By Vince Giuliano.  With contributions, suggestions and editing by members of the YOUNGING team: Steve Buss, Walter Crompton, Chris Wikman and Debbie Coehlo

5-1-2022

GENERAL CONTEXT

From the onset some 12 years ago, this anti-agingfirewalls blog has followed an implicit Mission of contributing to people having and enjoying longer healthy and productive lives.  Some of our posts have been discussions of practical and accessible interventions for doing this, such as taking certain dietary supplement,s or, more recently, exposing ourselves to PEMF interventions.  Other posts have been on theoretical scientific frameworks for describing aging and anti-aging processes, characterizing the main theories described in the world’s scientific, literature.  Many of the best practical interventions to secure health and long lives have been pursued for centuries or millennia with no understanding of how they work.  But understanding them can lead to whole basic new frameworks of science.  E.g. the drug rapamycin was discovered as something in the soil on Easter Island that extended the lives of small animals.  It led to identification and details of the mTOR (Mammalian Target of Rapamycin pathway which conveys longevity when inhibited.  A good theoretical framework can be very valuable for understanding interventions that work, and improving on them, and can lead to new interventions.  The best paydirt is when we can couple a whole slew of well-known anti-aging interventions with a sound theoretical framework for understanding them.  We have recently been successful in doing this, and decided that work using the term YOUNGING in multiple blog entries as well as Webcasts now available on YouTube.

YOUNGING Is our term for the innate restorative biological processes that go on in our bodies, like anti-inflammatory activity, epigenetic demethylation, wound healing, immune response, cell division, angiogenesis, stem cell replacement and DNA repair. There are a number of these processes that evolved as part of going from ephemeral, single-cell organisms, to extremely complex and highly regulated, long-lived creatures, with trillions of cells of many different kinds. Understanding YOUNGING mechanisms helps us understand known interventions to keep us as biologically young and healthy as long as is naturally possible. Understanding these mechanisms will also help us improve extant interventions and create new .

YOUNGING 1.0 describes YOUNGING processes that utilize extremely ancient, cellular, epigenetic (beyond genetics) histone demethylation approaches as well as more recent approaches that leverage the development of a Brain to Spleen mechanism for controlling inflammatory cytokine expression in the blood circulation.

Taken together, these two approaches make the activation of thousands of genes involved in YOUNGING growth and development possible.

So, please read the following blog entry in the context that it describes well-documented framework considerations that extend and enhance our earlier and narrower understanding of YOUNGING 1.0.  Again, this is an enhancement to what we have published before related to YOUNGING 1.0and in no way denigrates or throws into question points made in those documents or presentations.

PURPOSE OF THIS BLOG ENTRY

The purpose of this blog entry is to convey a deeper understanding of global histone post-translational modification (PTM) phenomena to apply to our expanding understanding of YOUNGING.  Specifically, this entry focuses on methyl- and acetyl- PTMs of  H3K4 ,H3K9, H3K27, and bivalent PTM domains.  These are complex topics, with my colleagues and I having only partial understanding to date.  Grasping a rich new body of literature relating histone dynamics to natural restorative processes, aging, and strategies for age reversal will provide an important advance in our understanding of all aspects of YOUNGING.  Further research in this area will help us understand how to trigger histone PTM processes and developmental or restorative in YOUNGING. Notably, this new area of knowledge fits with previous work on understanding YOUNGING, and I repeat that nothing we have published so far about YOUNGING is invalidated by this expanded view.

“Turning on” Genes

Previous understanding of the histone position stated, “Demethylation at histone position H3K27me2-3 by JMJD3 turns on genes near that position.”  It is more accurate to say “Demethylation and/or of H3K27me2-3 opens up the neighboring chromatin, potentiating expression (transcription) of proximate genes.” (That is, it establishes a necessary condition for transcription of nearby genes to generate their associated proteins.)

Genes are NOT, however, automatically expressed due to demethylation or acetylation.. The genes’ promoter regions, and in some cases, co-promoters must also be activated for gene transcription to take place.  A way to visualize this is that the bi/tri-methylation of H3K27me2-3 wraps the DNA into such tight knots that the promoter positions of the associated genes cannot be physically accessed by chemicals that would activate them.  Demethylation by JMJD3 makes this access and transcription possible.  So, you can think of the bi/trimethylation at H3K27me2-3 as a master lock that must be removed as a prerequisite of activation of nearby genes on Histone .

Unlocking this master lock via the histone demethylase JMJD3, we have asserted, is a NECESSARY condition for most if not all natural body restorative processes like stem cell renewal, expression of the OSKM factors or angiogenesis.  It is also likely a prerequisite for most all YOUNGING intervention we can contrive to be workable.  Being NECESSARY of course does not mean that induction of JMJD3 by itself is a SUFFICIENT condition to introduce general or specialized forms of YOUNGING.

More H3 histone trimethylation locations

Alas, this level of explanation is still overly simplified and ignores the roles of PTM at numerous other histone positions, including acetylation, SUMOylation, phosphoration, ribosilation and other  factors that modify chromatin accessibility.  I have focused recently on trimethylation of another two H3 positions: tri-methylation of histone H3 at the lysine located at position 9 (H3K9me3) and about tri-methylation of histone H3 at the lysine of position 4 (H3K4me3).  And, histone bi and trimethylation atH3 position 79 (H3K79me2-3) These are different from our old friend H3K27me2-3, in that:

• different methyl transferases and demethylation substances are involved, and
• the forms of methylation have different effects on neighborhood gene activation. The trimethylation of H3K4me3 and H3K79me2-3results in open rather than closed chromatin (H3K4 is referred to as a “repressor” protein), chromatin in which gene activation is possible.  Methylation at both H3K9me3 and H3K27me2-3 results in closed chromatin (I.e., they are “expressor” proteins); chromatin in which gene activation is impossible, So, H3K4me3 and H3K79me2-3are positive regulators of transcription and H3K9me3 & H3K27me3 are negative regulators (expressors) of it.
• Some genes are in regions of DNA neighboring two of these three H3 amino acid positions, that is positions 4, 9, 79 and 27. Such regions are called bivalent domains.

Further, there are methylation domains associated with H3K36 and with other histones in addition to H3  The situation can get maddeningly complex, so we need to take it on a little at a time, being always concerned for finding paydirt in effective health and longevity interventions.  This blog is about being a little ways further down what could turn out to be a very long trail.

