Notes
Slide Show
Outline
1
Towards a Systems Theory
of Aging
  • Presentation by:
  • Vincent E. Giuliano, Ph.D.
2
PREFACE: The current story on human longevity
  • In advanced countries, human longevity has been increasing for millennia.  Over the last 100 years, average lifespan from birth in the US increased from 55 to over 79 now.
  • Lifespan and health are mostly questions of epigenetics which can evolve rapidly, not genetics.
  • Attention to lifestyle and diet can likely increase human life expectation by 10 years or more – and lack of attention can decrease it by a lot more than that.  Knowledge of Nrf2 is an important newer factor.
  • Substances in the advanced research pipeline like resveratrol and rapamycin analogs possibly could further increase our average life  expectation by another 7 years
3
PREFACE: The story on enhancing human longevity
  • Maximum and average lifespans of simple organisms like nematodes can be increased by a factor of seven
  • The maximum established lifespan of humans is 122
  • Key questions of concern to me are:
    • What are the prospects for breaking through the limit to allow lifespans of hundreds of years?
    • Given what is known now, how is that likely to come about?
    • And, when?
  • This presentation addresses these questions.
4
"We all know what aging..."
  • We all know what aging is, a process through we progressively become more vulnerable to diseases and disabilities and eventually die.  Aging is growing older.
  • There are many special and candidate theories regarding the causes of aging, each with its own group of proponents, and each based on credible research evidence.
  • Each such aging theory is valid in its own domain but explains only a small part of the picture.
  • The author has studied 14 such theories and a number of additional  recently-identified candidate theories
  • Twenty of these special and candidate theories of aging are elaborated in the author’s treatise
    • ANTI-AGING FIREWALLS –    THE  SCIENCE AND TECHNOLOGY OF AGING
    • www.vincegiuliano.name/Antiagingfirewalls.htm

5
Special theories of aging
  • Oxidative damage
  • The most traditional theory: that aging is due to accumulated tissue damage due to oxidative stress created by free radicals.
  • 2. Cell DNA damage
    • That aging is due to accumulated damage in cellular DNA, leading to cancers, cell senescence or cell death, in turn leading to tissue and organ deterioration.
  • 3. Mitochondrial damage
    • Mitochondria (energy-producing organells in cells) are critical to the cell reproduction cycle and their DNA, different from the cell’s main DNA, is particularly vulnerable to damage.
  • 4. Tissue glycation
  • With aging, tissues become increasingly damaged and dysfunctional due to cross-linkages with sugar molecules.
  • 5. Lipofuscin accumulation
  • Metabolic product gunk called lipofuscin accumulates in cells and inhibits their functionality.
  • 6 . Chronic Inflammation
  • Chronic inflammation appears to be a core condition underlying many if not most age-related disease processes.




6
Sample newer candidate theories of aging


7
The theories are highly interrelated
  • A simplified example is that Oxidative Damage is not only responsible for Cell DNA Damage and but it also 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.
  • Oxidative Damage also leads to multiple other negative conditions including Cell DNA Damage and Mitochondrial Damage. 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.



8
The theories of aging are highly interrelated (cont.)
  • 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.  Examples:
    • Neurological degeneration could be triggered by oxidative damage, lipofuscin accumulation, inflammation, faulty mitochondrial signaling or defects in energy production.
    • 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 is one possible cause of 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.




9
"I suggest that two of..."
  • I suggest that two of the aging theories provide overall perspectives on which a SYSTEMS THEORY OF AGING could possibly be built.  These are:
    • Programmed epigenomic changes
    • Decline in functioning of the stem cell supply chain
  • These two “framework” theories have four important properties:
    • They are elegant and simple.
    • They explain how the other theories of aging fit in and the underlying mechanisms that are associated with them.
    • They are applicable across a wide variety of species, including mammals.
    • In fact, they themselves are two compatible ways of looking at aging from contemporary molecular biology and cell biology viewpoints.

10
Programmed Epigenomic Changes
  • 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 generalized kind of program that unfolds through life from conception to death. This is a relatively old concept based on evolutionary arguments, but one with strong new supporting evidence.
  • 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.
  • Cellular DNA and RNA mutational damage accumulates stochastically and is an essential contributor to the aging program.
  • 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.


