritis. These anti-inflammatories together with vitamin B-6 helped me to vanish what once was a serious and worsening case of rheumatoid arthritis, much to the amazement of my rhumatologist . They were far more effective in this regard than the toxic anti-arthritic medicines that had been prescribed for me. From time to time in my life I have also been plagued with tensovitis and carpal tunnel conditions. These have also nearly disappeared since I have adjusted my regimes of these anti-inflammatory substances about seven months ago.
The main thing is to adopt a lifestyle which supports regular functioning of the immune system and avoids unnecessary challenges to it. Sleep at least seven and a half hours a night on a regular schedule, avoid chronically stressful situations, do mild cardiac exercise at least a half-hour each day, avoid situations likely to lead to infections, Treat infections promptly with lots of rest. And of course, avoid oxidative challenge as outlined previously. Having good family and friend relationships and a positive mental attitude can also help. Meditation and Yoga can also be powerful tools, although I do not practice these myself.
Supplements for the immune system compromise firewall
Antioxidants like those already mentioned contribute to lessening the load on the immune system. For example, the activity of antibodies and immune system cells such as phagocytes and neutrophils is stimulated by Vitamin C. In addition I take certain plant-related substances which specifically enhance immune system functioning as well as protect against infectious diseases. These include astragalus extract, the most concentrated form I can find, olive leaf extract and allicin. Each of these have significant antibacterial and/or antiviral properties. Allicin is effective in killing many strains of methicillin-resistant staphylococcus aureus (MRSA), the forms of staph resistant to conventional antibiotics. Olive leaf extract has strong antiviral properties and, in the laboratory at least, inhibits acute infection and cell-to-cell transmission of HIV-1. Astragalus has demonstrated a wide range of immunopotentiating effects and has proven efficacious as an adjunct cancer therapy. Among other capabilities, astragalus protects against common colds and many virus strains. Contrary to a long-established pattern, I have had only one common cold since I started taking substantial doses of astragalus two years ago. It appears that astragalus extract and its derivative astragaloside IV have important immuno-modulating effects. See the discussion in the firewall section for the Telomere Shortning and Damage theory of aging. Also, studies show that several of the firewall substances tend to have synergistic effects on immune system functioning. For example. in chickens at least it appears that astragalus polysaccharides and probiotics work together to support immunity(ref). The blog entry Vitamin D3 and the immune response describes new research(ref) published in 2010 indicating how vitamin D3 is essential for the mobilization of a T-cell immune response.
I have devoted a blog mini-treatise specifically to research on lifestyle and dietary supplement interventions that can delay or reverse age-related cognitive decline , memory loss and other age-related forms of neural degeneration such as hearing loss. It is the July 2011 post Age-related cognitive decline: focus on interventions. The cited research stongly supports the firewall suggestions made here.
Lifestyle habits seem to be very important for maintaining an active and capable brain and nervous system. Previous advice is all relevant, particularly that related to the immune system. The advice “Use it or lose it” seems to be applicable when it comes to the brain. Meeting mental challenges, movement and exercise seem to be essential for maintaining mental agility as well as body flexibility. There is evidence that regular physical exercise contributions to control of blood glucose levels which tend to rise with age and are implicated in hippocampal dysfunction and the onset of dementia and cognitive decline. Avid and regular pursuit of work, travel or a hobby can be helpful. Keep active. Close and frequent social interactions with friends and family are also helpful. And don't poison your brain with excess alcohol, toxic or illegal drugs.
Recent research related to brain neurogenesis highlights the importance of this conventional wisdom. The March 2009 issue of Scientific American reports research on what happens to neurons after neurogenesis in rats. Under normal circumstances, thousands of new neurons are generated every day in the dendrate gyrus of the hippocampus. Within a few weeks most of those neurons die if the animal’s life is unremarkable. However, if the animal is confronted with a sufficiently daunting and important learning task and successfully learns something complex and new, then many of the neurons will stay alive. This appears to be particularly applicable to learning that affects future behavior.
There is an intricate set of interrelationships between neurogenesis in the brain, mood stabilization and cognitive capability, age, exercise, mental task involvement, environmental factors such as stress and respect of circadian rhythms including patterns of sleep. The lifestyle patterns and activities suggested above promote neurogenesis. Mental or physical stress inhibits it. Maintaining consistent daily rhythms, mood stabilization, and proper neurogenesis are highly interconnected. For example, it is well known that aberrant daily rhythms may induce bipolar disorder episodes. A key underlying mechanism could be abnormality in hippocampal neurogenesis which is time-of-day dependent. Maintaining a regular daily pattern of activity and sleep is important.
A number of blog entries are relevant to diet in relation to mental states, includiing Diet and cognition, and Warding off Alzheimer's Disease and things in my diet. I believe that care innutrition as well as dietary supplements can play important roles in delaying the onset of late-life dementia and quite possibly in reversing the debilitating effects of such dementias including Alzheimer's disease. There is a great deal of research in these areas which I have covered in three January 2012 blog entries: Dietary factors and dementia - Part 3: plant-derived substances that can make a difference, Dietary factors and dementia - Part 2: possible interventions, and Dietary factors and dementia - Part 1: important recent research.
Supplements for the neurological degeneration firewall
I have already mentioned the capability of acetyl-l-carnitine and alpha lipoic acid to penetrate into the mitochondria and prevent oxidative damage. This is particularly important in nervous system cells which regenerate very slowly. Pumping out lipofuscin from nervous system cells using acetyl-l-carnitine and meclofenoxate is also important for the same reason. Acetyl-l-carnitine also appears to have an ability to protect and increase receptors in the brain that normally decline with age. Besides removing lipofuscin, meclofenoxate produces DMAE when metabolized in the body, a natural substance found especially in fish and also produced in the human brain. DMAE, is a precursor to acetylcholine, an essential neurotransmitter. DMAE offers other benefits as well; for example it alters muscle contraction and is useful for increasing flaccidity and reducing wrinkles and in the facial region. I take another smart drug called piracetam which has an effect on brain energy metabolism and supports cognitive functioning. I also take meclofenoxate to improve my memory and cognitive capabilities. Also the hormones I am taking, pregnenalone, DHEA and melatonin, serve to enhance my mental functioning and my ability to be awake and sleep in regular cycles.
There is significant research establishing that curcumin promotes neurogenesis. This topic is treated comprehensively in the blog entry Neurogenesis, curcumin and longevity.
L-theanine is derived from green tea and crosses the blood-brain barrier. It promotes expression of the neurotransmitter seratonin. There is evidence that l-theanine is neuroprotective, and that it supports relaxation and enhances cognitive function. It appears to decrease the transmission of stimulating neurotransmitters while promoting the transmission of calming neurotransmitters. There is experimental evidence that l-theanine may be protective against strokes and may protect against the glutamate toxicity associated with Alzheimer’s disease. There is also evidence that the hormones I take, melatonin, pregnenalone and DHEA, have important positive neural and immunomodulating effects, as discussed later here.
L-carnosine, another component of this firewall, has a capability to reduce brain damage due to accumulation of beta-amyloid and possibly due to malondialdehyde or hypochlorite anions, factors in Alzheimer’s disease and other forms of senile dementia. See the blog entry Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation.
Excess homocysteine is associated with cognitive function decline. To buffer against this I take vitamins B-6, B-12 and folic acid as part of this firewall.
On another front, there is some evidence that excess angiogenesis (origination of blood vessels) is implicated in Alzheimer’s disease as well as in the proliferation of cancers. Alzheimer’s disease appears to arise through a combination of oxidative damage, inflammation and excess angiogenesis. Many of the flavinoids recommended in this firewall program work against all three of these causes. For example, green tea, curcumin, resveratrol and OPC are antioxidants, anti-inflammatories and have anti-angiogenic properties. Especially in combination, they show promise for prevention of Alzheimer’s disease. I have already mentioned other components of the firewall against Alzheimer’s disease and senile dementia: protection against DNA damage through use of antioxidants, and immunomodulation through taking hormones.
Resveratrol protects neurons against toxicity induced by beta-amyloid and provides another approach to defense agaainst Alzheimer’s disease.
Ginkgo biloba is another component of this firewall, a substance shown experimentally to enhance neurogenesis though not necessarily mental acuity(ref). It also appears that the levels of metals in the cerebrospinal fluid of Alzheimer’s disease patients is abnormal, for example showing an increased level of mercury. The supplements mentioned previously to control heavy-metal toxicity like l-carnosine and acetyl-l-carnitine are important for neurological health. Also, selenium has been shown to offset the toxicity of serum lead on the hearing function.
Some studies suggest that magnesium, another component of this firewall, can help in reducing the duration and frequency of headaches and improving learning, memory and cognitive skills for aged people. Apparently, magnesium locks into key brain neural receptors that participate in governing these mental capabilities.
As discussed earlier, there is evidence that mood disorders, bipolar and related diseases may be in part due to insufficient or abnormal neurogenesis. Neurogenesis is also promoted by several substances that are part of the anti-aging firewalls program: the neurosteroids melatonin, DHEA, and pregnenalone. Also, curcumin, resveratrol, Ginkgo bilboa and EPA fish oil according to published studies. Folic acid and the fish oil components DHA and EPA serve together to improve cognitive function and prevent depression, dementia and Alzheimer's disease, one of the mechanisms being the upregulation of neurogenesis(ref).I speculate that several other psycho-active firewall substances like piracetam, meclofenoxate, ginger extract and withania somnifera (ashwagandha) may also promote neurogenesis. I have been able to identify literature references that strongly suggest this speculation but none that experimentally confirm it.
As this discussion indicates, the firewalls provide in-depth defense against age-related cognitive decline and disease. Now, having recently turned 79, I am in an intensely creative period in my life and I believe my brain is working as well as or better than at any earlier time in my life. I intend to keep it that way for a long time to come.
Lifestyle is felt to play a major role in maintenance and natural regulation of hormone levels. Here I would emphasize the role of regular exercise. On most days I do at least 45 minutes of mildly cardiovascular exercise – yard work, brisk walks in the countryside, swimming or treadmilling. Regular good sleep, avoidance of too much caffeine or alcohol are also important. And I believe mental activity is also important – like researching and writing this article.
Supplements for the decline in hormone levels firewall
Since hormones play such an important role in regulating multiple body systems, my approach as been to take supplements to maintain higher levels of some of the most important hormones than would occur naturally at my age. My objective is to maintain the level of functionality of a healthy 55 year-old. I do not take HGH or HGH promoters because they can have serious side effects – I tried once and got a serious case of arthritis. I do take two precursor “mother” hormones, however: pregnenalone and DHEA. Pregnenolone converts itself in the body into all other steroid hormones including DHEA, progesterone, estrogen, testosterone and cortisone. The extent to which it converts into estrogen or testosterone is a function of gender. Studies show it provides benefits in terms of lessening joint pain, improving cognitive function, enhancing skin condition and helping prevent joint pain. DHEA is another precursor hormone with natural levels declining with age. It is depleted by taking certain drugs and by certain disease conditions including AIDS and diabetes. Research indicates it is useful for treatment of adrenal insufficiency, depression, and SLE (systemic lupus erythematosus). I also take melatonin for regularity of sleep and for several others of its possible anti-aging benefits, including immune system regulation. Melatonin appears to be a regulator of the 24-hour circadian rhythm of biochemical, physiological and behavioral processes. I also use melatonin to speed the adoption of my body rhythms when I travel internationally across several time zones. On the mineral side, magnesium and calcium supplements are very important for maintaining my bone density as natural levels of density-regulating hormones decline.
Resveratrol is another important firewall substance for protection against age-related bone loss. Resveratrol "enhances proliferation and osteoblastic differentiation in human mesenchymal stem cells" according to one study(ref). According to another research report "In the present study, resveratrol was found to exhibit bone-protective effects equivalent to those exerted by hormone replacement therapy -- "(ref) . See also the discussion below regarding curcumin and protection against bone loss.
Hormone levels appear to be implicated in the pathogenesis or prevention of many cancers, particularly breast cancers in women and prostate cancers in men. Melatonin has been shown to be protective against breast cancers. In about half of all prostate cancers, there is a common gene alteration. In the presence of this gene alteration, estrogen-linked signaling helps trigger an aggressive form of the disease. Stinging nettle extract, saw palmetto, selenium, zink, and lycopene are substances in my firewall regime that contribute to control of estrogen, testosterone and other related hormone levels.
With respect to insulin resistance, chromiom piclonate contributes to both weight management and burning-off of extra insulin. Other substances in this firewall that assist in controlling excess insulin are DHEA, fish oil, CoQ10, alpha-lipoic acid, l-carnosine, vitamins C and E, and magnesium. These as well as exercise also contribute to weight management and control of glycation.
Again, the interrelationships among the theories of aging are complex. Most of the lifestyle suggestions as well as firewall substances have pluripotent effects related to several of the theories of aging.
Most of the critical lifestyle actions have already been covered: minimize x-ray exposure, avoid sources of radioactivity, wear sunscreen, avoid contact with chemicals that induce carcioogenesis like paint removers, avoid foods with carciogenic additives. Do not smoke and avoid second-hand smoke. Eat a diet with a low glycemic index. Physical activity and regular exercise are also helpful, for example both in prevention of breast cancer and assuring positive health after breast cancer treatment(ref).
Supplements for the Susceptibility to Cancers Firewall
In this category I recommend a broad-spectrum approach involving different supplements each with different characteristics that fight cancer All the antioxidants previously mentioned help prevent cancer-inducing mutations. Vitamin D-3 has multiple cancer-fighting properties as do each of the phytochemical supplements I take. Resveratrol and curcumin, for example, activate the P53 gene in many strains of cancer cells, leading them to commit apoptosis. So does Green tea, OPC, lycopene and olive leaf extract. The genetics-related research evidence for these claims is impressive and growing though I cannot cite it here without losing the untrained reader. The pathways of of operation of these substances can be quite complex. for example, it appears that curcumin acts to control the proliferation of neurogliaoma cells by modulating gene expression related to at least four different pathways: oxidative stress, cell cycle control, and DNA transcription and metabolism.(ref) A comprehensive review of the actions of curcumin in cancers can be found in the blog entry Curcumin, cancer and longevity.
A cluster of research reports has appeared during the last few years looking at mechanisms through which substances rich in phytochemicals (e.g. coffee, chocolate, turmeric, olive oil, broccoli, red hot peppers, green tea, garlic, blueberries, rosemary, oregano, sage) are cancer-preventative. While these foods have been studied for many years a new focal point has been moving to center stage - study of what these substances are doing in terms of gene expression as a key to understanding their therapeutic value. The blog post Nrf2 and cancer chemoprevention by phytochemicals reviews and provides citations to some of this research and discusses the role of the nuclear factor Nrf2 in phytochemical cancer chemoprevention. The blog entry Back to blueberries lists a number of research publications describing the pathways of action of pterostilbene, a powerful anti-inflammatory substance in blueberries, and describing the anti-cancer properties of this substance.
Omega-3 oils offer other cancer-inhibiting capabilities. Selenium is another substance in the firewall; it has its own mechanisms for inducing apoptotic death of tumor cells. Magnesium seems also to be useful for reducing the risks of certain cancers, such as colon cancer. Several of the substances in the firewall including curcumin, vitamin D-3, and lycopene have been well researched and show sufficient anti-cancer capabilities that they are being investigated in Phase I and Phase II clinical trials. Astragalus also appears to have anti-tumorigenic potential for certain cancer cell types includong colon cancer(ref).
NF-kappaB cell signaling is deeply implicated in both inflammatory and carcinogenetic processes which have long been known to be intimately related. A host of recent studies illuminate how NF-kB signaling is involved at the heart of inflammation, inflammatory diseases like arthritis, and cancer initiation and progression. As pointed out in the 13th firewall below, thirty-nine of the substances in the combined firewall are NF-kB inhibitors contributing to reduction of inflammation, preventions of cancers and, possibly even, organ renewal.
Again, most of the critical lifestyle actions have already been covered. Do regular daily mildly-cardiovascular exercise(ref). But avoid extremes in exercising. Avoid foods and drinks with a high glycemic index. Maintain your weight within normal ranges. Monitor and maintain normal blood pressure, preferably under 130/70. Eat healthily, featuring vegetables, fruits and fish. Avoid browned or fried foods, foods cooked in trans-fats or saturated fats, fast foods and junk foods in general. Minimize stress and Type A behavior. Again, following a Mediterranean diet can be very helpful. Avoiding environmental toxins is also very important, starting with clean air and clean water. A recent study by Harvard School of Public Health and Brigham Young University(ref) researchers points to the importance of good air quality. It appears that improvements in air quality in the US, particularly in cities, added about five months to life expectancy in the U.S. over twenty years. If you can manage to live where the air quality is good, do so. Otherwise, using a HEPA air filter can help, particularly in the bedroom at night. If your water supply is poor or heavily chlorinated you can also consider installing a high-performance filtering system for your drinking and cooking water, one that can filter out lead and other heavy meals as well as microbes. Avoid drinking liquids that have been frozen or heated in plastic bottles and don't microwave food in plastic containers. And don't drink liquids that have been frozen in plastic containers.
Supplements for the Cardiovascular Disease Firewall
Millions of people have been taking statins like Lipitor as part of a presumed firewall against cardiovascular disease, but I do not take them. Nor do I suggest taking statins for people without a history of heart disease and having a C-reactive protein score in the normal range. The US population has been convinced by an immense advertising and propaganda campaign to blame cardiovascular diseases almost entirely on the presence of a high level of cholesterol. There is a multi-billion dollar market for statins to lower cholesterol levels and understandably the drug companies involved want to protect their profits. New research shows that longevity of people without initial cardiovascular problems and with a normal C-reactive protein score taking statins is no longer than longevity of people who do not take them. The presence of a high cholesterol level is only one factor when cardiovascular diseases are concerned, and probably not the most important factor. Coronary artery occlusion can be caused by combinations of 14 known factors, many involving glycation and inflammation. A high serum level of cholesterol is only one of them. So, the supplements already mentioned that control glycation and inflammation are important – including the polyphenols, benfotiamine and l-carnosine. Carnosine also counts being an anti-ischemic agent as among its pluripotent capabilities.
Omega-3 oils are at the heart of this firewall. Dietary intake of sufficient omega-3 polyunsaturated fatty acids reverses the Omega-3/Omega-6 fatty acid imbalance mentioned previously as well as dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production. The result includes improved tolerance of ischemia and reperfusion. Even the crusty anti-supplements American Heart Association now recommends taking Omega-3 oils. The active components are DHA and EPA and it is important that the supplement capsules taken contain adequate amounts of them. The risk of heart attack or unstable agina was reduced 62% for every 1.24% increase of EPA and DHA in serum blood level compared to age-matched controls, according to a recently-published study of over 1,000 patients. I suggest 1500mg of EPA and 1000mg of DHA twice a day.
Of course, obesity is a major predictor of many cardiovascular diseases. Resveratrol, curcumin, chromium piclonate, L-theanine, quercetin, Vitamin A, and green tea extract contribute to weight management and reduction of abdominal fat. Consumption of green tea appears to strongly support the health of circulatory endothelial cells, preventing or delaying the onset of atherosclerosis. Green tea and L-theanine also reduce fatty acids in blood serum.
A number of the plant flavinoids that I have mentioned can contribute significantly to lowering blood pressure, in turn lowering risk of stroke, congestive heart failure and other problems. Research indicates that dark chocolate alone can make an important difference in this regard. In at least one study, taking acetyl-l-carnitine is reported to result in reduction of fat mass and increase in muscle mass, again predictors of cardiovascular health. There is also evidence that astragalus contributes to improvement of cardiovascular system health. This can be seen in clinical measurements associated with angina, congestive heart failure and acute myocardial infarct.
Lycopene is another component in this firewall as is allicin, a garlic extract. Epidemiological studies have shown an inverse relationship between tissue and serum levels of lycopene and mortality from myocardial infraction, coronary heart disease and cardiovascular disease. A recent meta-analysis of 25 systematic studies indicates that garlic extract is as effective in reducing blood pressure as the usual prescription beta-blocker medications given for this purpose.
Magnesium is another pluripotent supplement in the firewall that is useful for preventing cardiovascular diseases and hypertension. It helps to stabilize blood pressure, prevent arrhythmia, reduce cardiovascular inflammation, and reduce the consequences of congestive heart failure. Maintaining proper electrolyte (potassium-sodium) balance is also key for proper functioning of the heart as well a number of other systems including muscles, nerves, kidneys, and the digestive track. Since I get plenty of sodium in my salt intake, I also take a potassium supplement as another component of this firewall.
An excessive level of blood homocysteine is associated with elevated risk of heart attacks and stroke. These levels may result from inadequate supplies of certain nutrients including vitamins B-6, B-12, and folic acid. These nutrients are also part of this as well as other firewalls. Finally, Vitamin D is another important firewall component. A recent eight-year study of 3,258 men and women indicates that the higher the blood level of Vitamin D, the less is the chance of dying from heart disease - and the less the chance of dying from a number of other diseases as well.