In summary, so far:

• Histone methylation at H3K27me2-3 is generated by operation of the polycomb repressive complexes (PRC1 & PRC2) and is removed by JMJD3 and UTX (another demethylase). – as laid out in earlier entries of this blog.
• Methylation at H3K9me3, in mammalian cells, can be catalyzed by at least six distinct SET domain enzymes: Suv39h1/Suv39h2, Eset1/Eset2 and G9a/Glp, and by operation of the PRCs. KDM4D demethylates di-and tri-methylation of histone H3 on the lysine at position 9.  KDM4D is also known as JM
• Methylation at H3K4me3 happens by complex mechanisms (“Histone lysine methylation is generated by a battery of histone methyltransferases (HMTs) that transfer the methyl group from S-adenosylmethionine to specific lysine residues. For example, H3K4 methylation is mediated by several SET [Su(var)3-9, Enhancer of zeste, trithorax-group proteins] domain-containing methyltransferases, including mixed-lineage leukemia 1–5 (MLL1−5), SET1A/B, SET7/9, SET and MYND-domain-containing protein 1–3 (SMYD1−3), Absent, Small, or Homeotic1-like (ASH1L), SET domain and Mariner transposase fusion gene (SETMAR), and PR-domain zinc finger protein 9 (PRDM9) [5–24]. Methylated lysines exist in three forms: mono-, di- and tri-methylation (me1, me2, and me3.”) (ref). Histone methylation at H3K4me3 is removed by KDM5C/JARID1C.
• Histone methylation at H3K79me2-3: “— the yeast protein Dot1 and its human homolog, DOT1L, are responsible for catalyzing the methylation reaction (Feng et al. 2002; Lacoste et al. 2002; Ng et al. 2002a; van Leeuwen et al. 2002). Both enzymes are capable of catalyzing mono-, di-, and trimethylation in a nonprocessive manner (Min et al. 2003; Frederiks et al. 2008). Dot1 and its homologs appear to be solely responsible for H3K79 methylation, since knockout of Dot1 in yeast, flies, and mice results in complete loss of H3K79 methylation (van Leeuwen et al. 2002; Shanower et al. 2005; Jones et al. 2008).(reference)” “Here, we show that KDM2B, also known as FBXL10 and a member of the Jumonji C family of proteins known for its histone H3K36 demethylase activity, is a di- and trimethyl H3K79 demethylase.(reference)

Bivalent domains

We have thus learned that there are more H3 trimethylation mechanisms to enable or disable masses of genes to be switched on or off than just the PRC/JMJD3 combo. This gives cells much greater and finer control for enabling or disabling large groups of genes.  It can do this by using different histone methylases/demethylases. Evolution no doubt put these mechanisms in place to facilitate turning expressibility of whole subsets of developmental genes off and on in the complex processes of organ and structure development in complex organisms like our bodies,  In many cases of natural adult renewal of body parts or systems, like stem cell differentiation, the same developmental genes are naturally invoked again and again. And the same steps of histone methylation and demethylation are necessary to allow or inhibit expression of those genes.

There is; however, a rub.  Some genes are located on nucleosome spindles so they are affected simultaneously by a PAIR of these methylated histone positions.  Such locations are called bivalent domains. What happens to genes in these bivalent domains, say when if both H3K4me3 and H3K27me3 are methylated, the former leading to open chromatin, the second leading to closed chromatin?  Again, there is a lot of research on this question and its implications which can get really complicated and involuted.  The bottom line is that the body uses these bivalent domains as epigenetic switches which figure significantly in original organism development, in natural regenerative processes, and almost certainly they will figure heavily in any effective YOUNGING interventions we can contrive.

View of some possible post-translation modifications associated with one histone.  On H3 on lower left, count over to position 27.  K stands for lysine.  Only acetylation and methylation are show as possible modifications.  Also, only the first 38 positions are illustrated.     Image source Wikipedia.

The methylation and de-methylation of the three different H3 positions discussed depend on different methylases and different demethylases.  So, our bodies body can control their methylation status independently.  This fact allows bivalent domains to act as powerful epigenetic switches for opening up or closing in the chromatin in them.  That is; the bivalent domains consist of sequences of genes that can all at once be switched from being transcribable or not transcribable, or the other way.  Consider this Table for a bivalent domain influenced by methylation-versus-acetylation both at H3, positions 4 (a repressor) and 27 (an expressor), for example, where ’me’ means the methylation is present, and ‘ac’ means acetylation is present.  So, by toggling between the situations described in B and C in the Table all the genes in the bivalent domain can be made accessible for transcription, or all can be made not accessible

Many promoter locations on embryonic stem cells are influenced by this particular bivalent domain situation.  Bivalent domains are thus like wall toggle light switches, which allow easy switching back and forth to inducing stable open or stable closed chromatin, as illustrated in this diagram.  They are what allow stem cells to have alternative fates.

“At bivalent domains, the simultaneous presence of repressive (red hexagon) and active (green hexagon) PTMs counterbalance each other. PRC1 and PRC2 confer repression by H3K27me3 catalyzed by the subunit Suz12. Ten − eleven translocation proteins (Tet) interact with bivalent domains and catalyze DNA demethylation. Activating transcription factors (TF) together with histone H3K27 demethylases (SET1 and MLL) and H2A-deubiqitinating enzymes (DUBs) tilt the balance towards activation, and replacement of repressive protein complexes. Conversely, loss of activating protein complexes switches bivalent domains into a repressed state by recruitment of H3K4 demethylase (KDM5). Histone methyltransferases (HMT) mediated H3K9 methylation and de novo DNA methyltransferase (DNMT3) mediated DNA methylation lock in repression.”  Source of diagram and legend:  Bivalent domains underlie epigenetic switches in stem cells

The following illustration shows how a bivalent domain of particular interest to us can be formed:

Activation of a bivalent domain     “Left: Protein complexes catalyzing H3K4 methylation (green flag). Right: The PRC2 complex catalyzing H3K27 methylation (red flag). Shown are only the main proteins and protein complexes catalyzing H3K4/H3K27 methylation. Less abundant subunits are not depicted. [Correction added on 2 December 2015 after first online publication: “H4K4” has been corrected to “H3K4”.]” Source: Chromatin remodeling and bivalent histone modifications in embryonic stem cells (2015) 

This publication describes one of the steps where bivalent domains are involved in creating mammalian life: Polycomb protein SCML2 facilitates H3K27me3 to establish bivalent domains in the male germline  “Our study identifies a possible germline mechanism by which differentiated and unipotent germ cells give rise to a totipotent zygote following fertilization.”

Difficulty of ChiP-seq identifying true bivalent domains

The following image refers to the same bivalent domain bordered by H3K4 and H3K27.  The point being made is that ChIP-seq measurements may show both H3K4me3 and H3K27me3, but these may or may not be originated in the same cell, so this may or may not represent the presence of bivalent domains.

Image source  “Bivalent domains and heterogeneity. Two scenarios could potentially explain the co-occurrence of H3K4me3 and H3K27me3 observed by ChIP-seq on bivalent promoters. As ChIP-seq cannot establish physical co-occurrence of two marks on the same allele, admixture of cells that either express (green) or do not express (red) the gene in focus could explain the occurrence of both marks as well as the low expression level in the overall population. In contrast, in the case of ”true” bivalency, virtually all cells in the population carry both marks simultaneously at the promoter in question, leading to low, if any, expression for that gene in all cells.”