11
Programmed Epigenomic Changes (cont.)
  • Epigenetic information is based on the experience of a cell, is stored mainly via DNA methylation,  histone acetylation, non-coding RNA and protein folding 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. In addition, nucleosome repositioning, higher order chromatin remodeling, and accumulated damage to DNA repair machinery, appear to be involved .
  • The epigenomic profiles of cells in an organism changes continuously over the lifetime of that organism and that set of changes defines what we call aging. I have outlined three current chains of research that partially support the idea of programmed epigenomic changes of aging leading to death.
  • Further, epigenetic information may be selectively inherited from generation to generation. Epigenetic patterns capture ancestral history of acell that is not in the genes themselves and is unique to every cell. Changing epigenetic information can drastically alter the nature and lifespans of organisms and is responsible for much of evolution.  Working much faster than genetic evolution, drastic changes can happen in a few generations.  Animals can grow bigger or smaller and change their shapes in response to changed environmental conditions
12
"Gene promoter-region DNA methylation"
  • Gene promoter-region DNA methylation
    • An important mechanism for storage of epigenetic information 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.  (Addition of a methyl group to the 5 position of the cytosine ring in a cytosine guanine basepair (CpG))
    • Methylation is carried out by DNA methyltransferases using S-adenosyl-methionine (SAM) as a methyl group donor.
    • Methylation is inheritable - passed on in the course of cell divisions and through generations of people.
    • Methylation generally suppresses gene expression by
      • physically impeding transcription of proteins. or
      • recruiting other CpG binding proteins that change histone structure.
    • Occurs in 60-90% of genes.
    • Transcriptional silencing due to gene methylation is a central action required for a number of basic biological processes including embryonic development, protection against intragenomic parasites, X-inactivation, genomic imprinting and cognitive functions.




13
"Gene promoter-region DNA methylation (..."
  • Gene promoter-region DNA methylation (continued)
    • At GpG islands containing regulatory genes, unmethylated DNA may become hypermethylated leading to aberrant conditions like non-small cell lung cancer and acute lymphoblastic leukemia.
    • Aberrant DNA methylation is implicated in multiple disease processes including atherosclerosis, helicobacter pylori infection and myelodysplastic syndromes.
    • Inappropriate silencing of tumor suppressor genes like P53 and P21 because of aberrant promoter methylation has recently been identified as a major cause leading to cancer.
    • Silencing of “junk DNA,” repetitive sequences between genes, is thought to be a major biological role of DNA methylation.  As it turns out most of the junk is far from junk
    • Abnormal methylation also  predominantly occurs at repetitive sequences, meaning herterochromatin are affected most.  (inactive genes become active)
    • Methylation patterns can regulate genes throughout life.
    • 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.
14
"Aberrant methylation may be due..."
  • Aberrant methylation may be due to multiple macroscopic causes
    • Aging
    • Diet : what people eat now, what they ate in the past and what their parents ate
    • Lifestyle factors  like exercise and sleep patterns
    • Inflammation, carcinogens, and diseases are known to cause methylation alterations.
    • Tobacco, alcohol, arsenic, and asbestos are associated with methylation-induced-gene-inactivation.
    • Hypermethylation of tumor suppressor genes is found in lung tissue of smokers.
  • DNA methylation is being intensely studied.  The database Pubmed.org shows 35,766 research publications related to this topic.




15
"Histone acetylation"
    • Histone acetylation
      • 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.
      • Histones regulate gene expression by affecting the structure of chromatin and thus affect the ability of transcriptional activators and repressors to access regulatory DNA sequences.   i.e. an unfolded (acetylated) histone provides more physical access to a gene promoter sequence than does a folded (deacetylated) histone.
      • Acetylation can be caused by stress, heat-shock factors, acetyltransferases (HATs).  Deacetylation is caused by histone deacetylases (HDACs).
      • Thus, via relaxing chromatin structure, gene expression is stimulated by HATs which allow transcription factors access to  get to DNA .  On the other hand, deacetylation of histones by HDACs promotes chromatin condensation and represses gene expression.  Histone deacetylation, like DNA methylation, can result in gene silencing.
      • Posttranslational modifications of histones is thought to be an important part of the epigenetic "code" that determines patterns of cellular gene expression.
      • The  mTOR “longevity” signaling pathway is affected in normal and cancer cells by HATs.