The general rule is to keep your telomeres long while you have them that way. This means avoiding excessive or prolonged stress of all kinds be it environmental, physical or psychological. It means avoiding radiation, infections, bug bites, wounds, excessively strenuous exercise and heavily stressful human situations. Actually some stress such as through regular not overly-stressful exercise might help keep your telomeres long. See the blog entry Stress, exercise and telomere lengths. Positive mental attitude and good relationships can help. So can all the other firewalls already mentioned. Be aware that chemotherapy and radiation therapy or personal crises can take years off of your life through telomere shortening. A quite thorough discussion of practical means for keeping telomeres long can be found in the October 2010 blog entry Lifestyle, dietary, and other factors associated with telomere shortening and lengthening. That blog entry also links to earlier blog entries relevant to telomere lengths.
Supplements for the Telomere Shortening Firewall
A study of 586 women reports " -- the relative telomere length of leukocyte DNA was on average 5.1% longer among daily multivitamin users." Antioxidant regimes and the other firewall supplements already mentioned can help maintain health and minimize undue cell replication resulting in telomere shortening. Shortening may be due to an excess rate of cell duplication or, more directly, to single-strand breaks in the telomeric DNA, both most-frequently resulting from oxidative damage. In metabolic syndrome patients with coronary artery disease an association can be observed in circulating endothelial progenitor cells between oxidative DNA damage and telomere shortening. Therefore, anti-oxidant measures can be very useful for preventing telomere shortening and disease progress in such patients. The blog entry Vitamins, supplements and telomerase - upregulation or downregulation? cites research literature references on population studies coupling supplementation with Vitamin E, fish oils, Vitamin D3 and resveratrol with having longer telomeres. L-carnosine also appears to reduce or even reverse telomere damage and shortening rates, at least in cultured human diploid fibroblasts. Studies going back to 1994 indicate that Carnosine can delay senescence and promote formation of a more juvenile phenotype in such cultured human fibroblasts, extending the Hayflick limit for reproduction of such cells by up to ten doublings. I conducted a literature review of l-carnosine a few years back and continue to be impressed by this substance. See the November 2009 Blog entry The curious case of l-carnosine .
For the author, up until recently the Holy Grail of life extension has been to rejuvenate organs and perhaps whole animals by extending telomere lengths. The idea has been to reset cells and therefore reset organs and entire bodies to an earlier biological state. Young bodies generally have a vastly greater capacity to handle diseases of old age like cardiovascular problems, cancers Alzheimer's, Parkinson's,diabetes, etc. Either these diseases are much rarer in young people, or have less serious consequences, or don't occur at all. Young bodies know how to avoid or get rid of AGEs and lipofuscin and have much more effective antioxidant defences and DNA repair mechanisms than older ones. The basic concept of life extension through telomere extension is to reset bodies and the organs in them to an earlier biological age, to an age when the body has the capacity to shrug off the diseases of old age. If this theory of aging is correct then it relegates most of the previously listed theories of aging to secondary status. The central anti-aging firewall needed is to reset the body to an earlier age. The other firewalls in combination might be capable of getting one in a healthy active state to 100 or 115 years of age. An effective firewall against telomere shortening might get one to 250 to 500 good years of life, so I thought for many years. Since 1994, I have been aiming for 240 good years but might extend that target if biotech research moves fast enough. I waited 14 years for the emergence of a safe and effective telomere-extending technology.
Now there is much more knowledge available about telomeres and a dietary supplement is available that is believed to work to extend telomeres. However, as described above I no longer see telomere extension as being the central key to extraordinary longevity. Over the years there have been no reported small-animal experiments resulting in significantly enhanced longevity due to telomere extension. So, the notion that enhanced telomerase expression can by itself lead to radical life extension in humans remains hypothetical. However, there has been continuing research evidence suggesting that maintaining both telomerase expression and telomere lengths is key in any program for extraordinary longevity. I have also not given up on the concept of resetting cells, organs and bodies to an earlier biological age. Rather, I have expanded my viewpoint to allow this to come about also through other means – such as through addressing two of the theories of aging I added after initially drafting this treatise: Programmed genetic changes and Decline in adult stem cell differentiation,
Achieving longevity through telomere extension is potentially tricky. One of the key transformations of a normal cell into a cancer cell is turning on the hTERT telomerase gene. Telomerase does not cause cancers but can cause them to go into high gear. Telomerase expression plays a role in tumor progression and it appears that the telomerase RNA component Terc is key as to what telomerase does regarding tumorgenesis. Telomerase-mediated telomere length maintenance could therefore possibly enable certain mutant cells to efficiently move into a fully malignant state, including metastasis. This is more than a bit scary, a high-stakes game. Possibly, the telomerase gene shutting down in older adults is an evolutionary defense against cancers.
Earlier versions of this treatise contained a discussion of how telomerase might possibly be activated via suplements which are extracts from astragalus. I continue to see telomeres and telomerase as extremely important topics from a longevity perspective. However, I no longer see taking a telomerase extender like astragenol as likely to be a useful anti-aging intervention. Instead, I believe there is ample research supporting the pursuit of certain conventional-wisdom lifestyle and dietary patterns as ways of keeping telomeres long. My thoughts are expressed in a series of blog entries, particularly The epigenetic regulation of telomeres, Lifestyle, dietary, and other factors associated with telomere shortening and lengthening, and particularly in the October 2010 blog entry Lifestyle, dietary, and other factors associated with telomere shortening and lengthening.
For historical purposes, I have moved the earler discussion of astragulus-based supplements intended to extend telomeres to here.
Going to my blog using this link will reveal a large number of earlier postings relating to telomeres and telomerase expression.
The main thing that can be said here is that the molecular pathways that relate diet, exercise, sleep and social patterns to epigenetic gene regulation have been under intense research scrutiny and are inreasingly being understood. Exercise, sleep patterns, foods and supplements can simultaneously affect multiple biological pathways related to health and longevity such as AMPK, Keap1-Nrf2, NF-kappaB, GH-IGF, the heat shock response pathway (HSR), p53, FOXO and the unfolded protein response pathway (UPR). Further, we are starting to understand how these pathways interact so as to reinforce or inhibit each other. The traditional advice for lifestyle mentioned in earlier sections still pertains. What has been changing has been understanding of how following that advice plays out in terms of epigenomic gene activation pathways. The previously-made suggestions are still valid.
The first theory I mentioned of aging as programmed genetic changes is the telomere shorting one and the firewall against it is described in the previous Section.
The second theory I mentioned, epigenomic changes involving DNA methylation and histone actetylation are of prime importance. A number of supplements in my combined firewalls list act via epigenetic mechanisms and act via the Keap1-Nrf2 pathways to modify gene expression in health-producing ways. The subject is fascinating and complex and I recommend that interested readers look at my some of the multiple blog entries that deal with it including (February 2012) * The pivotal role of Nrf2: Part 1 - a new view on the control of oxidative damage and generation of hormetic effects.Human healthspan and lifespan extension?, * Part 2 - foods, phyto-substances and other substances that turn on Nrf2, and * Part 3 - Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension? Also, a great many earlier blog entries are relevant, a sample being * Dietary factors and dementia - Part 3: plant-derived substances that can make a difference, * Dietary factors and dementia - Part 2: possible interventions, * Dietary factors and dementia - Part 1: important recent research, * Focus on phytosubstances - Danshen root - amazing properties of salvia miltiorrhiza Bunge, , * Phytosubstances - focus on cats claw, * Focus on bitter melon, * * Age-related cognitive decline: focus on interventions, * Health and longevity benefits of plant polyphenols - focus on grape seed extract, * Focus on ginger * PQQ - activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis, * The epigenetic regulation of telomeres, , * The many faces of folic acid, * Cancer, epigenetics and dietary substances, * JDP2 - linking epigenetic modifications, stem cell differentiation, cell senescence, cell stress response, and aging.,
The third theory I mentioned of aging as programmed epigenomic changes suggests that at least limited age reversal on the organ level can be achieved by blocking the expression of NF-kappaB. It happens that many of the supplements in the Anti-Aging Firewall regimen identified up to this point powerfully inhibit NF-kappaB cell signaling. In most cases these are substances often classified misleadingly as "antioxidants" that serve to turn on the expression of Nrf2. They serve the dual function of turning on the expression of multiple body antioxidant and stress protection genes and protecting against inflammation by surpressing the expression of NF-kappaB. My research of the literature indicates that significant but different effects on inhibition of NF-kappaB expression and/or binding activity are exercised by each of the anti-aging firewall substances in this table:
|Green tea (egcg)||Ashwagandha||Astragalus|
|Astragaloside IV||Gingo biloba extract||Vitamin C|
|Vitamin E||Vitamin D-3||Vitamin B-6|
|Folic acid||Grape seed extract||Avena sativa|
|Bilberry extract||Stinging nettle||Grape seed extract|
|Potassium||Vitamin B-12 (cobalamin)||Pantothenic acid|
Thirty-nine substances in the combined firewall! (and still counting) It is as if an overall objective of the firewall supplement program was to inhibit expression of NF-kappaB. In the case of antioxidants the protective mechanism is fairly clear. There is usually an ample supply of NF-kappaB in a cell’s cytoplasm, but it is sequestered there by proteins in the IkB family. Free radicals initiate a chain of signaling that causes unbinding of the NF-kappaB and its translocation into the cell's nucleus. Once in the nucleus, the NF-kappaB binds to and turns on a number of genes, potentially resulting in unwanted effects like inflammation and oncogenesis(ref). So, antioxidants reduce the numbers of such radicals and therefore inhibit the presence of nuclear NF-kappaB.
The majority of these thirty-nine
pluripotent substances work through multiple additional biological channels
(like suppression of TNF-alpha, IL-1beta and IL-6), are powerful anti-inflammatories,
cause cancers to commit apoptosis, and have additional unique positive properties.
At least three of them (resveratrol, Ginkgo biloba and curcumin) are capable
of upregulating telomerase expression, differentiation and proliferation of
certain somatic stem and progenitor cell types via the P13/Akt pathway. So
far I have found only one substance ithat has been n the firewall regime that activates
NF-kappaB. This is phosphatidylcholine. As of April 2011 I have removed phosphatidylcholine
from the firewalls regimen. I continue to be on the lookout for additional research that
demonstrates inhibition of NF-kappaB cell signaling leading to clear-cut age
reversal in organ systems. Numerous studies point to the efficacy of specific NF-kappaB
inhibitors in this list to address specific age-related health issues. Take
the case of excess bone resorption due to osteoclastogenesis, for example,
a situation typically created by the presence of inflammatory cytokines and
implicated in breast cancer metastasis(ref)
and in several degenerative bone diseases including rheumatoid arthritis and
osteomyelitis. Curcumin inhibits both the NF-kappaB activation and osteoclastogenesis
induced by by overproduction of the osteoclasts activator RANKL(ref).
As mentioned previously, resvertrol, another powerful inhibitor of NF-kappaB
activation, is also effective against osteoporosis,through induction of bone
morphogenetic protein-2. It is interesting that activation of Nrf2 seems to inhibit
activation of NF-kappaB, indicating a strong relationship between the body's
natural antioxidant defense system and expression of NF-kappaB. Numerous phytosubstances
in the supplement firewall both activate Nrf2 and inhibit expression of NF-kappaB.
I have reviewed and discussed a number of these in my blog, including less-familiar
ones such as epimedium,
rhodiola, and danshen root. You can find the relevant blog entries by using the blog's
search function and searching for the word phytosubstance. For those interested in delving deeper into the topic of
inhibiting NF-kappaB as an anti-aging strategy, I have started an interesting
discussion forum on this topic on the Immortality Institute site which can
be accessed here
(2010). Finally, I note that there seems to be paradox relating
to the role of NF-kappaB and neurogenesis. On the one hand, all of the anti-aging
firewall substances that stimulate neurogenesis (DHEA, pregnenalone, resveratrol,
curcumin, Ginkgo bilboa and EPA fish oil) are also known to be inhibitors
of activation of NF-kappaB, that is, translocation of NF-kappaB into the
cell nucleus. This seems to imply that inhibiting the expression of NF-kappaB
is consistent with if not necessary for neurogenesis to take place. On the
other hand a number of published papers suggest the opposite - that activation
of NF-kappaB is implicated in neurogenesis(ref).
It is thought that that NF-kappaB may be part of a signaling pathway that
is important for neurogenesis. The antidepressents Lithium and fluoxetine
(not in the firewalls) are known to activate neurogenesis(ref,
are also activators of NF-kappaB(ref,ref).
Animal experiments show that proteins in the NF-kappaB family are expressed
in actively proliferating neural progenitor cells. It is known that Tumor
Necrosis Factor alpha activates NF-kappaB which in turn results in a proliferation
of adult neural stem cells. There are multiple NF-kappaB proteins, and one
explanation is that these could act differentially. Another explanation
could be that the firewall substances primarily enhance neurogenesis via
their antioxidant impacts, and that this effect exceeds the effect of inhibiting
NF-kappaB insofar as neurogenesis is concerned. The signal transduction
factors involved are complex and still only partially understood. So for
the present at least, the exact roles of NF-kappaB expression or inhibition
in neurogenesis remains unclear. Much is yet to be learned. Assuming that this theory is correct, it would seem that an
appropriate anti-aging intervention strategy would consist of: 1. extending
the effective life of pools of somatic Type B and Type C stem cells, probably
by keeping their telomeres long via protective measures as well as telomerase
activation, 2. protecting the apoptotic capabilities of somatic cells and
averting activations of pathways that could decimate such pools, and 3. halting
the age-related decline in the rate of differentiation of the SSCs. I deal with the issues as usual in terms of Lifestyle
and Supplements. However, for this
theory I also include two additional subsections: one on stem cell therapies, and the other on radical future stem-cell based anti-aging interventions. All of the
lifestyle suggestions mentioned previously are oriented towards the above three
objectives, as is regularly taking the suggested supplements. "Caution is recommended in applying
telomerase inhibition to kill telomerase-expressing cancer cells, because it
would probably damage stem cells in essential organs and even increase the
likelihood of secondary cancers(ref) B. Supplements
for the Deterioriation of the Stem Cell Supply Chain
Firewall One of the antidotes to organ aging, given this theory,
would be to promote the expression of telomerase in SSCs. Reports of experiments
of such telomerase-based SSC activation are beginning to appear in the literature.
For example, "Resveratrol
reduces endothelial progenitor cells senescence through augmentation of
telomerase activity by Akt-dependent mechanisms." Experiments have been
done activating HERT (the catalytic component of telomerase) for certain
SSC types. For example by transfecting hTERT DNA into primary human marrow
mesenchymal stem cells, those cells can be immortalized and induced to differentiate
into chondrocytes(ref). “We have recently demonstrated that overexpression of human telomerase reverse transcriptase
(hTERT) in hMSC (human mesenchymal stem cells) reconstitutes telomerase activity and extends life span of the cells.”
In another experiment(ref),
activating HERT in the hair follicle stem cells in mice results in the production
of extremely hairy mice. It would seem that this intervention would be of
the first type mentioned above but, surprisingly it is of the second type
instead. In this case when the mice grew shaggy even with no TERC (the RNA
component of telomerase) around, it was clear the follicle stem cell stimulation
was due solely to TERT and that the telomere repair function of telomerase
played no role(ref). Another report indicates “We show that TERT(ci) retains the full activities of wild-type
TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis(ref).
Apparently, TERT can strongly promote differentiation of certain SSCs by
a mechanism that is independent of telomere extension. It appears to work
through activation of progenitor cells. For example. astragaloside IV can
significantly potentiate the differentiation of preadipocyte cells(ref). However, there seems to be some experimental evidence that
stimulating somatic stem cells via telomerase may increase the probability
of carcinogenesis when the HERT is expressed for a prolonged period(ref).
In the hairy mouse experiment, the TERT transcriptional response strongly
resembles that mediated by Myc, an oncogenic protein(ref).
I speculate that protection against carcinogenesis in the course of such
telomerase stimulation can probably be achieved through strengthening of
apoptotic mechanisms such as P53, P16 and P21. Credence is given to this
view by a very recent finding that mice which possess extra copies of both
telomerase-creating and antitumor genes live 26% to 40% longer than their
normal cohorts(ref). There appears to be an open question regarding the tradeoff
beween tissue rejuvination via stem cells and risk of oncogenesis. Recent
research indicates that the P16/Ink4a gene, a tumor supressor, becomes increasingly
active with age but at the same time shuts down adult stem cell function
and differentiation capacity in aging tissues(ref).
Activation of P16 to generate the protein P16/Ink4a and a few closely associated
genes seems to be an important natural strategy in mammals for both fighting
cancers and moving them along a programmed process of aging. To the extent
that longevity is achieved by preventing cancers, a number of powerful substances
are already in the combined firewall. Curcumin, green tea extract, resveratrol,
ashwagandha and many of the other substances in the anti-cancer firewall
fight cancers by various means. Can Ink4a be turned off on a temporary bases
to encourage tissue renewal without incurring risk of oncogenesis? I don't
know. There is a growing body of research relating telomerase, Ink4a, and
NF-kappaB, but much of this appears to relate to cancer strains. For example,
inactivation of Ink4a(P16) and activation of telomerase seem essential for
immortalization of meningioma cells though there seems to be no evidence
that one creates the other(ref).
Given that these two steps are important in oncogenesis, it seems potentially
dangerous to pursue them simultaneously in the interest of longevity. (Update 27 July 2009). One experiment brings good news, saying that transduction with human telomerase has opposite effects
on healthy and cancerous nerve stem cells(ref). On the one hand “Neural progenitor cells (NPCs) transduced with
human telomerase reverse transcriptase (hTERT), the catalytic component of
telomerase, have the potential both to proliferate indefinitely in vitro and to respond to differentiation signals necessary for generating appropriate cells for transplantation.” And on the other hand, for the
cancerous NT2 cell line, “– following hTERT transduction. RT-PCR and telomerase activity data demonstrated that persistent exogenous hTERT expression significantly inhibited the
differentiation of neurons from NT2 cells. Following retinoic acid induced differentiation, hTERT-NT2 cells produced only one fourth of the neurons generated by parental and vector-control cells.”
NT2 is a neuronally committed human teratocarcinoma cell line. Not only does exogenous telomerase
support the proliferation and differentiation of healthy stem cells, but it also inhibits the differentiation of cancer stem cells in the case of NT2. Of course, further research will be needed to determine how telomerase activation works in the case
of other cancer stem cell types besides NT2.
The anti-aging regimen proposed in my paper addresses the
issue of simultaneously activating telomerase while protecting against cancer
by time-alternating 1) the taking of substances which activate Ink4a/P16
and inhibit P53/P21 deactivation (NF-kappaB inhibitors which are strongly
protective against carcinogenesis) with 2) taking a telomerase activator
(astragaloside IV). In a normal day I take the telomerase activator in the
afternoon 4 to 6 hours after a number of the NF-kappaB inhibitors in the
morning, and another set of NF-kappaB inhibitors of 4 to 6 hours after the
telomerase activator in the evening. Several of these NF-kappaB inhibitors
are phytochemicals like curcumin and EGCG from green tea that are known
to activate Ink4a/P16. It appears that resveratrol, taken mornings and evenings,
is a telomerase activator in some progenitor cell types (ref)(ref).
Resveratrol also inhibits the expression of telomerase in many lines of
cancer cells but this could mostly be due to the fact that it kills such
cells. Although it is reputed to limit expression of telomerase in normal
somatic cells, I have had difficulty finding research that directly supports
this conjecture. I do not know what its net effect is. I also do not know
how effective this scheduling is. I prefer to play it safe but so far my
once-bald scalp is not getting shaggy as fast as the mice did. On the other
hand, bald on top at around 55, there is more and more grey hair there now
as I approach 80.
Numerous studies point to the efficacy of specific NF-kappaB inhibitors in this list to address specific age-related health issues. Take the case of excess bone resorption due to osteoclastogenesis, for example, a situation typically created by the presence of inflammatory cytokines and implicated in breast cancer metastasis(ref) and in several degenerative bone diseases including rheumatoid arthritis and osteomyelitis. Curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by by overproduction of the osteoclasts activator RANKL(ref). As mentioned previously, resvertrol, another powerful inhibitor of NF-kappaB activation, is also effective against osteoporosis,through induction of bone morphogenetic protein-2.
It is interesting that activation of Nrf2 seems to inhibit activation of NF-kappaB, indicating a strong relationship between the body's natural antioxidant defense system and expression of NF-kappaB. Numerous phytosubstances in the supplement firewall both activate Nrf2 and inhibit expression of NF-kappaB. I have reviewed and discussed a number of these in my blog, including less-familiar ones such as epimedium, andrographis, rhodiola, and danshen root. You can find the relevant blog entries by using the blog's search function and searching for the word phytosubstance.
For those interested in delving deeper into the topic of inhibiting NF-kappaB as an anti-aging strategy, I have started an interesting discussion forum on this topic on the Immortality Institute site which can be accessed here (2010).