Developmental and restorative processes depend crucially on the operations of bivalent domains

Specifically, cell reproduction and stem cell operations depend on bivalent domains as explained in the 2021 publication Histone Lysine Methylation and Long Non-Coding RNA: The New Target Players in Skeletal Muscle Cell Regeneration  “Transcriptional regulators, including Nanog, Oct4, and Sox2 that maintain the pluripotency of stem cells, must be deactivated for cellular differentiation to occur (Wang et al., 2012; Chu et al., 2016). In addition to transcriptional regulators, induced pluripotent stem cells (iPCS) and embryonic stem cells (ESC) are poised by a bivalent chromatin, consisting of histone 3 lysine 4-trimethylation (H3K4me3) and histone 3 lysine 27-trimethylation (H3K27me3) (Bernstein et al., 2006; Mikkelsen et al., 2007). These bivalent marks are located on the same nucleosome in an asymmetric configuration regulating the chromatin structure (Bernstein et al., 2006). Generally, H3K4me3 is associated with gene activation, while H3K9me3 and H3K27me3 are associated with gene repression (Black et al., 2012). Upon receiving differentiation cues, the H3K27me3 repressive mark is lost, and H3K4me3 activity dominates the promoter region lineage-specific genes to activate gene transcription (Collinson et al., 2016). The bivalent gene is essential to regulate the transition between pluripotency and committed cells. Moreover, the H3K27me3 repressive mark of the bivalent gene maintains low expression levels of developmental genes in iPCS and ESC while allowing for their transcription upon differentiation. Furthermore, H3K27me3 protects the cell from aberrant gene activation by permitting only the target lineage-regulating genes to activate (Vastenhouw and Schier, 2012). H3K4me3 has vital significance as a transcriptional activator. In addition to this main function, H3K4me3 may be essential to ensure that permanent gene silencing of developmental genes does not occur (Fouse et al., 2008; Vastenhouw and Schier, 2012).”

Chromatin Remodelers

There are certain “chromatin remodeler” proteins that work by affecting bivalent domains.  For example, the following chart and diagram are from Chromatin remodeling and bivalent histone modifications in embryonic stem cells (2015).  That document goes into a great deal of detail about processes of generation and destruction of bivalent domains and their effects on chromatin.  It is a good place to look if you wish to dig deeper.

ChromChromatin remodeling complexes regulating bivalent nucleosomes  “A single schematic bivalent nucleosome is shown (orange) marked with both H3K4me3 (green flag, left) and H3K27me3 (red flag, right). Chromatin remodeling complexes which were shown to regulate either or both marks are shown in green (esBAF), blue (NuRD), and mustard (INO80). Dotted arrows represent suggested regulation; dotted double lines represent potential interaction.”

SOME KEY OBSERVATIONS

Epigenetic regulation by bivalent domains is extremely ancient and applies to most living species, including mushrooms.

Heterochromatin regulation via methylation of these histone goes back over 400 million years of evolutionary history and applies widely across very diverse living species.  So, for example, experiments on an ancient mushroom species may be directed towards finding insights relevant to humans today.  See for example the paper Induction of H3K9me3 and DNA methylation by tethered heterochromatin factors in Neurospora crassa.  The Histone Code provides a systematic framework for biology as does the periodic Table for Chemistry. 

Potatoes also employ essentially the same bivalent domains as we do for epigenetic regulation.

The 2019 publication Cold stress induces enhanced chromatin accessibility and bivalent histone modifications H3K4me3 and H3K27me3 of active genes in potato makes this point.  Mushrooms, potatoes and people?  The same mechanism also applies to flies, nematodes(ref) and all mammals.  And oh yes, the vemon of tarantulas and snakes depend on bivalent domains(ref). This blog entry is talking about very basic tried-and-true mechanisms of biology.

The key roles of histone regulation in biology were discovered not that long ago, and their implications have not yet been appreciated in many areas of the science, including longevity science

Up to this point I have seen no mention in the longevity-related literature about bivalent domains, nor do I know of any longevity science researcher who have expressed any care about them.  Yet, just scratching the surface I already see much evidence that bivalent domains  are basic to natural YOUNGING processes.  They will no doubt figure heavily jn any YOUNGING interventions that work.  This timetable is from a 2012 publication and could be expanded considerably to reflect developments in the last10 years.  Image and legend source.

History, Mechanism, and Specificity of KMTs and KDMs

(A) Timeline chronicling important milestones in KMT and KDM research.  (B) Schematic depicting generalized reaction mechanisms of KMTs and KDMs.  (C) Schematic depicting substrate specificity of KMTs and KDMs”

THESE TOPICS ARE VERY RELEVANT FOR OUR EXPLORATION OF YOUNGING AND YOUNGING INTERRVENTIONS

For one matter they can point us to vast new chapters of the biomedical literature relevant to YOUNGING, with articles like these:

Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis

Complete loss of H3K9 methylation dissolves mouse heterochromatin organization

Histone Lysine Demethylases of JMJD2 or KDM4 Family are Important Epigenetic Regulators in Reward Circuitry in the Etiopathology of Depression

Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2

Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals

Synergistic lethality between BRCA1 and H3K9me2 loss reflects satellite derepression

Argonaute NRDE-3 and MBT domain protein LIN-61 redundantly recruit an H3K9me3 HMT to prevent embryonic lethality and transposon expression.

Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability.

Decoupling the downstream effects of germline nuclear RNAi reveals that H3K9me3 is dispensable for heritable RNAi and the maintenance of endogenous siRNA-mediated transcriptional silencing in Caenorhabditis elegans.

Repressive Chromatin in Caenorhabditis elegans: Establishment, Composition, and Function.

H3K9 methyltransferase G9a and the related molecule GLP.

SETDB1-like MET-2 promotes transcriptional silencing and development independently of its H3K9me-associated catalytic activity.

H3K9me selectively blocks transcription factor activity and ensures differentiated tissue integrity.

The Sound of Silence: How Silenced Chromatin Orchestrates the Repair of Double-Strand Breaks.

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer.

Bivalent Histone Modifications and Development.

Genome-Wide Studies Reveal that H3K4me3 Modification in Bivalent Genes Is Dynamically Regulated during the Pluripotent Cell Cycle and Stabilized upon Differentiation.

Differences among brain tumor stem cell types and fetal neural stem cells in focal regions of histone modifications and DNA methylation, broad regions of modifications, and bivalent promoters.