16
"Histone acetylation (continued"
    • Histone acetylation (continued)


      • Acetylation/deacetylation are  known to be involved in the activation or silencing of multiple “aging,” “longevity” and stress-regulating genes including FOXO4, SIRT1.
      • Longevity proteins SIR2 and SIRT1 promote global deacetylation of histones.  It is thought that this deacetylase activity is responsible for silencing, recombination suppression and extension of life span in vivo in lower organisms. FOXO4 is deacetylated by SIRT1 promoting stress-regulating genes and cellular survival
      • A main mechanism used by curcumin, resveratrol and other dietary polyphenols for inhibition of gene activation by NF-kappaB appears to be histone deacetylation.  Another is activation of Nrf2.
      • There can be significant interplay between histone acetylation and DNA methylation,  particularly when gene silencing is involved.



17
"Lifelong accumulated damage in cellular..."
      • Lifelong accumulated damage in cellular DNA repair machinery in adult stem cells appears to be a major cause of stem cell senescence
          • “Cellular aging is linked to deficiencies in efficient repair of DNA double strand breaks and authentic genome maintenance at the chromatin level. Aging poses a significant threat to adult stem cell function by triggering persistent DNA damage and ultimately cellular senescence.”
          • Further, “65% of naturally occurring repairable DNA damage in self-renewing adult stem cells occurs within transposable elements” of Alu RNA/DNA.

18
"Telomere shortening"
    • Telomere shortening
      • My current  view is that telomere lengths are downstream consequences of other cell state factors.  Telomeres generally shorten with cell reproduction but can also lengthen depending on complex feedback loops.  Cell senescence can lead to short telomeres which can contribute to, apoptosis, or malignant transformation.  Cell senescence is largely driven by other factors than telomere lengths.
      • Three years ago, I subscribed to the notion that extending telomere lengths could be a iife-extending intervention, but  no longer do.
      • Because  rats and mice have long telomeres throughout life, telomere shortening by itself does not fully explain mammalian aging.
19
"Increased expression of a nuclear..."
    • Increased expression of a nuclear factor NF-kappaB
      • expression of NF-kB appears to be one of the body’s regulatory means for handling situations of stress, cancer, damage and 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.
      • Recent studies indicate that  NF-kB signaling appears is  a major regulator of gene expression affecting hundreds of genes related to the aging progress. NF-kB cell signaling has been shown to be a meta-factor for determining aging of a number of key cell types
      • Inhibition of NF-kB signaling  is being researched  as a cancer therapy and is thought also to be a possible approach to life extension
20
"P16/Ink4a"
    • P16/Ink4a, a tumor suppressor gene, becomes increasingly active with age in 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 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.
    • aging-related decline of efficacy of DNA repair machinery might possibly result from promoter methylation of the Mms22 gene, resulting in increasing susceptibility to oxidative damage with age.
    • Promoter methylation of the P21 and P53 apoptosis genes can result in increased susceptibility to cancers.  HDAC inhibitors can help them turn back on again.
    • The P66Shc gene, associated with longevity in mammals, appears to be silenced through some combination of deactylation (resulting in protein folding) and cytosine methylation.


21
"In a simplified model"
  • In a simplified model, think of the 210 kinds of cells found in the human body as falling in five categories:
    • A.  Pluripotent cells, ones which are and capable of differentiating into any other cells.  Human  embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) are in this category,
    • 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.
    • D.  Normal body somatic cells (e.g.  cardiomyocytes, red blood cells, leukocytes, keratinocytes, melanocytes, and Langerhans cells).
    • 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.
22
"Cells in all categories except..."
  • 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 by some, are subject to replicative senescence.
  • 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.


23
"Type D cells are the..."
  • 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.
  • 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.


24
 
25
Operation of the stem cell supply chain is an essential mechanism of life Human Body is in a State of Constant Flux
26
"The supply chain mechanisms appears..."
  • The supply chain mechanisms appears to be operable throughout life in a manner controlled by several feedback mechanisms. E.g. In the absence of P21, hematopoietic stem cells would not remain quiescent in their niches but would instead prematurely differentiate when stress occurs exhausting the pools of those cells leading to premature death.
  • 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
  •  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.
  • Health for people of all ages requires continuing operation of the supply chain throughout life.   But it is a once-through process that runs out of adult stem cells with old age.