Finally, I note that there seems to be paradox relating to the role of NF-kappaB and neurogenesis. On the one hand, all of the anti-aging firewall substances that stimulate neurogenesis (DHEA, pregnenalone, resveratrol, curcumin, Ginkgo bilboa and EPA fish oil) are also known to be inhibitors of activation of NF-kappaB, that is, translocation of NF-kappaB into the cell nucleus. This seems to imply that inhibiting the expression of NF-kappaB is consistent with if not necessary for neurogenesis to take place. On the other hand a number of published papers suggest the opposite - that activation of NF-kappaB is implicated in neurogenesis(ref). It is thought that that NF-kappaB may be part of a signaling pathway that is important for neurogenesis. The antidepressents Lithium and fluoxetine (not in the firewalls) are known to activate neurogenesis(ref, ref) and are also activators of NF-kappaB(ref,ref). Animal experiments show that proteins in the NF-kappaB family are expressed in actively proliferating neural progenitor cells. It is known that Tumor Necrosis Factor alpha activates NF-kappaB which in turn results in a proliferation of adult neural stem cells. There are multiple NF-kappaB proteins, and one explanation is that these could act differentially. Another explanation could be that the firewall substances primarily enhance neurogenesis via their antioxidant impacts, and that this effect exceeds the effect of inhibiting NF-kappaB insofar as neurogenesis is concerned. The signal transduction factors involved are complex and still only partially understood. So for the present at least, the exact roles of NF-kappaB expression or inhibition in neurogenesis remains unclear. Much is yet to be learned.
Assuming that this theory is correct, it would seem that an appropriate anti-aging intervention strategy would consist of: 1. extending the effective life of pools of somatic Type B and Type C stem cells, probably by keeping their telomeres long via protective measures as well as telomerase activation, 2. protecting the apoptotic capabilities of somatic cells and averting activations of pathways that could decimate such pools, and 3. halting the age-related decline in the rate of differentiation of the SSCs. I deal with the issues as usual in terms of Lifestyle and Supplements. However, for this theory I also include two additional subsections: one on stem cell therapies, and the other on radical future stem-cell based anti-aging interventions.
All of the lifestyle suggestions mentioned previously are oriented towards the above three objectives, as is regularly taking the suggested supplements. "Caution is recommended in applying telomerase inhibition to kill telomerase-expressing cancer cells, because it would probably damage stem cells in essential organs and even increase the likelihood of secondary cancers(ref).
B. Supplements for the Deterioriation of the Stem Cell Supply Chain Firewall
One of the antidotes to organ aging, given this theory, would be to promote the expression of telomerase in SSCs. Reports of experiments of such telomerase-based SSC activation are beginning to appear in the literature. For example, "Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms." Experiments have been done activating HERT (the catalytic component of telomerase) for certain SSC types. For example by transfecting hTERT DNA into primary human marrow mesenchymal stem cells, those cells can be immortalized and induced to differentiate into chondrocytes(ref). “We have recently demonstrated that overexpression of human telomerase reverse transcriptase (hTERT) in hMSC (human mesenchymal stem cells) reconstitutes telomerase activity and extends life span of the cells.” In another experiment(ref), activating HERT in the hair follicle stem cells in mice results in the production of extremely hairy mice. It would seem that this intervention would be of the first type mentioned above but, surprisingly it is of the second type instead. In this case when the mice grew shaggy even with no TERC (the RNA component of telomerase) around, it was clear the follicle stem cell stimulation was due solely to TERT and that the telomere repair function of telomerase played no role(ref). Another report indicates “We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis(ref). Apparently, TERT can strongly promote differentiation of certain SSCs by a mechanism that is independent of telomere extension. It appears to work through activation of progenitor cells. For example. astragaloside IV can significantly potentiate the differentiation of preadipocyte cells(ref).
However, there seems to be some experimental evidence that stimulating somatic stem cells via telomerase may increase the probability of carcinogenesis when the HERT is expressed for a prolonged period(ref). In the hairy mouse experiment, the TERT transcriptional response strongly resembles that mediated by Myc, an oncogenic protein(ref). I speculate that protection against carcinogenesis in the course of such telomerase stimulation can probably be achieved through strengthening of apoptotic mechanisms such as P53, P16 and P21. Credence is given to this view by a very recent finding that mice which possess extra copies of both telomerase-creating and antitumor genes live 26% to 40% longer than their normal cohorts(ref).
There appears to be an open question regarding the tradeoff beween tissue rejuvination via stem cells and risk of oncogenesis. Recent research indicates that the P16/Ink4a gene, a tumor supressor, becomes increasingly active with age but at the same time shuts down adult stem cell function and differentiation capacity in aging tissues(ref). Activation of P16 to generate the protein P16/Ink4a and a few closely associated genes seems to be an important natural strategy in mammals for both fighting cancers and moving them along a programmed process of aging. To the extent that longevity is achieved by preventing cancers, a number of powerful substances are already in the combined firewall. Curcumin, green tea extract, resveratrol, ashwagandha and many of the other substances in the anti-cancer firewall fight cancers by various means. Can Ink4a be turned off on a temporary bases to encourage tissue renewal without incurring risk of oncogenesis? I don't know. There is a growing body of research relating telomerase, Ink4a, and NF-kappaB, but much of this appears to relate to cancer strains. For example, inactivation of Ink4a(P16) and activation of telomerase seem essential for immortalization of meningioma cells though there seems to be no evidence that one creates the other(ref). Given that these two steps are important in oncogenesis, it seems potentially dangerous to pursue them simultaneously in the interest of longevity.
(Update 27 July 2009). One experiment brings good news, saying that transduction with human telomerase has opposite effects on healthy and cancerous nerve stem cells(ref). On the one hand “Neural progenitor cells (NPCs) transduced with human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, have the potential both to proliferate indefinitely in vitro and to respond to differentiation signals necessary for generating appropriate cells for transplantation.” And on the other hand, for the cancerous NT2 cell line, “– following hTERT transduction. RT-PCR and telomerase activity data demonstrated that persistent exogenous hTERT expression significantly inhibited the differentiation of neurons from NT2 cells. Following retinoic acid induced differentiation, hTERT-NT2 cells produced only one fourth of the neurons generated by parental and vector-control cells.” NT2 is a neuronally committed human teratocarcinoma cell line. Not only does exogenous telomerase support the proliferation and differentiation of healthy stem cells, but it also inhibits the differentiation of cancer stem cells in the case of NT2. Of course, further research will be needed to determine how telomerase activation works in the case of other cancer stem cell types besides NT2.
The anti-aging regimen proposed in my paper addresses the issue of simultaneously activating telomerase while protecting against cancer by time-alternating 1) the taking of substances which activate Ink4a/P16 and inhibit P53/P21 deactivation (NF-kappaB inhibitors which are strongly protective against carcinogenesis) with 2) taking a telomerase activator (astragaloside IV). In a normal day I take the telomerase activator in the afternoon 4 to 6 hours after a number of the NF-kappaB inhibitors in the morning, and another set of NF-kappaB inhibitors of 4 to 6 hours after the telomerase activator in the evening. Several of these NF-kappaB inhibitors are phytochemicals like curcumin and EGCG from green tea that are known to activate Ink4a/P16. It appears that resveratrol, taken mornings and evenings, is a telomerase activator in some progenitor cell types (ref)(ref). Resveratrol also inhibits the expression of telomerase in many lines of cancer cells but this could mostly be due to the fact that it kills such cells. Although it is reputed to limit expression of telomerase in normal somatic cells, I have had difficulty finding research that directly supports this conjecture. I do not know what its net effect is. I also do not know how effective this scheduling is. I prefer to play it safe but so far my once-bald scalp is not getting shaggy as fast as the mice did. On the other hand, bald on top at around 55, there is more and more grey hair there now as I approach 80.
Regimen supplements and stem celll proliferation and differentiation
The research literature has some things to say about the impacts of certain substances in the existing combined anti-aging supplement firewall on differentiation and proliferation of stem and progenitor cells. A few hours of searching revealed a number of ineresting reports, including:
C. Stem cell therapies
It is important first of all to recognize that every proposed, experimental or practical stem cell therapy in an anti-aging intervention in the stem cell supply chain. They all involve activating, introducing or re-introducing stem cells for particular purposes whether those purposes be curing cancer, healing wounds, re-growing hair, treating neurological conditions or what have you. It is beyond the scope of this document to cover what is going on with stem cell therapies. However, I can point to recent blog entries describing recent progress on some such therapies and the interested reader will find they provide a good sample of what is going on. In order of appearance:
1. The January 28 post Geron in the news again relates to a clinical trial using proprietary oligodendroglial progenitor cells to treat acute spinal chord injuries. The trial has recently been put on hold because a small number of animals previously injected with the trial substance developed microscopic cysts. Although those cysts are reportedly nonproliferative, confined to the injury site, and had no adverse effects, the FDA felt it prudent to halt the trial at least temporarily.
2. Trojan-horse stem cells might offer an important new cancer therapy is about a stem cell therapy with a reverse twist. Since mesenchymal stem cells circulating in the blood are attracted to and seek out cancer cells, it is possible to attach a payload molecule to mesenchymal stem cells which cause them to kill cancer cells but not normal cells. There are other uses of stem cells as delivery vectors. For example, Stem cell transplants can be used to transfer new genes into patients, for example to protect them from some of the negative effects of chemotherapy treatments(ref).
3. The May 23, 2009 post State of autologous stem cell therapies provides a general discussion of therapies that are based on extracting, culturing and re-introducing a patient’s own Types B and C stem cells. How I opened the post is worth repeating: “I searched the news this morning for items related to stem cell disease therapies. I found over 60 items. My impression is that the situation is a bit like commercial aviation was in 1926: everybody is talking about it, visionaries are sure it will be a very big thing, there is a lot of disconnected activity going on all over the place, and safety is a big question. And, the regulatory rules-of-the-game still have to be worked out. Most potential stem cell therapies are still far from being part of mainline medicine and it is difficult to make sense about where things stand.”
4. The post A genetic fix for obesity? describes research involving introduction of a plant-based genetic pathway in mice that increases metabolism of fatty acids and induces resistance to diet-related obesity.
5. The post Genetic or antibiotic prevention for HIV? discusses a possible genetic fix that would prevent the occurrence of HIV.
6. The post More research insight on gray hair and adult stem cell reproduction discusses the relationship of gray hair to declines in melanocyte stem-cells, the possible basis for a future stem cell therapy.
7. The post Simple but powerful non-invasive adult stem cell cures discusses experimental stem cell treatment of Scleradactyly and blindness caused by corneal disease.
8. The post On cancer stem cells discusses a new approach to understanding and treating cancers. The concepts of the stem cell supply chain apply to cancers as well as to normal cells and as long as cancer stem cells are present, no amounts of radiation or chemotherapy are likely to be able to keep a cancer from recurring.
9. The post Now hear this discusses reasons for hearing loss including decline in the rate of differentiation of hair follicle stem cells in the cochlear canal, and speculates on the use of stem cells as a therapy for hearing loss(ref). See also this article regarding restoration of hearing through the growth of cochlear hair cells generated from stem cells in mice.
10. The July post Embryonic Stem cell research news focuses on research developments related to ESCs, particularly the transcription factors affecting their pluripotency and differentiation. Among the many topics discussed is using human ESCs to generate “natural killer” immune system cells that can can combat cancers.
11. The July post Hair stem cells looks in detail at the roles of hair follicle stem cells a possible approach to reversing baldness via telomerase activation.
12. Among other matters mentioned in the post Autoimmune diseases and lymphoma: Part I: focus on Lupus is a ”five-year study to see whether a therapy using transplantation of hematopoietic stem cells, blood stem cells found in bone marrow, can produce long-term remission for patients with severe, treatment-resistant systemic lupus erythematosus(ref).”
13. The August 2009 post Update on cancer stem cells reports new research indicating two advances with respect to cancer stem cells (CSCs): first, development of a high-throughput screening approach for agents that have high toxicity for epithelial cancer stem cells; second, identification of a compound that has very high toxicity for breast cancer stem cells, salinomycin.
14. In the August 2009 post Autoimmune diseases and lymphoma – Part III: focus on lymphomas, I discuss treatment options for lymphomas, including use of stem cell therapies. I discuss also discuss problems experienced in connection with such therapies: relapse in the case of autologous stem cell therapy, and Graft-versus-host disease in the case of transplantation from unrelated donors. Both problems result from failure to deal with all the factors involved. Of course, a transplantation from an unrelated donor is likely to be rejected by a patient’s own immune system. An autologous transplant will involve stem cells that have the same genetic susceptibilities that the patient had in the first place. For how this situation can be dealt with, please see the discussion below on Curing Genetic Diseases.
15. The September 2009 post More mTOR links to aging theories relates mTOR to the stem cell supply chain, and much of the content of that post is already embodied in the above discussion.
The October 2011blog entry In-vivo
cell reprogramming for longer lives unifies three themes that have
repeatedly been expressed in my blog and this treatise: 1. The possibility
of extending lives via using “rebooted” cells, that is induced pluripotent
stem cells (iPSCs), 2. the key role of epigenetic factors in determining the
health and longevity of cells, and 3. the health-producing and possibly life-extending
properties of certain phytochemicals like curcumin and resveratrol.
The October 2011blog entry In-vivo cell reprogramming for longer lives unifies three themes that have repeatedly been expressed in my blog and this treatise: 1. The possibility of extending lives via using “rebooted” cells, that is induced pluripotent stem cells (iPSCs), 2. the key role of epigenetic factors in determining the health and longevity of cells, and 3. the health-producing and possibly life-extending properties of certain phytochemicals like curcumin and resveratrol.
The October 2011 blog entry Progress
update on induced pluripotent stem cells reports on the extraordinary
pace of research related to induced pluripotent stem cells (iPSCs), a technology
stream that has been widely heralded as key for organ regeneration, for regenerative
medicine, and that, as I have pointed out, has the potential to enable very
Progress update on induced pluripotent stem cells reports on the extraordinary pace of research related to induced pluripotent stem cells (iPSCs), a technology stream that has been widely heralded as key for organ regeneration, for regenerative medicine, and that, as I have pointed out, has the potential to enable very long lives.
The June 2012 blog entry Insights
into the epigenetics and rejuvenation of adult stem cells - Improving prospects
for extraordinary longevity reports on an important new technique
for reversing senescence in adult stem cells, again contributing to the future
possibility of breaking the 122 year human age limit by providing the body
with unlimited stem cell self-renewal capabilities as discussed below here.
The June 2012 blog entry Insights
into the epigenetics and rejuvenation of adult stem cells - Improving prospects
for extraordinary longevity reports on an important new technique
for reversing senescence in adult stem cells, again contributing to the future
possibility of breaking the 122 year human age limit by providing the body
with unlimited stem cell self-renewal capabilities as discussed below here.
Insights into the epigenetics and rejuvenation of adult stem cells - Improving prospects for extraordinary longevity reports on an important new technique for reversing senescence in adult stem cells, again contributing to the future possibility of breaking the 122 year human age limit by providing the body with unlimited stem cell self-renewal capabilities as discussed below here.
One of my blog pots points out how defects in two genes, Fas and FasL are implicated in a number of diseases and may cause such diseases or increase susceptibility to them. The post leaves open the question of what can be done for people with such defective genes and suffering from associated diseases. I speculate that the treatment process will turn out to be something like this:
1. As a first step, a few drops of blood or a tiny piece of skin would be taken from a person suffering from a disease known to be associated with certain defective genes that have been detected in the patient. For example the defective genes could include Fas and FasL in the case Lupus or Lymphoma .
2. The cells in the blood or skin would be reverted to being induced pluripotent stem cells, known as iPSCs. Technolgy to do this is now being perfected. See the post Rebooting cells and longevity.
3. Using laboratory techniques of gene splicing, sometimes called DNA editing, the defective Fas, FasL and/or possibly other defective genes will be stripped out of the chromosomes in these cells, and good versions of the same genes pasted in their place. This is accomplished by established techniques of genetic engineering. The results will be the patient’s own pluripotent stem cells with good genes in place of the defective ones. Call these corrected induced pluripotent stem cells ciPSCs.
4. The ciPSCs will be encouraged to reproduce in the laboratory to increase their numbers. This is something commonly done.
5. The ciPSCs will be introduced back into the patient under conditions that they will differentiate into the stem cell types and somatic cell types involved in the disease process. Discovering exactly how to do this is probably the major challenge involved in the whole process. Success has already been realized in getting embryonic stem cells which are like iPSCs to differentiate into certain cell types. See the July blog post Embryonic Stem cell research news. Also, we know no immune reaction can be expected because the ciPSCs are the patient’s own cells.
6. As the ciPSCs reproduce and differentiate in the body, they will produce adult stem cells and differentiated tissue cells that are free of the genetic defect. The genetically corrected cells will supplement and possibly in time replace the genetically defective ones. In principle at least, as fewer and fewer body cells possess the genetic defect and more and more are normal, susceptibility to the disease should decrease, the hope being that the disease will go away. The process can be compared to replacing defective car parts with rebuilt ones from the original manufacturer.
Why such a complicated process using corrected induced pluripotent stem cells? If the disease is in T-lymphocytes for example , why not just collect some T-lymphocytes from the patient, correct the genetic defects in them, reproduce them and introduce them back into the body? I think a major problem would be that the body’s hematopoietic stem cells that make new T-lymphocytes would continue to have the genetic defect in them and would continue differentiating and producing new defective t lymphocytes. So, I believe it will be necessary to go to the stem-cell level to have a lasting fix. Many genetic engineering experiments have been tried with ordinary cells but with only poor or mixed success.
If the kind of treatment
process I outlined can be realized and fine-tuned, it could possibly be used
to control or vanish most diseases related to genetic defects, not just defects
in Fas or FasL. 5Type AWe have already seen a positive result using this kind of process in laboratory
animals. Mice have been rescued from sickle cell
anemia this way(ref).
Also, this general approach has been used to cure human cells of Fanconi-anemia.
"Most importantly, we show that corrected Fanconi-anaemia-specific iPS
cells can give rise to haematopoietic progenitors of the myeloid and erythroid
lineages that are phenotypically normal, that is, disease-free. These data
offer proof-of-concept that iPS cell technology can be used for the generation
of disease-corrected, patient-specific cells with potential value for cell
Mice have been rescued from sickle cell anemia this way(ref). Also, this general approach has been used to cure human cells of Fanconi-anemia. "Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications(ref)."Very recently, research has been reported in applying this general approach to "familial dysautonomia (FD), a rare but fatal neuropathy that has been impervious to functional analysis and drug validation(ref)."
To get to live to age 200 or 300, you have to live to 100 first. The dietary supplements may help you live a very long life but are almost surely insufficient to get you to 100 without adoption of a healthy lifestyle. In fact, the dietary and lifestyle recommendations go hand-in-hand and support each other. For example, some of the supplements can help with weight loss; others can support stamina for exercise; others yet can help provide mental clarity for intellectual activities. Likewise, mental clarity can help provide the resolve necessary for following both the lifestyle regimen and the supplement regimen.
Many of the lifestyle recommendations listed above show up in several firewalls. I pull them together into a single list here, adding a few more tips. They are closely parallel to the “conventional wisdom” of longevity that appears frequently in popular books, news reports, articles, Blogs and folk tales. There is now an increasing body of research that reveals the biomolecular mechanisms underlying such conventional wisdom. For example, exercise changes the body’s biochemistry by activating a number of genes and stimulating neurogenesis, hormonal, histological and other positive changes. And exercise appears to help preserve telomere lengths.
Also, large-scale population studies strongly support this conventional wisdom. For example, a study(ref) of 2357 healthy men (mean age, 72 years) within the Physicians Health Study looked at biological and key lifestyle factors that contribute to living to 90 years of age. “The probability of a 90-year life span at age 70 years was 54% in the absence of smoking, diabetes, obesity, hypertension, or sedentary lifestyle. It ranged from 36% to 22% with 2 adverse factors and was negligible (4%) with 5.”
Specific reasons for most of these recommendations are already given in the discussions for the firewalls. While the list seems very long, once these behavioral prescriptions are internalized they recede into the background and are recalled only when needed – like at a party where everyone seems to be gorging on beer, sugar sodas, pork rinds, twinkies and potato chips.
I suggest that you consider studying the science of nutrition if you are not already doing so. I have published a number of blog entries on the topic, the latest being Cancer, epigenetics and dietary substances. And the blog entry Public health longevity developments - focus on foods focuses on public health initiatives to create healthier diets supportive of longevity.