ON GOING DEEPER INTO THE HISTONE CODE

The material covered here represents highly selected aspects of the Histone Code, which is concerned with the impacts on gene expression of all histone modifications on all histones, (that is modifications due to histone methylation, acetylation, ribosylation, ubiquitination, threonine/serine/tyrosine phosphorylation, etc.); considering not only individual modifications but viable combinations of them.  The complexity is mind-numbing.  Wikipedia points out “Unlike this simplified model, any real histone code has the potential to be massively complex; each of the four standard histones can be simultaneously modified at multiple different sites with multiple different modifications. To give an idea of this complexity, histone H3 contains nineteen lysines known to be methylated—each can be un-, mono-, di- or tri-methylated. If modifications are independent, this allows a potential 4¹⁹ or 280 billion different lysine methylation patterns, far more than the maximum number of histones in a human genome (6.4 Gb / ~150 bp = ~44 million histones if they are very tightly packed). …And this does not include lysine acetylation (known for H3 at nine residues), arginine methylation (known for H3 at three residues) or threonine/serine/tyrosine phosphorylation (known for H3 at eight residues), not to mention modifications of other histones. – Every nucleosome in a cell can therefore have a different set of modifications, raising the question of whether common patterns of histone modifications exist. A study of about 40 histone modifications across human gene promoters found over 4000 different combinations used, over 3000 occurring at only a single promoter. However, patterns were discovered including a set of 17 histone modifications that are present together at over 3000 genes.^[16] Therefore, patterns of histone modifications do occur but they are very intricate, and we currently have detailed biochemical understanding of the importance of a relatively small number of modifications.”

Image source

Note that histone methylation compacts the chromatin as shown only for certain domains like H3K27, the opposite being true for others like H3K4

Also mind-numbing is the likely payoff of deeper understanding of the histone code for helping us move down the road to clarifying optimal science-based longevity interventions. This blog entry talks about only methylation modifications affecting only histone 3, so it provides only a start.  We need learn more aspects of this code as we go on, perhaps as the next step on the combined impacts of histone methylation and acetylation, given that we know a fair amount about many natural substances can be powerful histone acetylases/deacetylases.  They offer powerful natural approaches to activating key longevity pathways including SIRT1 andSIRT6 and the positive effects of enhancing NAD.  See several articles in this blog by myself and by Jim Watson, starting with my Histone acetylase and deacetylase inhibitors post.  Also, Jim Watson’s  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.  So, I expect there will be a lot more to come from me and my YOUNGING colleagues about YOUNGING and the Histone Code.

————–———————————————

Doe

By Vince Giuliano

There are two distinct faces of life extension which are often confused, even by the best researchers working in the longevity field.  This sometimes leads to paradoxical observations.  I seek to clarify what these faces are in this blog entry, present evidence for the distinction between them, state how and why both are important, and relate them to longevity interventions previously discussed in this blog.

Two categories of processes and interventions exist that can lead to longer lifespans.  They are very different.  Image source

1. Averting or neutralizing mortality factors, that is, actions and interventions which counter factors which are known to increase the probability of death.- leading to better health and longer functional lifespans. A great many such mortality factors are all-age killers.    If you are shot, run over by a bus or fall off a cliff or incinerated by napalm, taking multiple dietary supplements or being of young epigenetic age won’t help you at all.  There are thousands of such factors that can kill you rapidly or significantly increase the probability of your demise,  including accidents, diseases, smoking, toxic environments, natural disasters and wars.   For many species like wild mice – us no longer – predators who eat them are the main killers.   All public health measures are intended to avert mortality factors – such as seat belt laws, clean air and water and good sanitization systems, and vaccination programs.  These have been the main factors responsible for our long currently-expected lifespans.  Finding better treatments for cancers and new cures for diseases are in this category, for example, In all of these cases there is an increased longevity of a population while epigenetic aging in that population is unaffected.
2. Mortality can be induced by uncontrollable extrinsic factors which are independent of aging such as wars, road accidents, pandemics, natural disasters, or absence of medical health care. Because of such factors mortality of any population or individual can never be reduced to zero, even if actual age reversal is achieved.

Most “anti-aging” interventions’ are actually in this category, and do not actually affect aging.  They increase expected lifespans, but do not impact your epigenetic age.  Even some old standbys, like dietary calorie restriction, work to slow mortality at all ages and are in this category.  “Dietary restriction (DR) is the most robust environmental manipulation known to increase active and healthy lifespan in many species. Despite differences in the protocols and the way DR is carried out in different organisms, conserved relationships are emerging among multiple species. Elegant studies from numerous model organisms are further defining the importance of various nutrient-signaling pathways including mTOR (mechanistic target of rapamycin), insulin/IGF-1-like signaling and sirtuins in mediating the effects of DR(ref),”

Some mortality factors are intrinsic, especially those which assume great importance in the advanced aged, including compromised vision and hearing, compromised kinesthetics, and the diseases associated with hyper constitutional inflammation -such as diabetes, dementias, arthritis, many cancers and gout.  Many devices, work-arounds and treatments have been developed to neutralize these, examples being hearing aids, eyeglasses, cateract surgery, and prosthetic devices like canes, walkers,, wheelchairs, and grab bars.  These all contribute to probable overall longevity, for some very little, but they are very numerous.

Interventions in this category are unlikely to affect our human lifespan limit of 122 years, no matter which of them, how many are simultaneously applied, or how consistently they are used.  (A possible exception could be hypoxia-related interventions),  Very few of us will live beyond 105 and we all will be dead before we reach 122 years – unless we can slow or reverse actual aging..

Slowing or reversing epigenetic aging.  That is somehow slowing or turning back the ticking epigenetic clock in our DNA which is calendar-driven and which determines the multiple phenotypical symptom of aging on all levels – biochemical, cellular, tissue-specific, organ-specific, and systems specific.  Specifically Steve Buss and I have seen aging being to a significant extent due to age-related histone double and triple hyper methylation at the H3k27me2-3 position, and consequent deactivation of multiple genes that govern natural repair, protective and restorative processes in the body.  For example, tissue restoration due to stem cell differentiation is greatly reduced in the advanced aged due to such methylation,

Reversing biological epigenetic aging, what Steve Buss and I have called YOUNGING, is the only hope for anyone who wants to survive the vicious mortality probabilities that lead most of us to die by 105 and nobody to live beyond 122 years.

The case for aberrant histone methylation being the smoking gun that surely kills older people if nothing else is a strong one,  Degenerative diseases and conditions of aging, the ones that surely kill older people, are only very rarely manifest in mice younger than a year, or humans younger than 30 years – when the lifelong accumulation of H3k27me2-3 histone methylation is still minimal and protective and restorative genes are still strongly active.  ,(Of course there are numerous degenerative diseases of childhood and adolescence.  The point is that they are not dominant killers as are the degenerative diseases of old age)  A basic hope and intention of many longevity researchers is to prolong this protective state or to revert people to it – a process we have extensively discussed which we have called YOUNGING.  See our Webcast Younging – Triggering Ancient Mechanisms for Rejuvenation, and our articles on YOUNGING in this blog written in 2022(res)(res)(ref)(ref)(ref).