27
"Proliferation and differentiation of Type..."
  • Proliferation and differentiation of Type A, B, and C stem and progenitor cells decreases with aging.  This appears to be associated with buildup of NF-kappaB and P16/Ink4a.
  • Although the mobilization responsiveness of Type C stem cells declines with age, it appears that their regenerative capability can to some extent be restored through environmental messages or induction of Notch activity.
  •  The gene expression profiles in Type A human embryonic stem cells offer regenerative anti-aging potential not found in more mature stem cells.
  • This matter of concern here is that advanced aging is due to a slowing rate of organ regeneration due to declining SSC differentiation activity, this in turn being due to exhaustion of pools of Type B and Type C stem cells because of differentiation and replicative senescence.
28
"The stem cell supply chain..."
  • The stem cell supply chain is now a once-through in life process
    • Embryonic stem cells disappear during fetus development
    • All other stem cells are subject to replicative senescence and decline in differentiation capability with age
    • Thus with advancing age, normal somatic Type D cells are no longer replaced and the diseases and problems of aging ensue
  • In the longer view there is hope of “closing the loop” in the stem cell supply chain and making it a continuous process. The concept, for example, is:
    • to revert a person’s skin or blood cells to Type A cells using induced pluripotent stem cell (iPSC) technology,
    • To correct those iPSCs  for any genetic defects using gene splicing,
    • To induce those Type A iPSCs to differentiate into Type B and Type C stem cells, and
    • to introduce those adult stem cells back into their niches so they can continue to exercise their regenerative functions.
29
 
30
"For this concept to become..."
  • For this concept to become real a number of technical research challenges must be met including:
    • Obtaining iPSCs that are free of DNA contamination, that have long telomeres and full hESC pluripotency
    • Developing reliable means for assuring differentiation into Types B and C stem cells
    • Developing reliable and safe means for introducing  those cells into their respective body niches
  • Much research is being devoted to these approaches but 10-20 years are likely to be required  before the stem cell supply chain can truly be closed in humans.
  • If and as this happens I conjecture that extraordinary human longevity might become possible – lifespans of hundreds of years.
31
The Programmed epigenomic changes  and  the Decline in functioning of the stem cell supply chain theories of aging are complimentary and equivalent
    • They are two sides of the same coin, representing differing viewpoints of molecular biology and cell biology.
      • 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 kinds of cells including stem cells  is one of epigenomics, e.g. DNA methylation, histone acetylation,  binding-site molecular folding, alterations in non-coding RNA, etc..
      • Factors that can revert fully mature Type D cells to Type A pluripotent cells and possibly more differentiated stem cell types are being actively researched.  Many new combinations of reprogramming factors have been discovered in addition to the original ones:  (Oct3/4, Sox2, Klf4, cMyc)


32
The Programmed epigenomic changes  and  the Decline in functioning of the stem cell supply chain theories of aging are complimentary and equivalent
    • They are two sides of the same coin, representing differing viewpoints of molecular biology and cell biology.  For example: (cont.)
      • 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. FoxO family members play a critical role in these physiologic processes in the HSC compartment and thereby regulate maintenance and integrity of HSCs.
      • Effective mTORC1 negative regulation is essential for keeping the critical balance between stem cell self-renewal and differentiation: Too little self-renewal or too much differentiation of hematopoietic stem cells may jeopardize the ability to sustain hematopoiesis throughout life, whereas excessive self-renewal and/or aberrant differentiation may result in leukemogenesis.
      • TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging


33
Recent research supports the hypothesis that that “closing the loop” might be accomplished in-vivo via epigenetic manipulations
  • (Lunyak et al, others 2008 - 2012) have established that:
      • Stem cell senescence results from aging and demonstrably leads to diseases and aging.
      • Stem cell senescence is an epigenetic phenomenon. In fact, SINE/Alu Retrotransposons are transcriptionally up-regulated upon Senescence of hADSC, and this affects chromatin structure and impairs the DNA damage repair machinery.
      • Epigenetic interventions can reverse cell senescence markers affecting aging
      • Small non-coding RNA species (like IncRNAs, shRNAs, siRNAs and piALU RNAs) can play critical roles in gene regulation, DNA repair and chromatin regulation
      • In fact, SINE/Alu Retrotransposons are transcriptionally up-regulated upon Senescence of hADSC, and this affects chromatin structure and impairs the DNA damage repair machinery.