The blog post Exercise, telomerase and telomeres relates to how exercise promotes the expression of telomerase in cells and therefore promotes longevity. I suggest 45 minutes a day of mildly cardiovascular exercise such as swimming, vigorous yard work, cross-country skiing or walking at a brisk pace. In the winter in New England, many days I do 47 minutes of walking at a pace of 2.8mph and incline of 5 on my treadmill. A TV in front of the treadmill with a DVD player helps to keep my mind busy. I tend to use the machine during my favorite news-hour which helps keeps me on a daily exercise schedule. It is good to pursue a variegated exercise program, one that involves multiple joints and muscle systems. When possible I swim, simulatneously exercising a number of my muscle and joint systems. Balancing and proprioceptive exercises, ones that involve whole-body movement and awareness of states of body positioning, can help older folks maintain stability in movement and prevent debilitating falls. Some of the marital arts like Judo and Tai Chi can do the same. And so can dancing and playing ping-pong, tennis or basketball. Stretching exercises can also be important for staying coordinated and maintaining ease and range of motion. Exercise with weights can be used to maintain muscle and bone mass.
A gene coactivator known as PGC-1alpha is central to the metabolic process and appears to be the mediator of health benefits produced by exercise. A comprehensive discussion of this can be found in the blog entry PGC-1alpha and exercise.
Sleep and Rest
Be in a regular daily rhythm of wakefulness, activities and sleep. Sleep 7 to 9 hours a night on a regular schedule. I find taking 3mg of melatonin a half-hour before bedtime helps me to go to sleep promptly. Get ample rest and sleep when recovering from infections or diseases. The blog entry Sleep and longevity reviews a number of studies relating length of sleep to longevity.
Avoid or Minimize
Avoid circumstances that produce large number of free radicals (ROS) in the body. Avoid unnecessary x-radiation and exposure to microwaves. If your doctor recommends a cat scan, make sure it is really necessary. And if you do have to have a cat scan, fluoroscopy or other intensive X-ray procedure, load up on antioxidants before and after the event. Absolutely do not smoke and avoid breathing second-hand smoke. Use protective clothing, sunglasses and sunscreen under outdoors sunny conditions. Do not use tanning booths. Avoid exposure to heavy metals and toxic chemicals. For example, avoid handling arsenic-containing pressure-treated lumber without gloves or breathing the smoke of it burning. Do not consume liquids that are in plastic bottles that have been frozen or overheated, such as water bottles baked in a car in the summer sun. Avoid situations likely to lead to infections. Wash your hands frequently; many infections are communicated by touch. Avoid unnecessary stress, be it physical, circumstantial or emotional. Too vigorous exercise can be harmful or dangerous.
Avoid contact with carcinogenic chemicals and substances like tars, paint removers, solvents and insecticides.
Avoid end-game thinking when it comes to life, ideas like “Now that I am retired I don’t have to do anything and can just take it easy” or, “After I stopped working, nobody seems to be interested in what I can contribute anymore.” If you want to live for a very long time, adjust your thinking and life planning accordingly. If you really believe in longevity, you can use the same life-planning approach when you are 78 that you used when you were 28.
Minimize eating substances having a high glycemic index, that is, sugars and starchy substances your body converts to sugars. No candy bars, though a little 70% chocolate is OK. If you must eat ice cream, make it just a little. And don’t be fooled: frozen yoghurt has just as much sugar even if it is "low fat." Avoid sugary or caffeinated “power” soft drinks. Avoid junk foods that contain calories or fats and few nutrients like twinkies and potato chips. Avoid fried foods, fast foods, hydrogenated oils and ones preserved with nitrites. Eat mercury-containing fish like tuna or swordfish only once a week. Be careful eating raw seafood that might come from contaminated waters. Avoid excess consumption of coffee. I normally drink two large cups of 50% decaffeinated and 50% caffeinated coffee per day, mostly in the mornings.
Don't poison your brain with excess alcohol, toxic or illegal drugs. Damage could be permanent. Avoid usage of over-the-counter or prescription medications unless you really need them and fully understand what they are doing and their negative as well as positive impacts. Pay attention to the fine print. And don't expect all the possible negative impacts to appear in the fine print. For example, many medications can inhibit the expression of telomerase or the proliferation of progenitor and stem cells
With respect to glycation, avoid eating large amounts of substances where glycation has occurred, including burned or browned meats and fast foods of all kinds. Eat foods cooked at lower temperature, avoiding those cooked by grilling, broiling and frying.
Don't microwave or cook food or beverages in plastic containers.
If you can live where there is good air quality, do so. If you live in a city or location with polluted air, use a HEPA air filter in your workplace and bedroom at night. Wear sunglasses outdoors in the summer to help protect against cataracts. Even if it might feel good, sun damages your skin. Protect yourself with a wide-brim hat outdoors in the summer or at high altitudes. If your water supply is poor or heavily chlorinated, install a high-performance filtering system for your drinking and cooking water, one that can filter out lead and other heavy meals as well as microbes. And of course, don’t swim in tropical waters infested by parasites. . If you have to spend time in a city where the air is heavily polluted by particulate matter like Mexico City or Sao Paulo, you can bring along a small portable electrostatic particle precipitator which you can use in your hotel room.
Adopt dietary habits featuring large amounts of fruits and vegetables, some fish, moderate consumption of meats and consciously limit eating foods that contain excessive omega-6 fatty and trans- fatty acids. Cook foods only at moderate temperatures and avoid browned food. Use plenty of olive oil and drink ample amounts of green tea. Good foods include blueberries, sardines, and broccoli. Consider a Mediterranean Diet which features eating lots of vegetables and fruits, lean protein, fish, whole-grain pasta, lots of olive oil and moderate amounts of red wine. You can consume a moderate amount of dark chocolate daily – with 70% or greater cacao content. A small number of mixed nuts every day can also help. In any event, consume alcohol only in moderation. A small glass of red wine at dinner might help.
Substitute healthier foods for “bad” ones. For example, products containing corn syrup, soft drinks, sweetened breakfast cereals, white bread, refined-flour pastas and sugary deserts rank high on the glycemic scale and are “bad,” while whole-grain cereals, fruits, leafy vegetables and soybeans rank lower on the scale and are better.
Monitor your health
Maintain your weight within normal ranges. Monitor and maintain normal blood pressure, preferably under 130/70.. Take full advantage of the resources of your health provider. Have your blood lipids and c-reactive protein checked regularly. Have annual physical exams and other lab tests and examinations appropriate to your age and specific medical conditions. Have regular dental exams and cleanings and keep your oral health and teeth in shape.
Good mental and social habits
There is evidence that a positive mental attitude and regular participation in intellectually-challenging activities contribute towards longevity. As for your brain, “Use it or lose it. ”Social participation is also important. Enjoying the companionship of a partner, intimate friends or relatives seems to be key factors correlated with extended longevity. Meditation, Tai Chi, Yoga, Judo and Karate are thought also to be powerful tools although I do not practice these myself.
Avid and regular pursuit of work, travel or a hobby can be helpful. Obtain prompt and competent treatment for any infectious disease. Get orthopedic problems that are fixable by surgery (like a torn rotator cuff) fixed. If you are laid up by a sickness, broken leg or other orthopedic problem, do not withdraw. Instead, find forms of exercise that will work and keep intellectually and socially busy anyway. Do physical therapy to get yourself back in full operating condition as soon as possible. Find and stay in contact with a doctor or health practitioner concerned with keeping you healthy as well as with fixing any problems you may have. Link-up with others committed to life extension and health. And stay on your anti-aging supplement regimen.
The table below summarizes the supplements I recommend for the firewalls and daily doses.
First a comments on “Why so many pills,” and “How effective are these firewalls?” When I have shared some of the information in this article with friends and colleagues I have been typically told “I would like to start some of those supplements myself but don't want to take all those pills in your combined firewall. Can you tell me the ones that are REALLY important?” I have therefore come up with a top-10 supplements list, but I know it is not sufficient to provide the protection of the firewalls listed here. There is a common but false cause-and-effect presumption that if there is a problem there probably is some single solution to it – like a cure for cancer, a magic bullet solution. Unfortunately, things don't work that way. The bodies of higher animals are extremely complex, and so are the signaling systems, cells, genes and epigenetic materials. Hundreds if not thousands of genetic pathways are involved in aging processes. No supplement or substance I know of “cures” aging according to any theory. Instead, it appears that multiple approaches are required to address any of the underlying causes of aging.
The approach I take is use of multiple supplements with different but overlapping and synergistic affects. Most of the supplements I discuss here are pluripotent. Again, they have multiple positive effects. I already mentioned how there are many different antioxidants that operate through different cell and body mechanisms and accomplish different results. L-carnosine, for example, is a powerful antioxidant, is an important anti-glycating agent, helps chelate toxic metal molecules out of the body and may help regulate blood glucose levels. Vitamin C has been extensively studies and shown to have powerful effects in many domains including inflammation, glycation, nervous system health, cancer and cardiovascular diseases. Resveratrol is another powerful antioxidant that works on a genetic level to suppress tumor formation. It generates a chain of genetic-biochemial events involving the SIR-1 gene that may well enable 20% to 30% life extension in humans since it does so in many more primitive species.
Pluripotency of these substances is more the rule than the exception. A few decades back Vitamin D was seen to be useful mainly for bone maintenance for those deprived of sunlight. The medical establishment sternly warned that any daily dose over 400iu could be seriously toxic. It was not thought of in terms of cancer prevention. Today there are over 80 population and laboratory studies indicating that vitamin D can reduce incidences of and mortality due to multiple kinds of cancer with reductions of 50% or more in some cases. The biological impact of this substance is far from simple; it activates 200 or more human genes and has differential affects in regulating cancer cells with respect to cell proliferation, apoptosis and differentiation. It also regulates angiogenesis. Several studies of nursing home and residential care residents show that people taking vitamin D supplements suffer fewer falls – the reduction being between 23% to 53%. See the blog entry Vitamin D - don't fall for it. And I have already mentioned Vitamin D’s role with respect to reducing heart disease fatalities. Daily doses of 1,000 or 2,000iu are now thought to be harmless and often recommended for older people.
I repeat that the other side of pluripotency is that no one of the supplements is by itself a magic bullet cure for any specific disease of old age. The firewall substances can work through known biological and genetic mechanisms, exercise important positive effects, and improve the probabilities of positive outcomes. Causes and diseases of old age are very complex and work through many pathways. A breast cancer may involve modification or changed activity of 1,000 genes or more. Recent research shows that if one of the pathways essential to a kind of cancer is blocked by a drug, the cancer cells will simply modify themselves to use an alternative pathway. Simultaneous attacks on multiple biochemical pathways appear to be necessary to stop certain cancers. Many of the seemingly-simple individual herbal substances in the combined firewall act in multiple complex ways. A study, for example, shows that ashwagandha kills cancer cells via at least five different pathways: p53 signaling, GM-CFS signaling, death receptor signaling, apoptosis signaling and the G2-M DNA damage regulation pathway. Likewise, combining several substances with varied forms of action, the combined firewall offers simultaneous attacks on multiple pathways related to cancer and the other “causes” of aging.
The substances in the combined firewall are discussed in various contexts in a number of my blog entries, for example in Diabetes Part 2: Lifestyle, dietary and supplement interventions and in Alzheimers disease studies validate anti-aging firewalls suggestions.
Underlying the firewall concept is the idea of creating a multiplicity of defenses against multiple causes of aging taking advantage of multiple biochemical and bio-genetic strategies. Some substances in the combined firewall can produce somewhat similar results. But they can work in different ways and also produce some strikingly different results. For example, curcumin, resveratrol and epigallocatechin gallate (ECGC, an active ingredient in green tea) are each anti-oxidants, anti-inflammatories and have cancer-fighting properties. Yet, a recent study shows that resveratrol is protective of colon epithelial cells from harm created by the bile salt deoxycholate but curcumin and EGCG are ineffective in this regard.
Controversy crops up from time to time in the popular press about the safety of taking large doses of certain vitamins. I do not suggest taking very large doses of any substance. The general approach I take is to utilize normal doses of multiple supplements in a firewall rather than mega-doses of one or two supplements. The reasons for this are safety as well as enhanced effectiveness. The doses I suggest are generally within the range of ordinary supplement usage and are generally regarded to be safe for people with normal medical histories. However, taking certain of the supplements could be inadvisable for people with particular medical conditions, taking particular drugs, or possessing unusual gene variations. For example, it many be inadvisable for people taking immune system suppressants to also take astragalus or astragaloside IV supplements. Dietary supplements are not tightly regulated in the US and may vary widely in purity and quality. It is important to use reputable suppliers with high established quality standards. And many herbal and other supplements may produce side effects under particular circumstances. Responsibility for safety of supplement use must rest with the reader and his or her medical advisers, not with the author or any publisher of this document.
I can't explain all the known benefits and issues associated with each supplement here; that would require a much longer paper and more knowledge than I have. And, for several of the supplements, the benefits as well as the underlying biochemical mechanisms are not yet completely understood. However, I do want to mention that many of the supplements are known to be powerfully synergistic with one another. Coenzyme Q-10, for example, can recycle reduced forms of vitamin C and E, helping maintain the levels of those antioxidants in the body under conditions of stress. Another example demonstrated in animal studies is that when Carnosine and alpha-tocopherol are co-administered, the result is significant amplification of the therapeutic biopotency of both. In one study, a combination of alpha-tocopherol and Carnosine was administered to rabbits with atherosclerosis induced by feeding them polyunsaturated fatty acids. A 10-fold decrease of the impaired aortic area was observed. A recent research report indicates that, even at low concentration, lycopene and EPA synergistically inhibits the growth of human colon cancer HT-29 cells. Resveratrol and quercetin are chemical cousins which in combination prevent the growth of or facilitate the apoptosis of 3T3-L1 fat cells.
Do any of the supplement’s interfere with each other so as to create a dangerous combination? Not to my knowledge, and such situations are not described in any of the studies I have encountered. This is always a possibility, however, particularly for people with unusual gene variations.
How effective are the firewalls I am proposing? I don't know. There is published reseaarch evidence to support all of my assertions.
The firewall suggestions, both for following certain lifestyle patterns and for taking certain supplements, are based on scientific research even though some of them are also supported by folk lore or conventional wisdom. But what is the nature of this scientific research? It can be of several different kinds, including:
1. Macroscopic studies of large populations. These studies involve looking for correlations among selected factors. An example is a study of centenarians on Okinawa, an island where an unusual number of people live a long time. This study of some 900 centenarians, their families and control groups helped identify specific genes and gene polymorphisms that appear to contribute to longevity as well as contributing lifestyle factors, including eating relatively few calories, exercising and not smoking or consuming alcohol. And of course in Okinawa people eat lots of fish and drink green tea. These studies can reveal interesting correlations and clues. For example, the Okinawa study established that the centenarians studied have genetic polymorphisms that place them at lower risk for inflammatory and autoimmune diseases.
2. Large population cohort studies. These are studies that follow cohorts of thousands, tens of thousands or even hundreds of thousands of people over 10-20 or longer year periods, like the Woman’s Health Initiative or the Framingham Heart Study or the Bogalusa Heart Study. Again, they look for correlations such as the effect of smoking or being overweight on cancer incidence or longevity. These studies have been particularly useful for establishing the validity of conventional wisdom as related to longevity, such as clearly documenting the effect of having a positive mental attitude on longevity.
3. Controlled clinical trials. These are carefully controlled double-blind studies that proceed in well-defined phases, i.e. safety, dosage and then effectiveness. They are typically pursued for drug certification and may involve anywhere from a few dozen to thousands of carefully selected people over a test periods of several months for the final phase. These studies are usually quite narrowly focused and yield limited information with respect to longevity. For example, a list of clinical trials for patients diagnosed with gliablastoma, an incurable brain disease, can be found here. These trials are very specific with respect to substance being tested, patient conditions and their relationship to other therapies. Clinical trials typically cost tens or hundreds of millions of dollars so there is no incentive for a drug company to study a promising natural substance that is in the public domain. Also, for longevity purposes, a six-month study is not likely to tell much. If we wanted to test some kind of longevity concoction that we thought would double human life-spans, a clinical trial would have to be run for 40-100 years to yield definitive results.
4. Animal experiments. Mice and rats are genetically very similar to humans but live only 2-3 years, so are excellent subjects for longevity-related experiments. The studies can be quite technical and very narrowly focused. Here is an example relevant to the cell nuclear factor NF-kappaB known to be relevant to human longevity: Maintenance of NF-κB Activation in T-Lymphocytes and a Naive T-Cell Population in Autoimmune-Prone (NZB/NZW)F1 Mice by Feeding a Food-Restricted Diet Enriched with n-3 Fatty Acids. In combination, though, these studies can yield important insight. We know of several approaches that can extend the normal lifespan of mice by 30% to 50% We are not sure how many of these approaches will scale-up to work for humans but these experiments are providing valuable clues and are a source of optimism for longevity aficionados like me.
5. In-vitro and in-vivo studies of cell populations. There is a great number of experimental studies going on that look at specific cell populations under particular conditions that that have a bearing on longevity. For example, many such studies look at neurogenesis and adult stem cell differentiation as impacted by specific gene activation cascades and particular proteins, or as stimulated by certain dietary substances. These studies can yield specific nuggets of insight such as the roles of key proteins and activation factors like INK4a, P-53, and NF-kappaB. Again, there are very many of these studies and they can be quite technical each yielding a single piece of the immense longevity puzzle. An example related to eating pigmented fruits is A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer PC3 cells in vitro and in vivo: involvement of nuclear factor-kappaB signaling.
6. Synthesis and review studies. These are studies that consider results together from possibly many experiments and look at them in terms of the powerful forefront areas of genetics, cell signaling cascades, gene activation, genomics and epigenomics. They also draw on knowledge from related areas, such as computational genomics, epigenomic and protein-folding databases. Some of these studies are starting to link gene expression factors to longevity, such as described in We have identified various cell signaling cascades directly related to longevity such as the This axis seems to be the one that is involved in achieving longevity via calorie restriction. And it also seems to be activated by taking the supplement resveratrol.
All the actions and supplements in the anti-aging firewalls are based on one or more of these kinds of research. Most are supported by several of these kinds of research and, for a few firewall elements, supporting research exists on all of the above levels. For example, the value of green tea as a cancer preventative is established on all of the above levels as are the actions of Vitamin C and the value of regular hard exercise for longevity in general.
It is clear that radical life extension — to beyond age 110 — must depend on knowledge associated with the newer and more sophisticated ongoing studies in epigenetics, molecular biology, and medical research. Research suggests that certain substances already in the anti-aging regimen may act powerfully toward this end, but what they can actually do for human life extension will not be clearly known for many years. These substances include:
- Use of r-alpha lipoic acid and acetyl-l-carnitine to address cell mitochondrial longevity and inhibit unwanted cell apoptosis (self-destruction).
- Use of resveratrol or resveratrol homologs to activate the SIRT1 and FOXO3 “longevity” genetic pathway, the pathway known to confer life extension due to calorie restriction.
- Use of combinations of green tea, curcumin, and other phyto-substances for their powerful cancer-preventative effects and cardiovascular benefits that operate through genetic mechanisms
Extensive additional research will be required to test, refine and improve the firewalls, perhaps requiring another sixty years before they become optimal. A real clinical trial of the life extending capabilities of each of the firewalls would require many years and testing the entire program would require over more than 100 years. Personally, I can't wait. Besides, what is in the best firewalls will continue to evolve with time. The state of our knowledge with respect to the topics in this treatise is rapidly shifting to where it is increasingly based on hard science. From time to time, I report in depth in my blog on research findings relevant to specific firewall substances, examples being Health and longevity benefits of plant polyphenols - focus grape seed extract, Focus on ginger, and Neurogenesis, curcumin and longevity. I also occasionally update the supplement regimen based on new knowledge. A 1956 computer was vastly superior to a 1950 computer and a 1960 computer was vastly better yet. This pattern of improvement continues until today – 56 years later. The same is true today in the biotech-longevity field where we are near the start of a corresponding 60-year development period. Every week seems to reveal one or more new studies that bring new insight to the foreground. Back in 1956 for scientific and business purposes, having, a 1956 computer was vastly superior to having none at all. The philosophy of this paper is that right now for health and anti-aging purposes, a 2012 firewall regime is vastly better than none at all.
Tests are becoming available which will allow individuals to test their genes for variations which point to susceptibility to a wide variety of diseases. As time progresses, knowledge grows and genetic profiling becomes more widely available, more people will know they possess gene mutations which increase their susceptibility to any of a number of age-related conditions such as Alzheimer’s disease and diabetes. I expect it will also become possible to modify the firewalls for such individuals to give them more focused protection. Both medicine and health-maintenance will become more individualized.
Are my 135 pills a day an overkill? Perhaps. Perhaps I could eliminate taking 20% of them. Perhaps. The issue is that I don't know which 20%. How many more years of life span will these firewalls buy you or me? Again, I don't know. Part of the answer depends on your genetic makeup, age, lifestyle and history of course. But that ducks the question. Even if you were an “average” 65 year-old I would not know. Personally, in 2012 at the age of 82, I am looking for another 138 good years. Clearly this will require new breakthroughs and my hope and expectation is that these constantly improving firewalls will keep me going until these breakthroughs come along.