These two kinds of life-extension processes have been confounded.  Most of the putative “anti-aging interventions” pursued today are in the first category and in fact don’t impact actual or epigenetic aging.  Interventions in this first category are good and useful.  The traditional branch of medicine known as Geriatrics is concerned with many of them.  Many other social innovations, like pushbutton activated pedestrian lights on busy streets are taken for granted.  Several newer electronic techniques like video conferencing and GPS traffic guidance reduce time spent in traffic and traffic-related mortality.  If we want long, productive happy lives we need to take advantage of them wherever they exist.

YOUNGING interventions that slow down or reverse aging are the long-sought Holy Grails of longevity researchers.  We are well on the way to cracking that one, though we are not there yet.  What is at stake is the possibility of lifespans of hundreds of years.  We have learned much, including the root causes of aging and how in-principle to slow it down and reverse it.  And recent experiments with small animals give powerful evidence for the existence and feasibility of age reversal.  See the Section near the end of this document,  SHORT UPDATE ON YOUNGING.

Yet, we still have no safe, practical interventions that can reliably induce systematic YOUNGING.  One current barrier has to do with activation of the histone demethylase JDJM3, a necessary if not sufficient condition for YOUNGING.  In short JMJD3 demethylation at H3k27me2-3 histone sites promotes he expression of multiple growth and development genes, which means it is implicated in the development of cancers.  See, for example JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms.  “JMJD3 stimulates the expression of proliferative-related genes and increases tumor cell growth, propagation, and migration in various cancers, including neural, prostate, ovary, skin, esophagus, leukemia, hepatic, head and neck, renal, lymphoma, and lung(ref).”  In fact, a treatment strategy for some cancers like Lymphoma is inhibition of expression of JMJD3 via the recently developed drug  GSK-J1.    For discussions of both the benefits of JMJD3 and its roles in cancers, see the 2021 article The Functions of the Demethylase JMJD3 in Cancer.  ..JMJD3, also known as KDM6B can be both an inhibitor and promoter of cancer  “ Previous studies have pointed to a potential tumor-suppressive role of KDM6B in specific tissues (such as lung, colon, and pancreas) (30)(31)(32)63), while in others (such as blood, breast, and brain) it may play an opposite tumor-promoting function (24)(25)(26). This demethylase is an important player at the intersection between cellular senescence and cancer (22,29), and it also positively regulates epidermal differentiation (33). Interestingly, the KDM6B gene is located on chromosome 17 in close vicinity to the p53 tumor-suppressor gene, with allelic loss at this position occurring in a variety of cancers, including SCCs (1,22,(64)(65)(66)(ref)”.

WHAT IS AGING?

“Aging can be defined as the time-related deterioration of the physiological functions necessary for survival and fertility(Aging: The Biology of Senescence).”  In humans aging appears to be a lifelong process manifest in multiple ways on all organismal levels.  Aging involves shifts in biochemistry, the structures and operations of cells, organelles and organs, key processes like metabolism, organs, all body systems, and all key functionalities.”

The normal measure of aging of course is calendar age – how long a person has lived.  Evolution has endowed us with pretty good natural capabilities for detecting and assessing advanced aging.  Based on how a person looks, moves and talks we can generally estimate well whether that person is in his or her 60s, 70s,80s or 90 or beyond.  Scientists have long sought a reliable biological measure of how long people have lived, looking for concentrations of  substances in the body that correspond to calendar age.  Starting with the work of Horvath at UCLA, it appears that DNA methylation best provides such a measure.  Aging is accompanied by significant lifelong changes in promoter-site  methylation of many key genes.  For most genes, the state of promoter-site methylation changes year by year from birth to death. For some genes it systematically increases; for other genes it decreases.  So it is possible to create “aging clocks” by systematically looking at methylation status of a few dozen or hundred genes see Jim Watson’s and my blog entry(ref):

“Why is DNA methylation important?

This blog entry looks at aging, health and disease from the viewpoint of DNA methylation, that is, lifelong changes in methylation status of selected genes.  This is a highly useful viewpoint because it:

• provides a theory of aging and a fairly concise definition of aging,
• provides the most concise measures of human aging we have, and
• is a good predictor of all-cause mortality.

According to this viewpoint, genomic methylation:

• plays crucial lifelong roles in human development and maturation, from embryogenesis right up to death,
• is one of the three major epigenetic mechanisms for gene activation and silencing,

• is a major causal factor in the program of aging,
• provides an explanation of how chronic inflammation accelerates the aging program,

• explains several other basic known mechanisms and effects of aging;  E.g. loss of border proteins that protect CpG islands from methylation, and the fact that men age faster than women, and why women’s breasts age faster than the rest of their bodies,
• provides insights into the programs of aging that suggest possible hacks on those programs,
• has molecular mechanisms which are fairly well understood and well documented,
• helps explain a number of disease processes and disease susceptibilities. how hypermethyltion of the BRCA1 gene confers susceptibility to breast cancer,
• helps to explain how chronic stress leads to accelerated aging,
• plays a direct role in the pathogenesis of diabetes, cancer, other diseases,
• with aging, increases expression of repetitive DNA sequences and human endogenous retroviruses so as to lead to chromosomal/genomic instability, telomere attrition, and aneuploidy,
• helps explain selective hereditability of traits, and
• reveals important links to a number of other important topics and viewpoints related to health and aging we have discussed over the years such as other aspects of epigenetics, events in the NAD world, stress and hormesis, oxidative stress, importance of circadian rhythms, transposable elements and alternative splicing.”

PURPOSE OF AGING

Surprisingly, there is lack of agreement among scientists about the purpose or nature of aging,  A traditional view is expressed in this quote:  “Many evolutionary biologists (Medawar 1952; Kirkwood 1977) would deny that aging is part of the genetic repertoire of an animal.  Rather, they would consider aging to be the default state occurring after the animal has fulfilled the requirements of natural selection.  After its offspring are born and raised, the animal can die.  Indeed, in many organisms, from moths to salmon, this is exactly what happens.  As soon as the eggs are fertilized and laid, the adults die. However, recent studies have indicated that there are genetic components to senescence, and that the genetically determined life span characteristic of a species can be modulated by altering genes or diet(ref).”  This traditional view is no longer held by most longevity researchers.

Aubrey de Grey, a prominent aging researcher, and his followers continue to think that aging is caused by accumulated damage due to wear and tear(ref).  This approach to longevity is an engineering repair-shop one.  “If something in the body breaks with aging, fix it.”