34
Recent research supports the hypothesis that that “closing the loop” might be accomplished in-vivo via epigenetic manipulations
      • “Cellular aging is linked to deficiencies in efficient repair of DNA double strand breaks and authentic genome maintenance at the chromatin level. Aging poses a significant threat to adult stem cell function by triggering persistent DNA damage and ultimately cellular senescence.” Further, “65% of naturally occurring repairable DNA damage in self-renewing adult stem cells occurs within transposable elements” of Alu RNA/DNA.
      • Specific interventions involving removal of damaged specific segments of RNA, formerly thought to be “junk RNA,” can reverse adult stem cell senescence. Working with specific segments of RNA can add to the traditional epigenetic interventions that mainly have related to DNA methylation and histone acetylation. Specifically, by modifying a Lentivirus genome to express GFP and sh-RNA against Alu transcript, it is possible to knock down the generic SINE/Alu transcript in senescent adult stem cells, reversing senescence markers, rejuvenating the cells, and restoring their lost differentiation capability.
      • So far, this has been achieved in-vitro.  It is yet to be shown that it can be accomplished in-vivo

35
The Programmed epigenomic changes  and  the Decline in functioning of the stem cell supply chain theories of aging are complimentary and equivalent
      • They are two sides of the same coin, representing differing viewpoints of molecular biology and cell biology.  For example (continued):
        • Buildup of levels of Ink4a/P16 associated with aging slows down the rate of differentiation of adult stem cells. P16/Ink4a works together with three other genes (Arf, Hmga2 and let-7b) to articulate a process of simultaneously protecting against cancers and shutting down adult stem cell function and regenerative capacity in aging tissues.
        • In young cells, Polycomb group proteins act on the INK4/ARF gene regulatory domain so as to the keep the expression of P16(INK4a) turned off, the gene is silenced.  In senescent cells, however, there are epigenetic modifications (DNA and histone methylation changes) which block the inhibitory actions of the polycomb group proteins, so the P16(INK4a) and Arf genes are activated.  So, cell senescence leads to another pro-aging effect, the activation of the P16(INK4a) and Arf genes which in turn slows down stem cell differentiation
    • aging-related decline of efficacy of DNA repair machinery might possibly result from promoter methylation of the Mms22 gene, resulting in increasing susceptibility to oxidative damage with age.
    • Promoter methylation of the P21 and P53 apoptosis genes can result in increased susceptibility to cancers.
    • Recent research has shown that adequate expression of the P21 gene is necessary to keep adult stem cells from differentiating prematurely resulting in  exhaustion of their supply.
    • The P66Shc gene, associated with longevity in mammals, appears to be silenced through some combination of histone deactylation (resulting in protein folding) and cytosine methylation(ref).   The gene regulates mitochondrial metabolism.



36
Explaining the other theories of aging – examples
  • With respect to the accumulated damage theories (Oxidative damage, DNA damage, Mitochondrial damage, Incorrect protein folding ):
    • Such damage will of course occur; it occurs in younger as well as older people.  The difference is that apoptosis and DNA repair mechanisms work much better in younger people as is explained by the Programmed Epigenomic Changes theory.  Also, dead cells in younger people are replaced by ready stem cell differentiation but not so in older people as explained by the Stem Cell Supply Chain theory.
  • With respect to inflammation, immune system, susceptibility to cancer, cardiovascular and neurological disease theories
    • There is widespread acknowledgement that epigenomic reprogramming plays major roles in disease susceptibilities and development in these areas
    • There is much current  research on developing HDAC inhibitors as preventative and therapeutic agents for such diseases
    • There is also much research focusing on stem cell therapies in each of these disease areas  and on aspects of operation of the stem cell supply chain
  • With respect to the telomere shortening theory of aging
    • Expression of telomerase and other factors affecting telomere length is determined by the epigenetic state of the cell
    • It was once thought that telomere shortening could be a major factor in the age-related decline of proliferative and differentiation capabilities of adult stem cells.  Lunyak’s work at the Buck Institute suggests that the smoking gun is instead damage to the RNA-encoded DNA damage repair machinery in adult stem cells.



37
Resources
  • This presentation is available online at
  • http://www.vincegiuliano.name/AAAS5-18_files/frame.htm.  The blue hyperlinks are active in the online presentation
  • There is  far more of relevance than can be included here.  Details of he theories of aging can be found in my frequently-updated online treatise:
  • ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY  at
    •  www.vincegiuliano.name/Antiagingfirewalls.htm
  • And many detailed discussions on topics raised in this presentation can be found in  my BLOG:
  • www.agingsciences.com
  • Vincent E. Giuliano, Ph.D.                              vegiuliano@comcast.net