Finally, I need mention that a few of the supplements I take are primarily for specific conditions, like glucosamine to ward off osteo-arthritis and stinging nettle and saw palmetto for prostate health. These and others are interim firewall components, useful until substances that address the underlying issues become available. For example, I take pregnenalone and DHEA supplements because levels of these and their daughter hormones plunge down with age. I do not now know how to address the more root issue: why these hormones drop so steeply with age. If a new bio-genetics approach is found that keeps the level of natural production of these substances up despite age, then I could discontinue those hormone supplements.
TABLE I – SUPPLEMENTS IN COMBINED FIREWALLS
Vitamin C - 2gm
1gm morning, 1gm evening
Vitamin D-3 – 2000 IU
Probiotic - 10 major strains + fructooligosaccharides, a prebiotic
Curcumin extract – 1160 mg
B-50 complex - (50 mg for most)
Vitamin B-12 - 500mcg
Benfotiamine – 80mg
Vitamin B-6 – 100mg
Pantothenic acid – 500mg
Folic acid – 900mcg included in B-50. Do not exceed
N-Acetyl Cysteine (NAC) 600mg
Chelated copper 2.5mg
Potassium gluconate 100mg
Calcium (as carbonate, aspartate, citrate) 1 Gm
Magnesium (as oxide, aspartate, gluconate) – 500mg
Zink (as oxide, aspartate, gluconate) – 30mg
Selenium – 200 mcg
R-alpha-lipoic acid 200 mg
L-carnosine - 500mg
Before breakfast, before bed
Co-enzyme Q-10 – 300mg
Bitter melon extract (mordica charantia) 500 mg
Bromelain – 250mg
Lycopene – 15mg
Quercetin – 500mg
Ginkgo Biloba extract (stand. to contain 24% flavone glycosides and 6% terpene lactones) - 60 mg
Saw palmetto (stand. to 85-95% fatty acids) – 200mg
Ashwagandah extract (stand. to 1.5% withanolides) - 470mg
Boswellia Seratta (stand. to 70% organic acids and 20% boswellic acid)extract - 300mg
Astragalus extract (stand. 0.5% astragalosides – .25gm
Horny Goat Weed Extract (Epimedium
Olive leaf extract (stand.to 20% oleuropein) - 750mg
Green tea extract (stand. to 60% polyphenols) – 1.5gm
OPC grape seed extract (stand. 120 seeds/mg)
Omega-3 oils: DHA - 400mg; EPA - 800mg
Three morning; one evening
Micronized resveratrol - 250mg
Avena Sativa 19:1 extract – 1,150mg
Allicin or garlic extract- 1gm
Milk Thistle Extract (Silybum
Bacopa (Bacopa monnieri) (whole
Stinging Nettle Each capsule supplies 250 mg of stand. nettle extract (1% silicic acid) and 270 mg of powdered root.
Phosphatidylcholine – 385mg
Glucosamine sulfate 750mg -- Do not exceed
Piracetam - 800 mg
Meclofenoxate (centrophenoxine) - 500mg
Pregnenalone - 60mg
PQQ - 10mg
Melatonin - 3mg
As of March 31, 2010, over two years have elapsed since the original formulation of this treatise. During that period, several additional molecular phenomena and pathways that relate to aging have come to my attention. These have been identified and to some extent discussed in the blog that corresponds to this treatise or in a note in the treatise itself. Some of these suggests an additional candidate theory for what drives aging. I do not wish to identify these yet as theories of aging in this treatise because they are relatively new to me at least, and sometimes sketchy. Much is still to be learned about each of them. Some of these candidate theories may eventually be subsumed under one or more of the 14 theories already laid out above. Effective anti-aging firewall interventions against the aging processes described by the first five of these candidate theories either do not exist now or are unsafe for non-research use. I describe and comment on each of those candidate theories here: 15. Incorrect protein folding, 16. Accumulation of progerin, 17. Gene mutations leading to hellicase abnormalities, 18 Increasing mTOR signalling, 19. Declining hypoxic response, 20. Epigenomic changes in DNA methylation and histone actetylation, and 20. Micronutrient triage with aging. In May 2009, I integrated one such candidate theory 20. Epigenomic changes in DNA methylation and histone actetylation into the discussion of the 13th main theory of aging Programmed epigenomic changes. Finally I will briefly discuss a gene that may be involved with etraordinary longevity known as Klotho.
One candidate for an additional theory of aging in this Anti-Aging Firewalls treatise is Misfoldings of proteins. The basic notion is that stress often leads to the misfolding of proteins, a process that can accelerate with age creating dysfunctional conditions and vulnerability to a number of diseases. Misfolded proteins cannot perform their intended functions and can create active mischief. This is a relatively new area of science and is to a large extent still unexplored. Here is a simplified preview.
Biology gets things done using proteins, which are encoded by various genes. Proteins are the building blocks of our body tissues; they can also be enzymes, hormones, antibodies or be intercellular and extracellular signaling molecules. Proteins can be very large molecules, consisting of 20,000 or more amino acid units. Each protein begins through tiny ribosomes in the cell cytoplasm reading instructions from messenger RNA which comes from the cell nucleus. The ribosomes act to link up amino acids in a long linear chain (polypeptide) in a process called translation. Each amino acid in the chain attracts or repels the other amino acids in a complex electrochemical way, soon causing the protein to fold up naturally into a characteristic 3-dimensional structure for that protein – a sort of automatic origami folding process. The folding may take a microsecond or up to a minute. In the process new electron bonds are formed among the amino acids determining many of the chemical and biological properties of the protein. The shape of the protein helps determine its functionality.
The way the folding process takes place and the ultimate structure may also depend on surrounding conditions in the cell, and folded proteins can become parts of larger macromolecular structures. Proteins interact 3-dimensionlly with other proteins and the structures can fit into each other like locks and keys. Many proteins may have to unfold to do their work. Whether and how proteins are folded or unfolded affects their capabilities to perform a number of important functions, including their ability to activate genes or function as enzymes or antibodies. Protein folding and unfolding are involved in a number of critical cellular processes related to aging like apoptosis, stem cell differentiation and telomerase acting to extend telomeres. A simple introduction to the subject of protein folding as it relates to aging can be found here.
Lots can go wrong in the folding and unfolding processes and the building of larger molecular structures. Sometimes proteins can fold improperly, potentially resulting in a number of cancers or devastating neurological and degenerative diseases including Huntington's and Parkinson's disease and cystic fibrosis. Clumps of misfolded proteins are thought to cause the symptoms of Alzheimer's and Mad Cow(BSE) diseases. Self-assembly can go screwy such as in the case of Amyloidosis where proteins abnormally assemble into insoluble fibrils that impair organ function(ref). Benign folded proteins can unfold and refold into deadly types.
The rate of protein misfolding seems to increase with age and misfolded proteins are implicated in many of the major diseases of aging. Cellular machinery exists to get rid of misfolded proteins but doesn’t always work right. A category of proteins called chaperone proteins has evolved, their purpose being to assist in the processes of folding, unfolding, building of larger structures, and repairing folding errors. Chaperones also play other roles such as assisting in the translocation of proteins into organelles. Heat shock proteins are chaperone proteins that work to ensure proper folding processes under heat, oxidative and other forms of stress. It appears that thermodynamic stability is critical to the biology of proteins.
Protein folding is a hot research frontier area, looked at by many as one of the great little-explored mystery areas of molecular biology. The research area is rich in what it may tell us about signal transduction mechanisms, intracellular transport, turnover of normal and misfolded proteins, cell differentiation and development, malignant transformation, misfolding diseases and aging. Much of the study of protein folding is currently being done in the contexts of neurological diseases and cancers, two of the aging-theory areas covered here. But the research is likely also to be relevant to aging in several other ways. Stress, for example, particularly heat and possibly oxidative stress, can impair the proper folding of some proteins. Unfolded proteins in the endoplasmic reticulum appear to generate reactive oxygen species which lead to cell apoptosis; antioxidants can both reduce misfolding and enhance cell survival(ref). Stress-induced interference of protein folding may be responsible for some of the pro-apoptotic effects of resveratrol on colon cancers(ref). Telomerase expression is an aging-related area where there is active ongoing research related to the folding structures of telomerase components(ref)(ref). And I suspect protein folding disorders may be related to the accumulation of lipofusin and AGEs.
While it is known that protein geometry and the folding and unfolding processes are essential for biological processes to take place, how this works in specific instances is still largely unknown. Sophisticated tools are used in protein folding research like the Atomic Force Microscope which can exercise forces which unfold proteins(ref). Another new technology for studying protein unfolding is called pulse proteolysis. One promising approach has been based on a predictive computer program called Rosetta which combines data from nuclear magnetic resonance imaging and X-ray diffraction imaging to identify possible protein molecule structures(ref). Protein folding is too complex a process to predict without intense use of computer modeling. Determining the various ways proteins can fold and the kinetics of folding is a daunting computational problem. Even the largest supercomputer cannot analyze all the possible geometrical configurations for a large protein molecule in a reasonable amount of time. A protein may fold in a microsecond but it could require 30 years of CPU time to simulate that event thoroughly. A distributed computing initiative has been launched to tackle this task of studying protein folding and misfolding for specific proteins. The idea is to get thousands or tens of thousands of people to lend their PCs to work on the problem when their PCs would otherwise be idle. You can sign up to participate in that initiative here. An increasing number of papers on protein folding are being given at conferences and new research techniques are being reported(ref). So we can expect to hear a lot more about protein folding in the coming months and years.
At the moment it is difficult for me to identify additional specific knowledge derived from the area of protein folding/unfolding that can be translated into an anti-aging firewall, though there are a few initial hints. For that reason, I am not yet integrated Misfoldings of proteins into this paper as a theory of aging. However, I am on the lookout for such knowledge and expect to report back on this topic as I learn more
The aging mechanism under consideration here is that manifest in HGPS, standing for Hutchinson-Gilford progeria syndrome, an extremely rare but well-studied genetic disease. Young children born with HGPS seem to age at an extraordinary rate, exhibit many of the symptoms of old age, become wrinkled and bald, are particularly vulnerable to cardiovascular diseases and usually die of a cardiovascular disease of old age by the age of 14. Up until about five years ago neither the cause of the disease nor a cure were in sight. Then a chain of exciting research developments emerged indentifying not only cause and possible cure but also what might amount to a new theory of normal aging. The developments are complex and the puzzle is still far from complete. I attempt to summarize them here in simple language and speculate on the implications involved.
1. HGPS is caused by a mutation in the LMNA gene which is responsible for making lamin proteins which provide “scaffolding (supporting) components of the nuclear envelope, the structure that surrounds the nucleus in cells.” The mutation produces a lamin that is “farnesylated but cannot be further processed to mature lamin A.(ref)” That mutant farnesylated lamin is called progerin. (Farnesylation is a post-translational chemical modification of a protein involving addition of a farnesyl group.) In progerin, a DNA sequence of 50 amino acids which would normally appear in the lamin is spliced out.
2. Progerin targets itself to the nuclear envelope of a cell, “where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei(ref).” There is strong reason to believe it is responsible for the symptoms of HGPS(ref).
3. An obvious research idea was to see what could happen if the farnesylation of progerin is inhibited. An exciting development was the discovery that, treating cells misshaped by the expression of progerin, inhibiting farnesylation with a farnesyltransferase inhibitor (FTI) could restore their normal cell shapes(ref,ref,ref,ref). FTIs block the attachment of the farnesyl chemical group onto progerin. FTIs are a class of recently-developed anti-cancer drugs.
4. Sure enough and better yet, using the FTI drug Tipifarnib (Zarnestra) in a progeria mouse model it was possible to prevent both the onset and late progression of cardiovascular disease(ref). This led to a hope that a cure for human HGPS might be based on use of an FTI.
5. A clinical trial was launched in May 2007 to test FTI therapy in HGPS patients(ref). It was difficult finding patients because of the rarity of the disease. Twenty eight children from 16 countries are participating. The trial is scheduled for completion in October 2009 with reporting in 2010.
6. Progerin appears also to play possibly important similar roles in normal aging. Biochemical studies sugest that progerin may generate similar impacts in HGPS cells and aged normal cells and possibly a common molecular mechanism might underlie HGPS-type aging and normal physiological ageing. “Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A (progerin) whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging(ref).”
7. Supporting this idea, recent research indicates that progerin builds up in normal cells with age. A powerful new technique has been developed for measuring the expression of the progeria gene. A Swedish research group has found that both normal and progeria cells make larger and larger amounts of progerin RNA as they age(ref).
8. Supporting the idea of progerin accelerating aging even further, research indicates that progerin creates all kinds of downstream biomolecular signaling mischief, including the introduction of errors in the normal differentiation of stem cells. Progerin interferes with cell division in both HGPS and normal cells(ref). In one key study(ref), the presence of progerin produced a profound impact on renewal and differentiation of adult mesenchymal stem cells, affecting the rates at which they mature into different tissues. “Our results support a model in which accelerated ageing in HGPS patients, and possibly also physiological ageing, is the result of adult stem cell dysfunction and progressive deterioration of tissue functions.”
There are strong hints here of important possibilities
The candidate theory of aging suggested here is that aging is due to age-related accumulation of progerin in normal cells which creates age-related damage of all kinds similar to that observed in HGPS and inhibits the normal differentiation of adult stem cells into normal cells. At present I am not sure the extent to which such progerin accumulation is the cause of or the result of other age-related collateral damage and how serious its impact is. I also do not know if it may be possible to design a therapeutic intervention for normal aging based on use of FTIs. I am not sure how safe it is to use an FTI for anti-aging purposes given that farnesylation is important for protein binding and happens as part of normal biochemical body functioning. I have seen no research on the impacts taking FTIs may have on normal old people or even normal old mice for that matter.
(This description is adopted from the blog posting Werner Syndrome - another model for aging )
The aging mechanism under consideration here is that manifest in another rare form of progeria known as Werner Syndrome (WS). WS, sometimes called adult progeria, is characterized by the premature onset of age-related diseases, including inflammatory diseases, atherosclerosis and cancer. People with WS may develop the symptoms of very old age by the time they turn 30 or 40, including “wrinkled skin, baldness, cataracts, muscular atrophy and a tendency to diabetes mellitus, among others(ref).” Cells from people with WS when cultured have shorter life spans than cells from normal people. “In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions(ref).” It has recently been shown that WS is due to a mutation in a gene called WRN. It is a hellicase deficiency disease. Hellicases are enzymes important for many cellular processes including “, .” Normally, the WRN gene “ functions as a key factor in resolving aberrant DNA structures that arise from DNA metabolic processes such as replication, recombination and/or repair, to preserve the genetic integrity in cells(ref).”
Unlike the case for HGPS, there appears to be a direct link between the aging mechanisms operating in WS patients and at least one of the usual theories of aging, the telomere shortning and damage theory. For example, regarding study of a mouse model of WS the authors write “Recent studies of the telomerase-Werner double null mouse link telomere dysfunction to accelerated aging and tumorigenesis in the setting of Werner deficiency. This mouse model thus provides a unique genetic platform to explore molecular mechanisms by which telomere dysfunction and loss of WRN gene function leads to the onset of premature aging and cancer(ref).” Some researchers highlight the roles of cell senescence and telomeres in WS: “Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts(ref).” Normal hellicase structures can be very important for assuring normal telomere structures(ref), a situation not present in WS. Other researchers believe WS operates primarily through other than telomere erosion or damage: “– our data suggest that the abbreviated replicative life span of WS cells is due to a stress-induced, p38-mediated growth arrest that is independent of telomere erosion(ref).”
The suggested candidate theory of aging in this case is that aging is due to production of defective hellicase enzymes due to mutation in the WS gene and possibly in other hellicase-related genes. There is relatively little research on how this might work in the process of normal aging. Nor, with the possible exception of telomerase activation, are there any known therapeutic interventions that might possibly work with Werner Syndrome patients or even animal models of the disease.
Looking for bridges between the genetic mechanisms operating in HGPS and those operating in WS: 1 It is easy to find commonality of end-results, specifically premature aging phenotypes like baldness, wrinkled skin and cardiovascular disease, and 2. The underlying genomic mechanisms themselves are in the first instance quite different; they involve activation of different genes and the actions of different protein products. I do not see any easy “ Ah hah, here is the common mechanism of aging involved in HGPS, WS and normal aging.” Both HGPS and WS suggest means by which normal aging might work and possibly be slowed down, having to do with accumulation of progerin and possible treatment with FTIs in the case of HGPS, and having to do with P38, telomere shortening and telomerase activation in the case of WS.
(Updated August 2010)
The aging mechanism in this case is a very ancient one having to do with so-called “longevity genes” conserved across species for over a billion years. A number of these in humans (15 or so) are also found in primitive species such as nematode roundworms (c-elegans), and are associated with the target of rapamycin (TOR) signaling pathway. The mammalian counterpart of TOR is known as mTOR.
Mammalian target of rapamycin (mTOR) is a protein encoded in humans by the FRAP1 gene. As the name suggests, mTOR is targeted by the immunosuppressive drug rapamycin, a drug used clinically to treat graft rejection and restenosis and being tested as a treatment for autoimmune diseases. “The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism(ref, ref).” The mTOR pathway is “a central controller of cellular and organism growth that integrates nutrient and hormonal signals, and regulates diverse cellular processes(ref).”
The mTOR pathway plays important role in diseases. Recent studies link mTOR to several age-related human diseases including diabetes, cancer, obesity, atherosclerosis, nephrotoxicity, cardiovascular diseases and neurological disorders. Inhibiting mTOR using rapamycin or derivative drugs offers a promising therapeutic approach for dealing with several diseases and cancer lines(ref,ref,ref). “Dysregulation of mTOR signaling occurs in diverse human tumours, and can confer higher susceptibility to inhibitors of mTOR(ref).”
The 2/2011 blog entry The many faces of mTOR and rapamycin present a sampler of recent research relating to the mTOR pathway and the effects of rapamycin, focusing on recent and longevity-related results .
Inhibiting mTOR may also offer an approach to enhancing human longevity. Decreasing TOR signaling can extend the lifespans of flies and worms. It does this by upregulation of mitochondrial gene expression resulting in decreased production of reactive oxygen species. It turns out that the new findings are relevant to at least the Oxidative damage and Mitochondrial damage theories of aging. “Reduced TOR Signaling Extends Chronological Life Span via Increased Respiration and Upregulation of Mitochondrial Gene Expression(ref)” With respect to humans, much of the machinery of TOR signaling found in more primitive species is conserved. “Recent data have also revealed that mTOR is involved in the regulation of lifespan and in age-related diseases(ref).” TOR also plays a role in the longevity-producing effects of calorie restriction(ref).
The candidate theory of human aging here is that the mTOR pathway limits life span and inhibition of this pathway might result in life extension. As mentioned, there is reason for this conjecture based on studies of molecular processes and life-extension experiments in primitive species. Moreover there is one research report indicating that rapamycin fed late in life to genetically heterogeneous mice increases both their median and maximal lifespans, by an average of 14% for females and 9% for males(ref). So, the possibility of human life extension via mTOR inhibition appears to be a real one. However, there are possibly-serious adverse effects associated with chronic intake of rapamycin, enough to throw cold water on any idea of healthy people using this substance in an effort to enhance their longevity.
I have recently (as of August 2010) come across research indicating that curcumin inhibits the mTOR pathway. Curcumin, of course, is a workhorse substance in the combined firewall regimen that I have been taking for some time. It is possible that some of the longevity-enhancing effect of mTOR inhibition by rapamycin observed in mice might also result in humans who take curcumin supplements and consequently inhibit their mTOR pathway expression. I have discussed this possibility in two blog entries: Curcumin, cancer and longevity, and Neurogenesis, curcumin and longevity.
There are some tantalizing hints about how the mTOR pathway may relate to the other theories of aging. For example, there are complex feedback interactions between the pathways involving NF-kappaB, mTOR and PI3K-Akt related to both treatment of cancers and longevity(ref). A cancer treatment using a certain chemotherapeutic agent leads to simultaneous down-regulation of mTOR and telomerase activity in cancer cells(ref). Inhibiting mTOR via rapamycin resulted in impairment of pluripotency and prevention of adult stem cell differentiation, among other effects(ref).
Does the mTOR story lend light on whether mitochondrial activity is more important than cell signaling or protection against oxidation damage for determining longevity? The story actually lends light on the fact that this is the wrong kind of question to ask “Such notions are slowly giving way to a more nuanced view in which cellular signaling pathways intersect with the mitochondria, creating a two-way network of interactions between the consumer (the cell) and the supplier (the mitochondria) of energy(ref).” Instead of just focusing on the health of the inner operations of the cell or the mitochondria, perhaps we need to look more at what they are saying to each other.
(This description is adopted from the blog posting Another longevity-related biochemical pathway - the hypoxic response)
Another cross-species pathway has been discovered that allows
interventions to lengthen life in primitive organisms, C. elegans nematode worms
in this case. The pathway is related to the hypoxic response, how cells respond to
protect themselves when there is insufficient oxygen. It turns out that
if the hypoxic response can be turned on when normal oxygen is present, nematodes
live significantly longer. A recent research report indicates
that this was experimentally accomplished by breeding
nematodes that could not produce the protein VHL-1 which destroys another protein
called HIF which keeps the hypoxic response turned off when oxygen is present.