However, most longevity scientists today, including myself, think that aging is not in fact genetically encoded or due to wear and tear.  Rather, it is epigenetic, due to systematic lifelong changes in our DNA, particularly methylation status of numerous genes and changes in chromatin structure.  With the genes themselves remaining the same.  With advanced aging, gene regulation is so dysregulated that they can no longer do their jobs.  Evidence for this view is that with advanced aging, hundreds or thousands of genes concerned with natural restorative and repair on multiple levels in our bodies become gradually repressed due to age-related excess histone methylation at the H3K27 locus, and can no longer keep us young and healthy.  I have discussed this situation and its implications in several blog entries this year(see entries in this list).

Approximate maximum lifespans Image source

Members of virtually all species, us humans included, age, although at radically different species-determined rates, and are subject to species -determined maximum lifespan.  Even if we live to be in our 90s or 100s, we humans can expect with absolute historical certainty to die of one cause or the other by 123.

A typical pattern for mammals, including humans is a period of adulthood (up to around 27) where all-cause-mortality (ACM) is relatively low and fairly constant, followed by a period where numerous mortality factors become increasingly important (up to around 70), followed by old age where mortality factors steeply increase in importance.  All-cause mortality (ACM ) then continues to shoot up radically, becoming so large humans are near-certain to die before age 115.

Image source  Human lifespan appears to max out at 122,  We don’t know for sure that scientific advances will allow us to increase that number significantly.

It is controversial, as to whether maximum human lifespans may shift as time goes on (ref).  Certainly, expected lifespans of human populations have increased dramatically since pre-historical times, though they are affected by matters such as the COVID pandemic “They estimate that in the U.S., life expectancy — how long a person born today is projected to live, based on current death rates — has now dropped by almost two years. The U.S. declared a public health emergency related to the coronavirus in February 2020. Prior to that month, the nation’s life expectancy was 78.8 years(ref written April 2021).”  Some think we humans have already reached our maximum lifespan of 122 (ref).  Others think that expected and maximum human lifespans are correlated and may be expected to increase indefinitely as the years roll on(ref).  As I see it, every species has its own version of a program of aging, and that program fixes maximum lifespan for members of that species.  If aging were a matter of random damage, we would see a very few 10 year old mice, a very few dogs who live to 100, and a very few people who live to 300.  We do not.

My opinion is that the human lifespan limit of 122 will soon be significantly transcended and some us will be able to live hundreds of years.  My optimism is based on the fact that several groups are now researching age reversal approaches using small animals.  Descriptions of progress are appearing every few week.  My guess is that effective age reversal will clearly be demonstrated for a tiny number of people within 3-5 years from now.  My intent is to be part of that group.  However, it may require 15-25 years for YOUNGING to be practically available to the general public.

PHENOTYPES OF AGING

Phenotypes of aging are typical observed consequences – hundreds of them, for humans at all levels – biochemical, cellular, cell components, organs and organelles, and major body systems  Some of these provide the clues we use to deter advanced aging, like skin wrinkles, grey hair or no hair.  Many of these can be causative of diseases, like body states of hyper inflammation, or vulnerability for several diseases like cancers, Diabetes and Alzheimer s Disease.

Some phenotypes of aging have over the years been thought to define aging or be causes of it.  I think this is a mistake.  An example is telomere shortening.  14 years ago when I seriously started my studies of longevity science, like several scientists at that time I thought:

• In general, with advanced aging telomeres (specialized protein caps at the ends of chromosomes) tend to become shorter,
• A consequence of too-short telomeres is genomic instability, implying dysregulation of protein expression, causing what we experience as aging, and.
• Therefore a powerful longevity-promoting therapy would be stimulation of production of telomerase, a natural enzyme our bodies use to extend short telomeres

This line of argument for a root cause of aging appeared compelling but turned out to be contradicted by several facts, among which are 1  telomere lengths in humans wax and wane due to a variety of factors and are naturally coregulated by several feedback loops, 2,  When telomeres get to short, our bodies at all ages tend to upgrade the expression of telomerase and make them longer again, and 3. Promotion of telomerase, although proposed as a life-extending strategy more than 17 years ago, has never been proven to be that.  So shorter telomeres with advanced aging is one of hundreds of phenotypes of advanced aging but neither defines nor causes advanced aging,

Many phenotypes of advanced aging are in themselves mortality factors which move to center stage typically around age 75.  Loss of good kinesthetic balance is an example, which can result in bone-shattering mortality-inducing falls.  Another is the induction of chronic inflammatory state which can contribute to many pathologies of old age including to auto-immune diseases, diabetes, and many cancers.  Another is growing vulnerability to dementias like Alzheimer’s Disease.

ADVANTAGES AND DYSADVANTAGES OFINTERVENTIONS THAT INCREASE LIFESPAN

As pointed out above, we can distinguish two categories in which these belong:

• Interventional that slow, mitigate ot prevent operations of mortality-inducing factors

Advantages of these include:

• There are a great many of such interventions.
• Many of these are applied socially in our society , such as sanitation and safety laws, clean air and clean water regulations.
• Many others are readily available and economical for individuals to practice.
• How they work is usually readily understandable.
• Results of their application is cumulative up to a point.
• Living according to a properly selected regimen of them can probably enable most of us living in advanced societies to be highly functional and live full lives until age 95 or beyond (not applicable for a limited set of us who have identifiable genetic disease predispositions).
• They are likely to be necessary even if advanced interventions are discovered and implemented that actually address aging.
• You can’t live to be a healthy 200 or 300 unless you live to be healthy and functional100 first.  I think we now know how to likely do that.  And I am doing it personally. 
• These interventions got me to where I am now.

Disadvantages of these

• They are unlikely to get most of us in a highly functional state much beyond age 100.
• They are highly unlikely by themselves to extend the maximum observed human lifespan beyond 122 years.
• To the extent that deaths are caused by uncontrollable events like natural disasters, plagues, wars or shootings, even those following he most rigorous life-extending program cannot be guaranteed very long lifespans.

Interventions that actually slow or reverse epigenetic aging

Advantages of these include:

If and as these become available they could enable maximum lifespans of hundreds of years or more, since they address the actual issue of aging

Disadvantages of these

• Basically, none exist for humans now, though there is much promising research that some may be known soon.
• A clinical trial that definitely establishes the efficacy of an intervention without side effects would have to run 30 years or more.

INTERVENTIONS DICUSSED IN THIS BLOG ARE OF WHAT KINDS?

Essentially all interventions discussed in the history of this blog except the ones related to YOUNGING are ones that slow, mitigate or prevent operations of mortality-inducing phenotypes of aging that are themselves mortality factors:

• Dietary restriction-promoting techniques
• Drugs known to be life-extending such as metformin and rapamycin
• Techniques that depend on Hormesis, be these exercise, or heat-shock or old-shock approaches
• Good social interactions
• 40 haze vagal system stimulation
• Regular patterns of sleep maintaining
• Oxygen therapy
• Reduction of chronic inflammation
• Sanitary conditions; clean air and water
• Dietary supplements in general

Many interventions in the first category are highly likely to be necessary for YOUNGING although by themselves not sufficient for YOUNGING to occur.  These include:

Reduction of chronic inflammation, this being necessary for expression of JMJD3, the demethylase necessary for activation of multiple restorative and repair genes associated with the H3K27me2-3 histone site.  We have hypothesized that such demethylation is a necessary condition for the process we have identified as YOUNGING01(ref).

Good regular sleep

Regular physical exercise

Alternative H3k27me2-3 histone demethylases

In earlier blogs on YOUNGING01 as well as this one, I have emphasized the importance of histone demethylation at the H3k27me2-3 position as a means of activating large numbers of genes involved in natural restorative process.  I have focused almost exclusively on the JMJD3 demethylase – also known as KDKM6B  However as pointed out above, JMJD3 activation can be involved un and trigger certain cancer processes, so great care must be taken in considering its use as a longevity anti-aging treatment.  Actually the situation is more complex where three different histone demethylases work at the H3k27me2-3 position, and safer initiation of YOUNGING01 may entail activation of more than one of them.  These three demethylases are

• JMJD3 also known as KDKM6B
• UTX also known as KDKM6A
• UTY, a relatively feeble demethylase not discussed much in the literature

The roles of these demethylases in developmental and cancer processes are treated in the 2019 publication The histone demethylase UTX/KDM6A in cancer: Progress and puzzles. 

SHORT UPDATE ON YOUNGING

In the last ten days, the popular news media including CNN, TIME magazine, and the New York Times have carried stories about Dr. David Sinclair’s work on age reversal and how YOUNGING in laboratory mice was actually demonstrated in his lab.  David, of course, is a Professor at the Harvard Medical School, and is responsible for a major Lab there that has conducted several important research studies related to aging.  He has gained considerable notoriety for his various works. He is author of the book Lifespan: Why We Age and Why We Don’t Have To.  David has used three of the four Yamanaka factors (Oct3/4, Sox2, Klf4,) delivered by viral vectors to reverse epigenetic again in mouse systems, back to the adult stage when reproduction is finished.  David promotes a theory of aging – loss of epigenetic information  – which I believe is highly credible. .  David does not use the term YOUNGING as Steve Buss and I have and only mentions but does not highlight the importance of histone demethylation, as we have.  But David highlights the possibility of systematic age reversal as we do. The CNN link contains a video of David talking this work.  Two of the recent publications coming out of  his lab that describe recent work in detail are: Loss of Epigenetic information as a cause of mammalian aging (published 8 days ago) and a paper on mouse vision restoration Reprogramming to recover youthful epigenetic information and restore vision (Dec 2020)

Image source

COMING SOON IN THIS BLOG

I celebrated my 93^rd birthday, on November 17, 2022.  I will discuss my continuing personal heath, vitality, and productivity and how I keep these up in a soon-forthcoming blog entry.  I will broadly characterize the lifestyle actions and interventions that I believe have kept me largely heathy, active. functional and productive up to this point.  And, I expect, at least until I am 100.  Finally, I will describe a new educational program I am now planning, the intention of which is to empower a small number of others in their 60s and 70s to have another 20 to 35 years of health, vitality and full functionality as I have been enjoying.

For those of you not satisfied with the 20-30 years of life extension that can be offered to you right now and want more, I have the following reminder to offer.  If you want to live until you are 300 in good shape, you have to make it to 100 first in good shape.  I believe I can advise you on steps that will provide you a good probability for doing that.  Hopefully, by the time you get to 100, science will provide you and me with means to reach 150 in good shape.  That is what I am personally betting on.

By A. Christopher Wikman

Preface by Vince Giuliano

I see this article by Chris Wikman as highly relevant for anybody who wants to understand their own health or enhance their longevity. Historically, fundamental scientific discoveries and technologies have been based on new instruments that allow us to observe phenomena that we had no clue existed because they are are unperceivable to our native senses.  In astronomy, the telescope, and new space telescopes like the Hubble and Web led us to radical new understanding the universe in which we exist.  In physics, generations of atom smashers enabled us to understand the fine structure of matter and energy. In chemistry, spectrascopes allow us to differentiate between tiny samples of materials and tell us the compositions of impossibly distant entities in the universe. In biology the microscope led us to discover microbes and viruses. And X-rays MRIs and PET Scanners enable us to understand what we are made of and how we work. Most of what goes on in our bodies relevant to our health and longevity is invisible to our conscious senses.  But much of it can be observed and monitored by available instrumentation. If we want to optimize our health and longevity, the first step is to know what it is.

Introduction

In my last article for this blogsite, Biometrics and Aging, we talked about how to assess your Biological Age, which could be helpful in finding out how well the various anti-aging interventions you may be using are working for you. Beyond waiting for those results, there are of course many other and related things you can do to improve your health and fitness, some of which may not be apparent without some analysis. 

Welcome to the world of the quantified-self – also referred to as self-tracking, self-monitoring, lifelogging, personal analytics, and personal informatics.  (BTW, bio-hackers are often also self-trackers.) Being the analytical and data-driven guy I can be at times, and subscribing to the idea of ongoing self-improvement, I’ve been keeping detailed, quantitative as well as qualitative personal records related to my health and fitness for over 10 years. (As with many self-trackers, this was initiated by some personal health issues.)  But without the subsequent analysis, conclusions, and resulting actions and changes in my behavior, all that data would not be worth much.

As noted by Dr. Allen Neuringer back in 1981, and later by Swan, [The Quantified Self: Fundamental Disruption in Big Data Science and Biological Discovery, 2013], Sanctorius of Padua studied energy expenditure in the 16th century in living things by tracking his weight vs. food intake for 30 years. Self-experimentation examples can be found onwards through to today, but often in isolation.  While an actual Quantified-Self (QS) community was initiated in 2007, studies and articles about this movement seem rare until around 2012.  Even today, though, most people seem unaware of this pursuit outside of those who do it and their close relatives and friends. Although there are exceptions, a general bias against personal science by the medical community exists. The bases include valid concerns such as n=1 sample sizes, lack of rigid objectivity and the resulting possible effects of expectations, and questions about expertise. The QS organization has established a study protocol to help address this.  But many self-trackers may not even be aware of it. A Pew study in 2012 estimated that 35M Americans were self-tracking (QS website, accessed Jan 2023).  And by 2019, 62M, per a Gallup poll (FiveThirtyEight, an ABC Internet News outlet), access Jan 2023.  But I suspect these numbers are based merely on how many people are using wearables. Many are gathering and saving reams of data, intentionally or not, but probably not that many are actually managing their health and adjusting their behavior using that data.