Also, it appears that the cells in such long-lived nematodes are relatively
free of lipofuscin and toxic age-related protein aggregations such as seen in
Alzheimer’s, Huntington’s and other age-related diseases(ref).
So, as is the case for dietary restriction the increase appears to be not only
in lifespan but also in healthspan. See the blog entry Mechanisms
and Effects of Dietary Restriction. The hypoxic response pathway is
different than that which is involved in calorie restriction. “VHL-1 and
HIF-1 control longevity by a mechanism distinct from both dietary restriction
and insulin/IGF-1-like signaling.” As of yet, however, just how HIF works
downstream to extend longevity is still unclear. The hypoxic response
appears to operate in higher animals as well, including humans. See
the blog entry Mechanisms and Effects of Dietary Restriction.
See the blog entry Mechanisms and Effects of Dietary Restriction.
The candidate theory of aging in this case is keeping the hypoxic response turned on can contribute to longevity. Again, as far as I know this hypothysis has not been tested with humans or mammals including mice. Dr. Matt Kaeberlein, University of Washington assistant professor of pathology and the senior author on the cited study is reported to caution that “mutation of VHL-1 is associated with a variety of tumors, and any therapies targeted toward activation of HIF would most likely need to be specific for cells that are not rapidly dividing, such as brain cells or muscle cells.” It is too early to know if a practical human anti-aging intervention can be tied to the hypoxic response but the possibility is intriguing.
(Added in December 2009) The micronutrient triage theory of aging is laid out in detail in the 2008 publication Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage by Bruce N. Ames, a giant in the field of anti-aging science. This theory is based on two well-documented observations. The first observation is that most of us do not consume adequate quantities of a number of important micronutrients, these including minerals like zinc, iron, copper, magnesium, calcium, potassium and selenium and vitamins like D, B12, folic acid, pyridoxine, pantothenate, riboflavin, and biotin. The second observation is that evolution built our bodies so as always to prioritize short-term survival over long-term wellbeing whenever there a need to choose between the two. A familiar example is the “fight or flight” response in case of an emergency. A flood of cortisol is released that speeds up our responses and facilitates us to react quickly. The price is a weakening of our immune response and a shortening of our telomeres(ref), events that tend to be life-shortening. Thus, evolution seems to reason that it is better for us to live a bit less-longer at the end of our lives than to risk being eaten by a tiger or being killed in an auto crash while younger.
The Micronutrient triage theory of aging essentially says that the body is careful and intelligent in its allocation of micronutrients, allocating them according to triage priorities favoring short-term functionality over long-term health. The topmost priorities are for minute-to-minute and day-to-day body functioning, immediate energy metabolism, keeping up circulation and blood pressure, maintaining digestion and things like that. The lowest priorities are those that make for longevity: keeping up a strong antioxidant response, DNA damage repair, minimization of glycation and excess inflammation, prevention of senescence, preservation of telomere lengths, and matters like those. When not enough of a micronutrient is available to handle the lower-priority needs, those needs are left unmet. The consequences may be completely unnoticed in day-to-day experience but are likely to show up late in life as cancers, Alzheimer’s disease, Parkinson’s disease, diabetes, cardiovascular diseases and the other maladies that kill older people.
Ames summarizes his theory this way “I propose DNA damage and late onset disease are consequences of a triage allocation response to micronutrient scarcity. Episodic shortages of micronutrients were
common during evolution. Natural selection favors short-term survival at the expense of long-term health. I hypothesize that short-term survival was achieved by allocating scarce micronutrients by triage,
iin part through an adjustment of the binding affinity of proteins for required micronutrients. If this hypothesis is correct, micronutrient deficiencies that trigger the triage response would accelerate cancer,
aging, and neural decay but would leave critical metabolic functions, such as ATP production, intact.”
Supporting the theory is the fact that deficiencies in a large number of micronutrients seem to produce the same kinds of DNA damage produced by radiation. “Approximately 40 micronutrients are
required in the human diet. Deficiency of vitamins B12, folic acid, B6, niacin, C, or E, or iron, or zinc, appears to mimic radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions,
Ames cites a formidable collection of research studies to support his theory and builds a strong case for it. Ames, you may recall, has long been a key researcher in the
areas of mitochondrial functioning, DNA damage and the roles of micronutrients(ref).
He was also the lead researcher involved in the discovery of the impact on mitochondrial health of the Acetyl-l-carnitine and alpha-lipoic acid combination back
7 years ago(ref), a supplement combination discussed elsewhere in this treatise. If you have never been in Ames’ presence you can get a sense of the man and what he about by
viewing his online lecture Understanding Aging.
A problem of course is that micronutrient needs can vary by age, individual, and individual circumstances, and further studies are needed to nail these down. “The elderly may need more or less of certain
vitamins and metabolites compared with younger people, but this issue has not been thoroughly examined(ref).” The situation is further complicated in that, for many micronutrients like iron, DNA damage
can be produced by either too much or too-little of then. In general in our society, however, most of us get too little of several critical micronutrients rather than too much.
Ames points out that seven micronutrients (pyridoxine, pantothenate, zinc, riboflavin, iron, copper, and biotin) are particularly important because they are required for heme synthesis in mitochondria.
“It is likely that a deficiency in any of these seven will cause a deficit of heme and therefore of complex IV, of which heme-a is an essential component – The normal complement of complex IV keeps
oxidants to a minimum; deficits of complex IV result in oxidant leakage, DNA damage, accelerated mitochondrial decay, and cellular aging(ref). “
In the publication, Ames strongly advocates micronutrient dietary supplementation. “Evidence is accumulating that a MVM (multivitamin-mineral) supplement, or smaller combinations of vitamins and minerals,
also improve long-term health, reducing heart disease, cancer, and cataracts and improving immune function for those who consume inadequate diets.”
Almost all the micronutrients mentioned in the Ames publication are included in ample quantities in the combined firewall supplement regimen laid out in this treatise:
vitamins B-6, C, D, B-12, A, pyridoxine, riboflavin, pantothenate, folic acid, biotin, zinc, calcium, magnesium, copper, selenium, omega-3 fatty acids, tocopherol, and lycopene.
The main micronutrient discussed by Ames but missing from the regimen here is iron. I have not included iron in the supplement regimen because it is included in many foods
normally eaten by most people in the US (see the listing here) and because it creates damage when consumed in excess. Also, vitamin C, which is included in the regimen
in generous quantities, facilitates iron absorption. Individuals in categories likely to be suffering from iron deficiency,
however, might wish also to take an iron-containing supplement. These include * Infants, children, and adolescents who are growing quickly, * People who do not get enough
iron in their diet, * People who use aspirin, ibuprofen, or other arthritis medicines long-term , * Pregnant or breastfeeding women who need extra iron, * Seniors, and
*Women of child-bearing age who have lost blood through heavy menstrual periods (ref).
The regimen contains a B-complex tablet as a source for riboflavin and biotin. There are also many additional important micronutrients
in the regimen that are not mentioned in the Ames paper like Vitamin K and a number of powerfully-acting phytochemicals. Klotho, often described as "an anti-aging gene," is attracting increasing research attention and could possibly be targeted for anti-aging
interventions in humans. It is known that that mutations of the Klotho gene can lead to over-expression of advanced glycation products and
other phenomena of advancing aging, while over-expression of Klotho can be significantly life extending in small animals. For a comprehensive
picture of Klotho and its possibilities,see the October 2009 blog entry Klotho anti-aging gene in the news, the September 2010 update Klotho,
phosphates, cola drinks and longevity. and the December 2011 blog entry More about Klotho - spinner of the thread of life. What do these additional
candidate theories and the discussion of Klotho mean for the overall anti-aging picture? So what do the above seven candidate theories of aging and
consideration of Klotho contribute to the longevity picture beyond what has
been discussed previously? As I see it, they are all interesting areas
of a gigantic longevity jigsaw puzzle, areas that are still only partially integrated
with each other. As time goes on, other areas will probably also
be identified, yet-more candidate theories of aging and longevity-related paths.
As the puzzle gets more filled in we will see better where they all fit.
See my blog post The
Longevity Jigsaw Puzzle. What is required for now is patience and tolerance
for multiple pathways that affect aging without clear understanding of how they
relate to each other. We are only now starting to work seriously on the puzzle.
As critical new pieces are revealed and come to my attention, I report on them
in the blog that accompanies this
document. For example, see the blog post on Linking
up the theories of aging. A March 2010 blog posting
SIRT1, mTOR, NF-kappaB and resveratrol links up three different theories
of longevity: suppression of mTOR signaling, activation of SIRT1, and inhibition
of expression of NF-kappaB. "Activating SIRT1 does all of these things, and
this seems to be accomplishable to some extent by taking resveratrol supplements."
22. The Klotho pathway
Supporting the theory is the fact that deficiencies in a large number of micronutrients seem to produce the same kinds of DNA damage produced by radiation. “Approximately 40 micronutrients are required in the human diet. Deficiency of vitamins B12, folic acid, B6, niacin, C, or E, or iron, or zinc, appears to mimic radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both(ref).’
Ames cites a formidable collection of research studies to support his theory and builds a strong case for it. Ames, you may recall, has long been a key researcher in the areas of mitochondrial functioning, DNA damage and the roles of micronutrients(ref). He was also the lead researcher involved in the discovery of the impact on mitochondrial health of the Acetyl-l-carnitine and alpha-lipoic acid combination back 7 years ago(ref), a supplement combination discussed elsewhere in this treatise. If you have never been in Ames’ presence you can get a sense of the man and what he about by viewing his online lecture Understanding Aging.
A problem of course is that micronutrient needs can vary by age, individual, and individual circumstances, and further studies are needed to nail these down. “The elderly may need more or less of certain vitamins and metabolites compared with younger people, but this issue has not been thoroughly examined(ref).” The situation is further complicated in that, for many micronutrients like iron, DNA damage can be produced by either too much or too-little of then. In general in our society, however, most of us get too little of several critical micronutrients rather than too much.
Ames points out that seven micronutrients (pyridoxine, pantothenate, zinc, riboflavin, iron, copper, and biotin) are particularly important because they are required for heme synthesis in mitochondria. “It is likely that a deficiency in any of these seven will cause a deficit of heme and therefore of complex IV, of which heme-a is an essential component – The normal complement of complex IV keeps oxidants to a minimum; deficits of complex IV result in oxidant leakage, DNA damage, accelerated mitochondrial decay, and cellular aging(ref). “
In the publication, Ames strongly advocates micronutrient dietary supplementation. “Evidence is accumulating that a MVM (multivitamin-mineral) supplement, or smaller combinations of vitamins and minerals, also improve long-term health, reducing heart disease, cancer, and cataracts and improving immune function for those who consume inadequate diets.”
Almost all the micronutrients mentioned in the Ames publication are included in ample quantities in the combined firewall supplement regimen laid out in this treatise: vitamins B-6, C, D, B-12, A, pyridoxine, riboflavin, pantothenate, folic acid, biotin, zinc, calcium, magnesium, copper, selenium, omega-3 fatty acids, tocopherol, and lycopene. The main micronutrient discussed by Ames but missing from the regimen here is iron. I have not included iron in the supplement regimen because it is included in many foods normally eaten by most people in the US (see the listing here) and because it creates damage when consumed in excess. Also, vitamin C, which is included in the regimen in generous quantities, facilitates iron absorption. Individuals in categories likely to be suffering from iron deficiency, however, might wish also to take an iron-containing supplement. These include * Infants, children, and adolescents who are growing quickly, * People who do not get enough iron in their diet, * People who use aspirin, ibuprofen, or other arthritis medicines long-term , * Pregnant or breastfeeding women who need extra iron, * Seniors, and *Women of child-bearing age who have lost blood through heavy menstrual periods (ref). The regimen contains a B-complex tablet as a source for riboflavin and biotin. There are also many additional important micronutrients in the regimen that are not mentioned in the Ames paper like Vitamin K and a number of powerfully-acting phytochemicals.
Klotho, often described as "an anti-aging gene," is attracting increasing research attention and could possibly be targeted for anti-aging interventions in humans. It is known that that mutations of the Klotho gene can lead to over-expression of advanced glycation products and other phenomena of advancing aging, while over-expression of Klotho can be significantly life extending in small animals. For a comprehensive picture of Klotho and its possibilities,see the October 2009 blog entry Klotho anti-aging gene in the news, the September 2010 update Klotho, phosphates, cola drinks and longevity. and the December 2011 blog entry More about Klotho - spinner of the thread of life.
What do these additional candidate theories and the discussion of Klotho mean for the overall anti-aging picture?
So what do the above seven candidate theories of aging and consideration of Klotho contribute to the longevity picture beyond what has been discussed previously? As I see it, they are all interesting areas of a gigantic longevity jigsaw puzzle, areas that are still only partially integrated with each other. As time goes on, other areas will probably also be identified, yet-more candidate theories of aging and longevity-related paths. As the puzzle gets more filled in we will see better where they all fit. See my blog post The Longevity Jigsaw Puzzle. What is required for now is patience and tolerance for multiple pathways that affect aging without clear understanding of how they relate to each other. We are only now starting to work seriously on the puzzle. As critical new pieces are revealed and come to my attention, I report on them in the blog that accompanies this document. For example, see the blog post on Linking up the theories of aging. A March 2010 blog posting SIRT1, mTOR, NF-kappaB and resveratrol links up three different theories of longevity: suppression of mTOR signaling, activation of SIRT1, and inhibition of expression of NF-kappaB. "Activating SIRT1 does all of these things, and this seems to be accomplishable to some extent by taking resveratrol supplements."
A final thought regarding the 21 theories and candidate theories of aging: a single master theory may not exist. There are lots of biomolecular actions and genetic pathways that can lead to accelerated aging, and it appears there are also several that can delay aging somewhat. Some may be more fundamental than others. But it may well be that there is no one master theory or mechanism of aging that drives all the others. It may be that we are looking at a large system of interacting feedback loops in which all the mechanisms of aging work together affecting each other in multiple ways. All are primary, somehow necessary. Think of a mechanical wrist watch. It contains numerous gears, wheels, cogs and bearings. Which is the main gear or wheel or bearing, the key component for operation of the watch? Wrong question. They are all needed. Taking out or breaking almost any gear or cog or wheel or bearing will stop the watch or make it run screwy. If you want a healthy functioning watch it is important that all the parts be in good shape and well-aligned with each other. The same appears to be true for us mammals.
The statements made in this document are opinions based on my continuing efforts to keep up with the genetic and biomedical research literature related to aging. I typically spend 30-60+ hours a week on this task, attempting to keep new findings in perspective of what is already known, and assessing their potential impact on my longevity program. Yet, with respect to this research I feel like a small dog trying unsuccessfully to keep up with a large truck. The more I learn, the further behind I feel I am getting from grasping all there is to know of relevance.
Pursuant to an earlier footnote, I have not here attempted the pedantic exercise of citing hundreds of references from tens of thousands of research sources on the topics covered. Rather, I invite the interested reader to do his or her own research to check out my assertions and dig deeper in the area of his or her interests. Searches using Google or Yahoo will turn up lots of references. I suggest that you take claims made for supplements on selling sites with a grain of salt but there will be many other good references from impartial organizations as well. Jim Green has created Anti-Aging Medicine: Longevity & Life Extension in Review, a detailed compendium of articles, opinions and research citations related to different theories of aging. In several instances that document goes into much greater detail than this one. Green's document was originally written in 2000 and its third edition is dated September 11, 2008. If you want to dig really deeper into the biochemistry and genetics involved, you can search on the National Library of Medicine’s extensive but free research database www.pubmed.org or in other subscription research databases such as Elsevier’s EMBASE, Ingenta Connect or Medline. Free guest accounts are available for the Science Direct database. Use the Quick Search feature. Finally, for the sake of those who do not know me I need to stress that I have no financial stake in any of the products, services or ideas mentioned here. My hope is that I can make a positive difference in the lives of some of my readers who want to live long healthy lives.
This Section provides a history of important updates to this treatise over time and past blog entries.
What’s new September 24, 2011: Consistent with discussion in the recent blog entries End of the free radical theory of aging and negative consequences of indiscriminante antioxidant supplementation and Editorial - A shift in a key aging sciences paradigm, I have significantly modified the discussion related to the Oxidative Damage theory of aging and the firewalls against oxidative damage.
Previous substantive blog postings include: * Editorial - A shift in a key aging sciences paradigm, * Aging and the immune system - focus on naïve T-cells, * End of the free radical theory of aging and negative consequences of indiscriminante antioxidant supplementation, * Medical ghostwriting and dangerous misinformation, * Focus on bitter melon, * Napping and Human Sleep, * Age-related cognitive decline: focus on interventions, * Health and longevity benefits of plant polyphenols - focus on grape seed extract, * Observations on Lyme Disease, * Aging as a genomic-epigenomic dance, * Kinase Inhibition - A Magic Bullet?, * Longevity of stem cells and the roles of stem cells in aging, * Update on induced pluripotent stem cells, * CETP, a Longevity Buffering Mechanism, * Quantum biology, * Focus on ginger, * p53 and Longevity, * Living on the Brink of Chaos, * Systems Biology and its tools, * Longevity and the GHIGF Axis, * Brown Adipose Tissue - and Modern Ambient Conditions, * Welcome Victor new Associate Researcher-Writer, * Shift to the wellness-longevity paradigm, * Age-related memory and brain functioning focus on the hippocampus, * Call for associate researcher-writers, * The 2011 Bio-IT World Conference & Expo On the way to Personalized Predictive Preventative Participatory Medicine, * Revisions to my dietary supplement firewall regimen, * PQQ - activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis, * Personal protection against nuclear radioactive substances, * The epigenetic regulation of telomeres, * Alzheimer's Disease Update - March 2011, * Aging and diseases - video blog, * Radio interview on aging sciences, * New name - same blog, * The many faces of mTOR and rapamycin, * Evolution and the prospect for much longer lifespans video blog, * Age reversal - video blog, * We are evolving to live longer - video blog, * The many faces of folic acid, * The evolution of my perspective as a longevity scientist, * Cancer, epigenetics and dietary substances, * JDP2 - linking epigenetic modifications, stem cell differentiation, cell senescence, cell stress response, and aging, * US falling behind in longevity increases - why?, * Public health longevity developments - focus on foods, * SIRT3 research - tying together knowledge of aging, * The Nuclear DNA Damage/Mutation Theory of Aging, * Nitrates and nitrites - Part 2: good for you, * Nitrates and nitrites - Part 1: bad for you, * The reputation of aging in ancient and current mythology.
* Human growth hormone treatment - a fountain of accelerated aging?, * Epigenetics of cancer and aging, * Additional 2010 research progress with induced pluripotent stem cells, * Stochastic epigenetic evolution - a new and different theory of evolution, aging and disease susceptibility, * Mouse age reversal - very interesting but misrepresented research, * Biomarkers for cardiovascular diseases , * When reading press releases and newspaper articles about research discoveries, beware!, * Sleep and longevity, * Past blog postings on stem cells and epigenomics, * Interesting recent stem cell research, * Social evolution and biological evolution - another dialog with Marios Kyriazis, * Closing the loop in the stem cell supply chain - presented graphically, * Telomere lengths, Part 3: Selected current research on telomere-related signaling, * Telomere lengths, Part 2: Lifestyle, dietary, and other factors associated with telomere shortening and lengthening, * Telomere lengths, Part 1: Telomere lengths, cancers and disease processes, * Genomic stability, DNA repair and the sirtuin SIRT6, * Another guided-missile cancer therapy - that works, * A breakthrough in producing high-fidelity induced pluripotent stem cells, * Indefinite life extension - Dialog with Marios Kyriazis, * Gearing up for the war on aging, * If we can multiply lifespans of nematodes by seven, why have we not been able to get anywhere with significant human lifespan extension?, * New extraordinary longevity lessons from the nematode, * Klotho, phosphates, cola drinks and longevity, * Smurf2 in senescence, aging and diseases, * HSP70 to the rescue - But, no, no! That's not what we want for cancer cells, * Valproic acid - The phoenix drug arises again, * Antagonistic pleiotropy revisited - for the last time.
On August 27, 2010: I updated discussion of the IIncreasing mTOR signalling candidate theory of aging based on new research that lends credance to this theory. I have also added several hyperlinks to blog entries where they are particularly relevant to the discussion. Recent blog postings include: * Curcumin, cancer and longevity, * Neurogenesis, curcumin and longevity, * PGC-1alpha and exercise, * Skin Cancer immunotherapies, * Contrarian research findings: newly-identified aging villain substances; calorie restriction longevity is not due to calorie restriction, * Turning P53 on in cancer cells, * Diabetes Part 2: Lifestyle, dietary and supplement interventions, * Diabetes Part I: Biology and molecular dynamics of diabetes, * Alzheimer's disease studies validate anti-aging firewalls suggestions, * Induced pluripotent stem cells - developments on the road to big-time utilization, * Three years exploring longevity science, * HSP70 to the rescue, * AMPK and longevity, * Stress, exercise and telomere lengths, * Humanin, health and aging, * The free radical theory of aging. Is it really a theory of aging?, * Ghrelin hunger, obesity and aging, * Back to blueberries, * Calorie restriction mimetics - focus on avocado extract, * Is acetaminophen an anti-aging drug? Probably not, * A near-term application for iPSCs - making cell lines for drug testing, * Epigenetics, inflammation, cancer, immune system, neurological and cardiovascular disease and aging, * Something new about P21, an old familiar gene - it blocks limb and organ regeneration, * Draft of American Aging Society Presentation - Towards a Systems Theory of Aging, * Melanoma research update, and * Contrarian current research outcomes. On May 7 2010, I integrated what had been a candidate theory of aging Epigenomic Changes In DNA Methylation and Histone Acetylation into the main discussion of the 13th theeory of aging Programmed Epigenomic Changes. Recent blog postings include: * Alzheimer's Disease research update, * Extra-virgin olive oil , * The PROOF Centre of Excellence, * Towards a systems view of aging, * Harnessing the engines of finance and commerce for life-extension, * Progress in stem cell oncolytic virotherapy, * DNA Methyltransferases, stem cell proliferation and differentiation, * More on DNA repair strategies, * What does resveratrol do?, * Telomerase activators - what do they really do?, * Induced pluripotent stem cells - second-rate stem cells so far, * Setting the record straight on three favorite approaches to longevity, * Believing news reports and scientific publications, * Another piece of DAF-16 research, * What are aging, life-extension and anti-aging?, * Niacin or niacinamide supplementation - good or bad idea?, * SIRT1, the hypoxic response, autophagy and hormesis, * Visit with Leonard Guarante, * SIRT1, mTOR, NF-kappaB and resveratrol , * Cell import and export traffic control signaling, * Telomeres and telomerase in Induced Pluripotent stem cells - not what we thought, * Recent diabetes-related clinical trials , * Fucoidan, * The social cost of Alzheimer's disease and late-life dementia, * Vitamin D3 and the immune response, * Sestrins, longevity and cancers, * BDNF gene -- personality, mental balance, dementia, aging and epigenomic imprinting, * DNA repair cleanup failure - a root cause for cancers?, * Joy and sadness of aging - and the impacts of longevity, * New views of Alzheimer's disease and new approaches to treating it, * iPSCs, telomerase, and closing the loop in the stem cell supply chain, * Genome-wide association studies, * "I have never seen a doctor," and * MicroRNAs in cancers and aging, and back-to-the-nematode.
On Feb. 15, I tweaked a few the dosages in the firewall supplement regimen to reflect those I am actually taking. Previous blog postings include: * Getting the world ready for radical life extension, * New telomerase finding only a small-medium sized deall, * Personalized medicine - reducing the cost and improving the effectiveness of health care, * Epigenetics going mainstream, * Patentability of genes, * Human embryonic stem cells and Alzheimer's disease, * My personal longevity - the race between death-stalker and life-prolonger, * Drug and herbal remedy incompatibilities, * What every vampire already knows - and something he doesn't know, * Direct cell reprogramming, * Progress in closing the stem cell supply chain loop, * Sierra Sciences, * Blog birthday notes - original contributions made in the first year of this blog, * Vitamins, supplements and telomerase - upregulation or downregulation?, * GABA, beta-alanine, carnosine, homocarnosine and gabapentin, * Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation, * CETP gene longevity variants, * Exercise, telomerase and telomeres, * Stem cell cartilage regeneration, * Surprise! Just when we thought we knew everything about vitamin C, * The evolution of this blog, * Important new mesenchymal stem cell therapies, * Calorie restriction research roundup - Part II.
Between September 27 2009 and and Dercember 31 2009, I posted the following blog items: * Ginkgo Biloba supplementation has no effect on cognitive decline (but it does have other impacts), * Calorie restriction research roundup - Part I, * Age-related surgery risk, * Genes discussed or mentioned in this blog, * Progress in genetically profiling cancers, * New-science approaches to detecting, preventing and curing cancers, * News on disabling cancer stem cells, * When Nanotechnology meets Epigenomics, * Terminator stem cells in the early pipeline, * Brain-activated speech synthesis, * Avoidance Magazine stories, * Diet and cognition.
On December 6 2009, I posted a seventh "candidate" theory of aging, bringing the total number of theories and candidate theories of aging treated here up to twenty one. It is called The micronutrient triage theory of aging, is based on the blog entry with the same name, and deserves significant attention.
Previous to December 13, 2009, I posted these blog entries: * Personalized medicine and genetic drug interactions - another long way to go, * The micronutrient triage theory of aging, * Getting skinny from brown fat, * Bacillus polyfermenticus - not just for mice, * The curious case of l-carnosine, * Heavy metal detoxification, * Anti-aging simplified, * Timely telomerase tidbits, * It's a long way to stem cell treatment, * Breakthrough telomere research finding, * Hormesis and age retardation, * A gene therapy home run, * Senesco and the Factor 5A1 gene, * Longevity gods and goddesses - old and new, * ALD and lentivirus vectors for gene therapy, * Vitamin D - don't fall for it, * Spinal cord injury pain - a personal story and a new paradigm, * DNA demethylation - a new way of coming at cancers, * Revisiting the naked mole rat - two factors we can emulate for longevity, * MicroRNAs, diseases and yet-another view of aging, * Homicide by DNA methylation, * The NRG1 Gene - an important new tumor suppressor gene? And press sensationalism about it, * Rosmarinic acid, * Nrf2 and cancer chemoprevention by phytochemicals, * Hypervitaminosis D and premature aging, * Klotho anti-aging gene in the news, * Pythons, cell senescence and telomere torments, * Big pharma is targeting cancer stem cells, * The human liver - a model for organ regeneration?, * The Pill - mating, sex, and the kind of kids we were getting, * “Footprint-free” iPSCs – and a crazy wager offer, * Who is doing gene reprogramming?, * Telomere and telomerase writings, * Toward a genetic cure for Parkinson's disease, * Partner up to keep your wits about you, * Single-cell spectrometry and Giuliano's Law, * Another possible negative for antioxidants, * Niche, Notch and Nudge, and * Revisiting telomere shortening yet-again.
I enhanced the discussion of the Stem Cell Supply Chain Breakdown theory on September 27, an original theory added to this treatise ten days before. This theory is based on insights I have accumulated this year in generating blog entries and is more general than the former 14th theory of aging which it subsumes, Decline in Adult Stem Cell Differentiation.
September 27, 2009: This treatise is now more than a year-and-a-half old and has evolved significantly from its original form. In addition to a great deal of new and updated content, much additional relevant research material has also been discussed in the companion Blog. I am continuing to integrate much of that material into this treatise. Again, my intention here is to keep a running current survey about what science has to say about aging, and what can be practically done now to slow, halt or even possibly selectively reverse aging. To reflect what the treatise has become I have added the tagline to the title THE SCIENCE AND TECHNOLOGY OF LONGEVITY. I added a new section ADDITIONAL CANDIDATE THEORIES OF AGING. This section draws together materials from the blog and a Note and characterizes six additional candidate theories of aging - ones based on early-stage and incomplete research.
As of 27 September 2009: * The stem cell supply chain - closing the loop for very long lives, * Cordyceps militaris and cancer, * Immunosenescence - No thanks for the memories, * Hard work and hard-wired, * Progress on fighting glioblastoma, * FOXO genes and protecting stem cells - What does resveratrol do?, * Health and longevity benefits of dark chocolate, * The "skinny" about the "fatso: gene FTO, * Hidden research laboratories, * More mTOR links to aging theories, * Blueberries and health - the research case, * Longevity - deadly for defined benefit pension plans, * The blood-brain barrier and triple quadrupole mass spectrometry, * Recent research on the Mediterranean diet, * A new anti-inflammatory and possible hair color restorer, * Medical radiation risk - you can do something about it, * What motivates me to write this blog, and * The evolution of this blog. The August 23 blog post: Autoimmune diseases and lymphoma - Part III: focus on lymphomas, the August 19 blog post: * Autoimmune diseases and lymphoma: Part II: focus on inflammation and the August 14 blog post * Autoimmune diseases and lymphoma: Part I: focus on Lupus are parts of a three-part series designed to look at two related classes of disease, the fundemental processes going on in them, and relevant new-generation therapies. Other recent blog posts were * Update on cancer stem cells, * Itch vs. Ouch, Folk remedies, and * The anti-antioxidant side of the story. On August 7 I posted a discussion of central relevance to this treatise: * An emerging new view of aging: the stem cell supply chain. Other recent blog posts include * Your skin detects problems, computes solutions, produces hormones and sends solution-bearing messages to far-flung parts of your body, * Mental exercise and dementia in the news again, * Cerebral white matter and protection of functionality with age, * Treating genetic diseases with corrected induced pluripotent stem cells, * A Fascinating dance of death and life: Fas, FasL and diseases, * Nerve regeneration, * Life extension by a factor of 10, and * Chimeras.
On July 27, I updated or added to several discussions here based on recent research insights reported in my blog. The updates involved are found in the discussion of the Decline of Adult Stem Cell Differentiation theory of aging, the firewall for the Mitochondrial Damage theory of aging, in the discussion related to the Telomere Shortening and Damage theory of aging, and in the firewall for the Decline in Adult Stem Cell Differentiation theory of aging. I also posted these blog entries: * Research evidence for the Decline In Adult Stem Cell Differentiation theory of aging, * Hair stem cells and hair growth, * Salamanders and human limb regeneration, * Extra-telomeric benefits of telomerase - good news for telomerase activators, * Embryonic Stem cell research news, * Impact on longevity of older men being with younger women and frequent sexual intercourse, * Ever-increasing longevity- is epigenomics involved?, * APOE4 gene variants, memory loss and Alzheimer's Disease risk, * Bubble Gum, Cat in the Hat, Qi Gong, humidity, stupidity, cannibalism and longevity, * Telomerase activation - upside and downside, * Now hear this, * Calorie Restriction, longevity, and waiting for proof of what works, * Viva mTOR! Caveat mTOR!, * Dendritic cell cancer immunotherapy, * Warding off Alzheimer's Disease and things in my diet, * On cancer stem cells, * Gene variations and diseases - far from simple, * Obesity in the news again, * Stress and Longevity, * More on DHMEQ and a no-no mind bender, * MEDICAL DISCLAIMER, and * Anti-inflammatory effects of the hormone alpha-MSH. Previous blog entries include: * Research Roundup on the Lipofuscin Theory of Aging, * Update on induced pluripotent stem cells, * Inflammation, cancer and stem cells in autoimmune diseases, * Dental Pulp Stem Cells - the big needle vs the tooth fairy, * Emodin - a moving substance, and * Mama Ji's Molecular Kitchen.
On June 20, I posted a 39-slide PowerPoint presentation, THE SCIENCE OF AGING AND PRACTICAL ANTI-AGING INTERVENTIONS. This presentation provides an overview of and introduction to the content in this treatise. It you are not familiar with this treatise, I suggest you start with this presentation. Other recent blog entries include * Simple but powerful non-invasive adult stem cell cures, * Fertility of older men: sperm health and dietary supplements, * More research insight on gray hair and adult stem cell reproduction, * Spices of life, * P38, P39 and P40 channel receptor functions inhibit activities of BF-110, HE111 and HE177 leading to reduced expression of (SC)1000 in BOB, * A genetic or antibiotic prevention for HIV? , and * Do resveratrol, curcumin and EGCG from green tea really inhibit the expression of telomerase?
I added additional comments June 9 about how the theories of aging relate to one another, some additional research citations, and a few more cross-links to relevant blog entries. Recent Blog entries include: * A genetic fix for obesity, * How am I doing?, * Linking up the theories of aging, * A simple treatment for genetic diseases, * Making the best use of this Blog, * Epigenomic complexity, * Transformed State of Medicine - 2025, * Histone acetylase and deacetylase inhibitors, * Another rare genetic disease, and shortevity genes, and * Social ethics of longevity.
Previous Blog entries include * Hoyeraal-Hreidarsson Syndrome and telomere dysfunction, * State of autologous stem cell therapies, * On the TRAIL of a selective cancer treatment, * Trojan-horse stem cells might offer an important new cancer therapy, * Consumer genomics, * A further update on NF-kappaB, * Red wine, hot peppers and my uncle Gigi, * Progerin, HGPS and a possible new theory of aging, * Werner Syndrome - another model for aging, * The longevity jigsaw puzzle, * Longevity genes, mTOR and lifespan, * Anti-Aging Firewalls anniversary - and a thought, * Gene therapy for fruit flies with Parkinson's Disease, * Why do females live longer than males?, * Women who give birth late in life live longer – and so do their brothers, * Half glass of wine a day – good for longevity or bad because of increased cancer risk?, * Individual DNA testing, * P53 gene, normal and mutant, in the news, * Another longevity-related biochemical pathway, * Human heart muscle cell renewal, * Scientific integrity and advertising on my sites, * US Army longevity research, * “If you think you can do a thing or think you can't do a thing, you're right.” -- Henry Ford, * Dr. Jekyll and Mr. Hyde proteins, * Anti-Aging Firewalls 1.9 – State of progress, * Phytochemicals – focus on caffeic acid, * “Sonic hedgehog requires interactions with proteoglycans to achieve cell proliferation, but not tissue patterning,” * Secrets to longevity, and * Longevity – the sad personal side of it.
On April 18 I modified the names of a few of the theories of aging to improve their accuracy, e.g., the 13th theory is now Programmed Epigenomic Changes instead of Programmed Genetic Changes. I nave also added an extended discussion on the relationships among the 14 theories of aging and have revised the discussion of Programmed Epigenomic Changes to reflect the clearer science picture that is emerging. Earlier Blog entries include * Exercise your brain, don’t nap, have a pleasant personality and keep driving – Well, not so fast! and * Deconstructing Alzheimer’s Disease – role of mitochondria. Other relevant Blog entries in the preceeding several days included * Nanoceuticals, * Nutrigenomics, and * The new omics and longevity research. On April 3 I added a short section to this document with references having to do with the relationships among three of the aging theories, corresponding to a new Blog entry made the day before * Stem cells, telomeres, telomerase and DNA repair.
I made minor additions here to the discussion of the Telomere shortening theory of aging on April 1. New Blog entries on April 1 were * DHMEQ and * Polypill, fish oil or exercise? In the preceding few days I generated three important new Blog entries that I plan to combine soon into an online paper: * Giuliano’s Law: Prospects for breaking through the 122 year human age limit, * More on Giuliano’s Law; calculating my longevity prospects, and * Factors that drive Giuliano’s Law. Other recent Blog entries include * Longevity Genes and two Fantasies, * Rebooting cells and longevity, * DNA methylation, personalized medicine and longevity, * Why does your hair turn gray? and * Use it or lose it and sexual intercourse.
I made some minor updates on March 15 and 17 in the technical discussions of the Mitochondrial DNA mutation and the Programmed genetic changes theories of aging to reflect recent research findings. I also added new Blog entries: * Longevity of poor people correlated with IQ, * Mitochondria and Parkinson's Disease and * Updates on NF-kabbaB. On March 12, I added a short new section to this treatise; it describes the various kinds of research studies I draw upon in creating the anti-aging firewalls. I also posted the same information in the Anti-Aging Firewalls Blog. I also added additional postings in the Blog: a Blog item From the fringe to the center relating to the time it has taken to acknowledge the central relevance of telomerase in biology, an item on * Optimism and epigenomic activation, an item called * The 7 Ps of health and longevity, an item * Do your proteins get tied up in knots?, an item * Tough learning and neuron survivability, a rather long entry on * Epigenetics, Epigenomics and aging, a short item on * Can you think yourself into longevity?, and * More telomerase tidbits discussing telomere lengths and susceptibility to coronary artery disease and how the longest-lived birds manage to keep their telomeres long.
What’s New February 25, 2009: I have added new postings in the Anti-Aging Firewalls Blog: * Consistency - the hobgoblin of small minds, and * Animal models of aging - the African naked mole rat.
What’s New February 20, 2009: This treatise is intended to be dynamic reflecting the rapidly changing scientific knowledge base related to longevity and the my evolving understanding of that knowledge. This is a main reason for publishing on-line instead of in book form. Today I have embodied a major update and addition to the discussion of the Telomere shortening theory of aging and to its associated firewall highlighting a new evolving perspective on that theory. Also I have posted a number of new Blog posts: * Melanoma and stress, * Oxidative damage -cause or effect?, * Oxidative damage and mitochondrial health, * Re-creating Neanderthals among us, and * Thoughts of a lucky soldier - or is it just luck?
What’s New February 21, 2009: Finally, readers are now able to post comments on my Anti-Aging Firewalls Blog. I posted a Blog entry today * Stem cell differentiation and nanotubes. On Feb 18 I posted a Blog entry * You may be able to keep your telomeres long. On Feb 14, I posted an item there called * Engines of longevity research, and on Feb 11 I added an item * Polygamy helps men live longer. I also wrote an item * Brain fitness, Google and longevity. On Feb 10, I added a bit to the neurogenesis discussion in this document, highlighting the paradox that the biomolecular pathways for stem cell self-renewal and cancer promotion seem to be the same. On Feb 9, experiencing frustration in my research, I wrote a Blog entry * Everything relates to everything else – at least in the science of longevity . On Feb 4, I created a new Lifestyle Regimen Section in this document combining the life style recommendations for all of the firewalls and adding a few additional tips. The idea is that if you want to live to 200 or 300 years you have to live to 100 first, and that now requires applying lots of conventional wisdom related to life style as well as taking advantage of emerging discoveries in molecular cell biology. Previously these life style recommendations were scattered throughout the document. They are still justified in more detail under the individual firewall sections. Also I added items in my Anti-Aging Firewalls Blog in the last few weeks, * From four-pound hammer to smart molecules – on cancer treatments", * This week’s anti-aging news Jan 31, 2009,with short items on * More research progress on telomerase, * Mating with a female and male sexual longevity, * Aging and Testosterone in men, and * Getting to living really long. Finally, I have added internal hyperlinks to help navigation within this document as it grows longer and more complicated.
What’s New January 30, 2009:In the past week I have added four entries to my Antiaging Firewalls Blog: * This week’s anti-aging news Jan 22, 2009, *Are the Firewalls Working for me, *On the conventional wisdom of exercise, and * Geron in the news again.
What’s New January 22, 2009:There is an important new developments today. I have created a companion Blog for informal plain-language reporting of emerging longevity-related research news and discussion of related topics. One purpose of the Blog is to report and interpret current developments in non-technical terms understandable by all. Those following updates to the present document will note that the disussion is becoming ever-more technical representing the state of the art of longevity-related research. But ordinary readers can find themselves lost in the intracies of the biomolecular and genetic jargon of nuclear translocation, S-phase arrest, NF-kappaB activation, AKT, SIRT6, P53, etc., One purpose of the Blog is to help those readers keep up with what is going on without having to get a Ph.D. in molecular biology. A second purpose of the Blog is to allow followers of this site to raise probing issues that they are concerned with. All are welcome to register themselves and participate. I will "prime the pump" of the Blog with items from time to time. I put in short postings today on this-week's reserch news relating air quality to longevity, and relating a telomere gene defect to a number of types of cancer. Important research developments will continue to be incorported into this central Anti-Aging Firewalls document which I am striving to make ever-more comprehensive. It is also likely to become more technical as time progresses.
What’s New January 18, 2009:New pieces of the aging puzzle have been showing up just about every day in the course of my scouring the research literature. Sometimes I can put together a few of these pieces with ones that have been lying around and identify an interesting new pattern. Today, I have posted a Note on some new research evidence linking the aging theories. The Note shows crosslinks between at least four of the theories: Programmed genetic changes, Oxidative damage to tissues, Chronic inflammation, and Telomere shortening.
What’s New January 14, 2009: In the last several days I have been focusing on neurogenesis and its relationship to the theories of aging and the protective firewalls. Today, I updated several sections of this paper accordingly, a significant upgrade.
What’s New January 11, 2009: I have added a number of minor updates during the last week, primarily related to anti-aging characteristics of resveratrol and to increasing evidence implicating NF-kappaB as being a master regulator of programmed aging. The reader will also note that as new pieces of the anti-aging puzzle are becoming identified and fit into this document, I have started to provide on-line reference links to them.
What’s New December 31, 2008: I have added a Note on recent newspaper reports that taking traditional vitamins like C and E may not prevent cancers, and why these reports tend to confirm the conclusions of this paper.
What’s New December 21, 2008: Based on a research paper that was recently brought to my attention, I am deleting N-Acetyl Cysteine (NAC)from the combined firewall regimen. The substance was added to the regimen on November 7, 2008, at which time I also posted a Note on it. I have revised this note to explain both why NAC was originally added to the regimen, and why I am now removing it pending further research clarification.
What’s New December 12, 2008: I expanded the firewall section today for the Decline in adult stem differentiation theory of aging. I list research citations that establish that at least six of the substances in the already-defined combined anti-aging firewall can enhance the viability and proliferation of some stem and progenitor cells. I am continuing to explore current research relating to stem cell senescence, and stem and progenitor cell differentiation and proliferation. I have been focusing on the roles of certain key genetic pathways like P13/Akt and P16/Ink4a in the processes of somatic cell renewal as well as carcinogenesis. I am continuing to discover interesting activation-path properties of some of the firewall substances. I expect to report further on these matters fairly soon.
What’s New December 3, 2008: I have been looking into the roles somatic (adult) stem cells may play in aging and have concluded that yet-another theory of aging should be treated in this document. This theory, the 14th, is that aging may be due to decline in adult stem cell vitality and differentiation. Formerly included in a Note, this theory is now integrated into the body of this document. On November 8, 2008,I expanded the discussion of the Programmed Genetic Changes firewall.
What’s New October 28, 2008: I have been continuing to explore the ability of the suggested firewall substances to inhibit NF-kappaB signalling as another way of looking at their impacts on health and longevity. On October 25, as a result of this exploration I added another theory of aging to this paper, that aging results from programmed genetic changes, and have also added a firewall discussion corresponding to this theory. These discussions incorporate what was formerly in a Note Firewall Supplements and the NF-kappaB cell signalling pathway. I am excited by what I think may be breakthrough finding - that at least thirty nine of the substances in my combined anti-aging firewall are inhibitors or blockers of NF-kappaB, providing a genetic-science underpinning to the regimen.
What’s New NOTES: Besides continuing to update the body of this article, I have been adding notes on specific topics at the end. On October 5, 2008, I added a note On telomerase expression and nervous system cells. September 14 and 15 I added notes on : Three strategies for dealing with cellular senescence, on the Firewall against osteoarthritis, and on Telomere binding proteins.
Note 9/14/08 : Three strategies for dealing with cellular senescence
There are three basic intervention strategies for dealing with age-related tissue and organ degradation due to cellular senescence. All three are reflected in the combined firewall program outlined in this document. The first strategy is to delay senescence through minimizing the number of stress-related cell divisions, such as through taking antioxidants, avoiding heavy metals and radiation, etc. The idea is to stave off telomere-length loss and consequent cell senescence. The second strategy is to seek to maintain or increase telomere lengths through telomerase activation. The idea is to greatly extend the replicative lifespans of mitotic cell lines, even nearly immortalizing them. Firewall substances intended to do that are astragaloside IV, astragalus, l-carnosine and ginger. The third strategy is minimization of presence of senescent cells in tissues through encouraging the natural apoptotic cellular mechanisms which lead them to apoptosis. Senescent cells wreak havoc to their neighbors by the cytokine messages they give off, can turn cancerous and can fail to function normally. The idea here is that tissues and organs are better off without them. I personally suspect that several of the firewall substances, including curcumin, resveratrol and other flavinoids, stimulate apoptotic expression in senescent cells belonging to certain cell lines although I have seen little direct research supporting that conjecture. There is suggestive research evidence however, for example that senescent endothelial cells die from apoptotic activity. And, the above-mentioned supplements definitely promote apoptosis in many cancer lines. I will be on the lookout for further research related to this hypothesis.
In osteoarthritis the cartilage structure becomes abnormal over time; the number of chondrocytes (cartilage cells) declines, cartilage extracellular matrix is lost, the composition of the matrix becomes abnormal, and there is pathologic matrix calcification. Osteoarthritis is another disease of aging in which the mitochondria are implicated. There is research evidence that these processes are caused or facilitated by altered mitochondrial respiratory activity in chondrocytes resulting in abnormal ATP energy production, that is, by mitochondria that have become de-energized.
Therefore, elements of the mitochondrial DNA mutation firewall also become part of the firewall against osteoarthritis. Glucosamine supplementation is another element of the anti-osteoarthritis firewall. There is limited clinical evidence that this substance can not only relieve joint pain due to osteoarthritis but also contribute to rebuilding cellular matrix. Its exact mode of operation is not well understood though it is known to affect matrix gene expression in chondrocytes. Finally, in both osteoarthritis and arthritis there is evidence that tumor necrosis factor alpha (TNFalpha) inhibits matrix synthesis by chondrocytes, particularly during inflammation. The anti-inflammatory firewall is therefore also highly relevant in warding off osteoarthritis. Several of the substances in this firewall, including curcumin, resveratrol and other flavinoids, serve to inhibit the expression of TNFalpha.
Telomerase is by far not the only actor in telomere lengthening or shortening and how telomeres are replicated as part of cell mitosis is much more complex than once thought. Recent weeks have seen publications revealing the three-dimensional structure of telomeres and increased understanding of the roles of several proteins that bind to telomeres to form stable loop structures. These proteins with names such as PTOP, TRF1, TRF2, TIN1 and POT1 can variously and in combination facilitate or inhibit telomerase lengthening of telomeres. They can regulate stable telomere length and even combine to produce dramatic telomere uncapping. Much is yet to be learned about telomere lengthening and it may be naïve to assume that increased expression of telomerase will by itself simply and safely result in longer cell telomeres and increased replicative capacity across all mitotic cell lines.
Neurons are non-mitotic. That is, they don’t divide. So what is the possible anti-aging role of promoting telomerase expression in the brain and central nervous system (CNS), given that the main actor cells do not divide and therefore do not lose telomere length? Glial cells, as pointed out above, are vitally implicated in maintaining a well-functioning nervous system and these are mitotic. In particular, studies with rats show that microglia divide rapidly, that of course their telomeres shorten with divisions, that they are subject to cell senescence with age like other mitotic cells that do not express telomerase, and suggest that senescent microglia lead to many negative consequences. Therefore it can be conjectured that promoting telomerase expression in microglial cells could ward off at least one cause of CNS deterioration with age. I am looking out for further research on this topic.
On 11/07/08 I added N-Acetyl Cysteine (NAC) to the combined firewall regimen, and I am removing it from the regimen as of 12/21/08. The case for NAC is that it is a pluripotent substance that contributes powerfully to most of the individual firewalls. For example, with respect to the Oxidative Damage to Tissues theory of aging, NAC is itself a powerful antioxidant and has a capability to increase intracellular glutathione, itself an important pluripotent antioxidant. It also has a capability to chelate heavy metals like lead, arsenic and mercury. With respect to the Immune System Deterioration theory of aging, glutathione is known to be of central importance for the normal functioning of lymphocytes and phagocytes and their capability to mount an effective immune response to any challenge. Glutathione has low bioavailability when taken as a supplement and is thought to be best induced by taking NAC. NAC has been shown to prevent cyclic decrease in numbers of CD4+ T cells in healthy people. NAC has been suggested as an adjunct therapy for AIDS patients. With respect to the Susceptibility to Cancers theory of aging NAC is known to inhibit growth and induce apoptosis in several human cancer cell lines, such as malignant fibroblasts and keratinocytes and the human signet ring cell gastric cancer cell line (SJ-89). NAC has been shown to exercise positive effects with respect to most of the other of the aging theories as well. With respect to the Programmed Genetic Changes theory of aging, NAC is known to inactivate NF-kappaB in multiple cell lines as do at least 38 other substances in the combined firewall. Since the metabolite of NAC lingers in the body and can be toxic unless neutralized, it is strongly suggested that NAC supplementation should be accompanied by three times the NAC dose amount of Vitamin C.
The reason for removing NAC from the combined firewall at least temporarily is a recent study that suggests NAC might not be as safe as was once thought to be. The study, widely reported in the press, reports "Strikingly, the NAC-treated mice developed pulmonary arterial hypertension (PAH) that mimicked the effects of chronic hypoxia." The effect is imputed to result from NAC falsely signalling that an oxygen shortage exists in the body. According to Dr. Ben Gaston, pediatrician and researcher who led the study. “We found that an NAC product formed by red blood cells, know as a nitrosothiol, bypasses the normal regulation of oxygen sensing. It tells the arteries in the lung to ‘remodel’; they become narrow, increasing the blood pressure in the lungs and causing the right side of the heart to swell.” It is unknown whether this effect also applies to humans at customary dosage levels, but prudence suggests removal of NAC from the firewall regimen until this issue can be clarified. I am grateful to Bart Decker for bringing this research to my attention.
Note 12/31/08: On vitamins and cancer
According to Google News this morning, 102 news articles are reporting on yet-another large-scale well-controlled study that indicates regularly taking antioxidant vitamins may not reduce the incidence of cancers. This latest study to be published in the January 7,2009 issue of the Journal of the National Cancer Institute, focuses on vitamins, C, E, and Beta Carotene. Recent news headlines reporting on other studies involving these and other traditional 1940-era vitamins carried similar messages such as “Vitamins Don’t Protect Against Cancer.” I offer two comment regarding the relevancy to what is included in this Anti-Aging Firewalls paper. First, these studies are important but may not justify the sweeping conclusions given in the headlines. Reading beyond the headlines with respect to the current study, one learns that the study participants were in a very special group; all were women who had cardiovascular disease or were at risk for it. The authors of the study caution that the study results lack generalizability, and they point to known health benefits of dietary antioxidants.
Second and more directly relevant to the point, these traditional antioxidants are not the central supplements suggested here for the anti-cancer firewall. The recent study reports are confirming that the traditional antioxidants by themselves lack sufficient power – a central point in this paper. As antioxidants, these traditional vitamins tend to be secondary to more recently researched and more powerful substances in the combined firewall like co-enzyme Q-10, alpha-lipoic acid, acetyl-l-carnitine, l-carnosine and melatonin. Moreover, the anti-cancer firewall suggested in this paper depends centrally on non-vitamin substances like curcumin, resveratrol, EGCG and other phyto-substances that have well-researched capabilities to induce apoptotic death in cancer cells. My guess is that it is probably true that a 1940s vitamin regimen won’t protect very well against cancers. This is 2009, 69 years later, and scientific understanding of dietary disease interventions has progressed incredibly during that period. I strive to keep these 2009 firewalls up to date on a weekly or more-frequent basis.
Note 1/18/09: New evidence linking the aging theories
Every week seems to see the surfacing of new pieces of the aging puzzle that add cross-links between the major theories of aging. Specifically, recent research publications show crossover links between at least four of the theories: Programmed genetic changes, Oxidative damage to tissues, Chronic inflammation, and Telomere shortening. And, of course, many links between these and the other theories of aging are already identified in this publication. Some highlights of the newer research are:
1. Oxidative damage and reactive oxygen species activate NF-kappaB, a nuclear activation factor treated here under the Programmed Genetic Changes theory of aging. When NF-kappaB is activated by binding to DNA in cell nuclii, a number of pro-inflammatory genes are expressed(ref). These, as identified elsewhere in this paper, in turn lead to age-related susceptibility to cancers, cardiovascular diseases, and other problems of old age.
2. It appear that activation of the longevity pathways FoxOs and SIRT1 can inhibit NF-kappaB signaling and simultaneously protect against inflammation-driven aging(ref). Thus, many researchers are starting to see NF-kappaB expression as a master regulator of inflammation which drives aging itself. As pointed out here in the firewall for the the Programmed Genetic Changes theory of aging, 39 of the firewall substances inhibit the expression of NF-kappaB.
3. Resveratrol, curcumin and other dietary polyphenols in the anti-aging firewall regimen represses inflammatory gene transcription by promoting DNA winding thereby limiting nuclear access to transcription factors including NF-kappaB. In simplified language, these polyphenols keep nuclear DNA tightly wrapped up and less amenable to being affected by NF-kappaB so as to send out signals which promote inflammation. The result is protection against oxidative-damage induced inflammation(ref).
4. The presence of the sirtuin SIRT6 seems to be important for inhibiting excess NF-kappaB expression and therefore for human longevity.(ref).
5. The sirtuin SIRT6 also seems to be important for maintenance of integrity of telomeres and protection against premature cellular senescence due to telomere dysfunction. Cells depleted of SIRT6 exhibit abnormal telomeric structures with end-to-end chromosomal fusions (ref).
6. The longevity-related sirtuin SIRT1 has been extensively studied recently and is known to be activated by the firewall substance resveratrol. The March 2010 blog entry Visit with Leonard Guarante describes important early and current research on SIRT1 and its relationships to longevity. Relatively little research has been published about SIRT6, however, particularly about what activates or inhibits it. I expect to hear a lot more about it and its relationship to longevity in coming months.
Earlier discussion of astragalus-based telomerase activatorss
(Archived November 15, 2010)
Much of the basic research on telomerase has been done privately by the Geron corporation which owns 279 US and foreign patents related to the substance. Most of Geron’s focus has been on turning telomerase off in cancer cells – a promising new avenue for cancer therapy. In addition, Geron is the majority owner of TA Therapeutics, a Hong Kong subsidiary which is focusing on telomerase activation for organ renewal and prolonging the lives of AIDS patients. This company is focusing on specific extracts of traditional Chinese medicine which have proven capability to activate telomerase and extend telomeres. A key Geron patent indicates that one powerful telomerase activator is an extract made from the herb astragalus. A US company, TA Sciences, has licensed one such extract from Geron called TA-65 and is marketing it to the public for $25,000 for a year of treatment, called the Patton Protocol. So far, however, there has been only anecdotal evidence as to its efficacy. I am waiting for published research data which shows that the Patton Protocol indeed elongates telomeres or that any significant health benefits have resulted from its use.
Notwithstanding all of the above, I have been taking special astragalus-derived supplements that I am hopeful will result in telomere extension and that I believe are reasonably safe.
While the chemical identities of the TA-65 and TA Therapeutics telomerase activators are proprietary, Geron’s patents are in the public domain and show that a very potent but unamed telomerase activator is derivable from astragaloside IV, which in turn is a component of astragalus root. This activator substance is thought to be cycloastragenol. In larger but still very reasonable doses according to the patent, astragaloside IV itself appears to have the same telomerase activation capability. Up until mid-2008, astragaloside IV was not been available in supplement form in the US, so as an interim measure starting in July 2007, I took four capsules daily of the most concentrated astragalus extract commercially available – one with .5% standardized astragaloside content. The astragalacide content of my four daily astragalus pills was only 5mg daily, probably too little to exercise any significant telomere extension effect. There has been much research on the biochemistry and health benefits of astragulus in recent years and it is known that it has powerful effects in maintaining potency of the immune system, preventing viral diseases, and as an adjunct cancer therapy. Further, there is no evidence of astragalus inducing cancers. Of course, astragalus root is a mainstay of traditional Chinese medecine. Ginger-root extract also appears to have some telomerase activation capacity, and is also part of this firewall.
In late August 2008, I discovered that a supplement featuring high astragaloside IV content, 33 mg per tablet, had just come on the market at reasonable cost – RevGenetics’ Astral Fruit. I switched then to using this supplement, two a day, dropping the daily astragalus dose to two tablets. Early in 2009 RevGenetics started to offer Astral Fruit with a potency of 100mg per capsule and I switched to taking that. Starting in about September 2009 RevGenetics has also been marketing Astral Fruit C capsules containing 5 mg of cycloastragenol. As of mid-December 2009, I switched to taking a 5mg cycloastragenol capsule together with a simple astragalus-extract pill which may possibly increase bioavailability. On February 14 2010, I upped the daily cycloastragenol dose to 10mg. It is interesting that Revgenetics discontinued selling its Astral Fruit products in late December 2009 because a patent was finally issued to Geron covering Astragaloside IV and cycloastragenol. I understand that TA Sciences has progressively upped its recommended daily dose of TA-65 for its clients, and that the dose now stands at 100mg a day. TA Sciences continues to keep the chemical identity of the TA-65 substance a proprietary secret.
Astragaloside IV has been systematically studied for its medicinal properties only recently, mostly in Chinese and European research centers. It is an antiinflammatory, antifibrotic and antioxidant. It is known to have vasodilation and cardioprotective properties. It is neuroprotective and can protect the myocardium against ischemia/reperfusion injury. There are no reported negative side effects. Yet, my impression is that much is yet to be learned about this substance. Specifically, there appears to be little if any research available in the public domain relating astragaloside IV’s medicinal properties to its ability to induce telomerase expression. Cycloastragenol is thought possibly to be identical to Geron's TAT2 or to the TA65 product marketed by TA Sciences. The Geron patent suggests that 5mg of have started taking has roughly the same telomerase activating capability as 100 mg of astragaloside IV. Other than for what is in the Geron patent, there appears to be virtually no published information on the saftey or bioactivity of cycloastragenol. Assuming that cycloastragenol and TAT2 are indeed identical, it does appear based on a November 2008 report of a preclinical study that "exposure of CD8(+) T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) modestly retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity.' I note that "modestly retards telomere shortening " is something that can also probably be said of vitamins C, D and E and is very different than saying "extends telomeres."
Several of the other substances in my combined firewall, including green tea, resveratrol, allicin and curcumin, are known to supress the expression of telomerase, at least in cancer cells. I am continuing with these substances because they have powerful anti-cancer and other beneficial effects. RevGenetics suggests that users wait three or more hours after taking such supplements before taking Astral Fruit. I do this, taking my other supplements in the mornings and evenings and Astral Fruit late afternoon. Presumably this schedule results in telomerase activation taking place for 6-8 hours a day with telomerase expression otherwise being shut off as protection against cancers. I am not sure that this staggering of supplements is necessary. See the blog entry Do resveratrol, curcumin and EGCG from green tea really inhibit the expression of telomerase? I need caution that human telomerase activation using astragaloside IV or cycloastragenol is very new and relatively little is known about it, including any potential hazards. I am unsure of what the results of taking this supplement will be but am monitoring the results carefully with significant excitement.
THIS INFORMATION IS NOT A SUBSTITUTE FOR A LICENSED PHYSICIAN’S MEDICAL ADVICE. IF ANY ADVICE, OPINIONS, OR INSTRUCTIONS HEREIN CONFLICT WITH THAT OF A TREATING LICENSED PHYSICIAN, DEFER TO THE OPINION OF THE PHYSICIAN. THIS INFORMATION IS INTENDED FOR PEOPLE IN GOOD HEALTH. IT IS THE USER’S RESPONSIBILITY TO KNOW HIS OR HER MEDICAL HISTORY AND ENSURE THAT SUPPLEMENTS HE OR SHE TAKES DO NOT CREATE AN ADVERSE REACTION.
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 There are hundreds of reference documents and thousands of relevant research publications relating oxidative damage to aging. To begin your own research on this topic I suggest doing a Google search on “antioxidants and aging,” and skipping over links to commercial supplement-selling sites. You can also search in a number of medical subscription data bases like www.medscape.com. For grasping a bit of the underlying science, I suggest you search www.pubmed.org (the National Library of Medicine’s extensive research database) with a more specific search such as “carnosine and aging.” The results of one search will lead you to search terms for another. Similar comments apply to researching the other theories or illnesses of aging.
 For example, it appears that vitamin D activates the G6PD gene, enhancing the production of the glucose-6-phosphate dehydrogenase enzyme which in turn works to clears cells of ROS. Vitamin C, on the other hand, can directly scavenge aqueous peroxyl ROS before they have a chance to create lipid damage. The flavinoids work through multiple yet-other antioxidant mechanisms. The flavinoids as well as many of the other supplements are pluripotent and are also part of the firewalls against the mechanisms of other theories of aging including inflammation.
 For example. it appears that the activation of NF (nuclear factor) kappaB is inhibited by curcumin (please see the Note Firewall Supplements and the NF-kappaB cell signalling pathway at the end of this article.) Curcumin also inhibits and the expressions of many oncogenes including PI3K, Akt, c-jun, c-fos, ELK, c-myc, NIK, MAPKs, ERK, CDKs and iNOS. It appears that curcumin-induced apoptosis of cancer cells is mediated through the impairment of a ubiquitin-proteasome pathway. As an example of a different chain of action, grape seed extract appears to induce apoptosis in leukemia cells through activation of the JNK pathway (ref).
 Resveratrol affects certain genes in the FOXO family which are important in the downstream suppression of the life-shortening effects of insulin/insulin-like growth factor-I receptor signaling pathways. Upregulating expression of FOXO, it appears that resveratrol can retard aging in part through reduced generation of reactive oxygen species (ROS).
 Linus Pauling was a pioneer in research on vitamin C, and studied the effects of that substance on cancers. He took very large doses of C, yet Pauling eventually died of prostate cancer, at the age of 93. Not bad for age, but could Pauling have lived longer yet? By itself, the C was not enough to fight off the cancer. Today we know of a number of other natural substances like resveratrol, vitamin D and curcumin that fight off cancers through different bio-genetic pathways. Possibly Pauling could have lived longer if he knew about them. I any event I am very indebted to Pauling for his powerful role in creating the context of supplement-supported health and longevity, a context that allowed the writing of this paper.
 I do know of a few instances in which the supplements may work at cross purposes, although not creating harm in doing so. For example, l-carnosine not only chelates toxic heavy metals out of the body but also “good” metals taken as supplements including zink, magnesium and copper. Zink and copper compete with each other for absorption. Niacin, a b-vitamin, inhibits telomerase activation. I do not view these as serious issues.