And so, while some people use their devices and thus capture data, but rarely look at it, some review it, some log it, analyze it, do correlation studies, make conclusions about what works and what doesn’t, and use the results to manage their behavior and health. With self-knowledge, one is better prepared to self-advocate, such as with your healthcare providers.  Knowledge is power, or as Dr. Allen Neuringer stated in 1981, “knowledge utilized is power”).  One would strive to be healthy longer than otherwise, if not live longer too.

There are steadily increasing research studies and reviews regarding the self-tracking movement. A seemingly obvious and important research question is “are self-trackers actually healthier?”  Are we actually benefiting from the effort?  There does not seem to be much evidence yet, perhaps due to lack of research on this specific question.  Much of it seems focused on whether or not the subjects simply used a wearable device.  The 2019 study “Impact of Personal Health Records and Wearables on Health Outcomes and Patient Response: Three-Arm Randomized Controlled Trial concluded that people who wore wearable devices and used an associated app lost more weight than controls.  There were “positive effects of digital self-tracking by patients undergoing cardiac rehabilitation on performance of the cardiovascular system”, from Vogel, 2017, vs. the control group who did not use wearable fitness trackers during rehab. Others reported some evidence that using a wearable fitness tracker also benefits other household members.  But on the other hand, a study (summarized on “The Conversation” news site, accessed in Jan 2023) by scientists Conger, Bassett, and Toth, found that physical activity levels have actually declined from 1995 to 2017, despite the surge in wearable fitness trackers. So it seems we can’t really say whether the QS community as a whole is healthier for doing so, but I’m confident that the work I’ve done has been beneficial (see below), and I’m also sure that many self-trackers would say the same.

How to Conduct Self-Tracking (in a Nutshell)

Now for a short digression to review what’s involved for new aspirants.  Typically, there are two approaches  – 1) review existing data and look for patterns, etc., or 2) create a hypothesis and/or experiment, collect the data, and see if the hypothesis is confirmed. The knowledge and skills involved may include making informed decisions about what data to collect and analyze, and some familiarity with analysis tools or apps/applications (such as spreadsheets) – which also entails using some type of computing and data storage device.  For do-it-yourselfers, some knowledge of statistics can be helpful.  While this approach gives you greater flexibility on what to look at, the apps associated with wearable devices is becoming very sophisticated, such as the WhoopTM strap’s monthly insight report.  While there are many options to choose from (or not – I have at least four), there are those in this community who use just paper and pencil and manually collected data, without a fitness tracker at all.  Figure 1 below is sample process flow diagram.

                                                                        Figure 1 – Example of a Self-Tracking Process

My Self-Tracking Story

Now, more specifically, I’m going to review here many aspects of what I do, and what I’ve learned, concluded, or verified.  Many of them seem obvious, but one-size-fits-all doesn’t always apply. The monthly summary report by WhoopTM lists the positive and negative impacts on your overnight recovery, in terms of percentages.  The results of some of my interventions are at odds with the averages of the general Whoop user population, and I suspect that this is the case for many other users.

Table 1 below lists the devices I use.

Table 1 – Personally-owned and used data gathering devices

Table 2 below provides details on the data I’ve collected.  The list is not exhaustive, as I have somewhere around 150 spreadsheet tabs (some being graphs only) in my four main files.  Generally I have 8-10 years of data, some as little as 2, some as much as 33 (at times sparse) years.  Some of my ideas did not bear fruit, and so I abandoned further data collection, some served their purpose and I moved on, and some of my records are from before I became serious about this.

Table 2 – Personal Data Collection Inventory

What have I learned or uncovered?

The extent of all this may lead the sympathetic reader to be concerned about my health.  Most of us go through good and not so good periods as we get older.  But I can say that I’m generally healthy enough and physically fit, to the extent that often I’m the oldest person on my trekking and mountaineering trips, and can generally keep up with the group.  During this period of intense data collection, there was a day when I expended 7,000 calories, followed up by another very active day of hiking with a heavy pack. On another trip I averaged 4,000 to 5,000 calories per day for a week – almost like doing a marathon a day. So no worries.

General Health

Devices like the Whoop strap help you to manage your training or even just general activity levels.  I found that when my overnight Recovery was poor, and then was too active, drank alcohol, and stayed up late, I felt very poor the following day.  But to my surprise, I also found that if was too sedentary, I also didn’t do as well. Some minimal level of activity was better for me, even though I felt that I needed the rest.

The strenuous trips which I take do seem to eventually take their toll.  In the past, I would seem to succumb to a cold or some other illness shortly after a stressful event.  While I seem to have overcome that issue, there still seem to be dips in my health a few months afterwards.  Something to work on.

I concluded that my blood calcium scores are higher during the not-so good periods.  Also something to figure out perhaps.

Along the way, my doctors have helped me uncover some micronutrient deficiencies. (Many people are probably deficient in magnesium, for example.)  Over a period of years, and by obtaining assays (some specialized) at the levels of blood/serum, WBC intercellular, and functional pathway metabolites or cellular viability, one can get clues to possible gut absorption issues or cellular membrane issues, for example.  Further, by creating and analyzing a matrix of co-factor dependencies, and perhaps comparing to symptoms, one may get insight into unsolved issues (e.g. Vitamin B6 and magnesium affect a lot of process in the human body). I was able to significantly reduce my triglycerides by correcting a deficiency which “no one is deficient in”. For every medication or supplement that I take, I have dated records of changes/add/deletes, dosages, why (assay results, empirical symptoms, and/or medical research (i.e. longevity benefits), and sometimes other notes.  With this, I have been able to look back in time and pose questions about what was I taking at that time.  Most of what goes on in our bodies is invisible to our senses but much of it  can be observed and monitored by relatively available instrumentation. 

By looking at my HRV records, I was able to ascertain that my SNS activity was higher on one of two alternative medications, and to decide on which one to use accordingly.

My blood pressure records allowed me to conclude that my BP didn’t actually change much while on two different medications, together and alone.  When I suspected that they were causing unacceptable side effects, I made the decision to discontinue their use, in consultation with my physician.  I was also able to conclude that fatigue and BP were not correlated during the day.

Sleep

I’ve looked into how the following effect my sleep quality and quantity, and made adjustments and decisions accordingly – bed firmness (adjustable), melatonin dose, using an extra blanket (not), and whether I exercised or not that day.

The OuraTM ring, among other devices, calculates your respiration rate (RR) overnight.  An observational analysis of mine revealed that my RR has been generally and steadily declining over the last 18 months or so, totaling about a 13% decline overall, after being somewhat steady or even some slight increase for the prior 18+ months.  After some thought, I realized that this trend coincided with my developing interest in Breathwork (and a topic of an upcoming blog article).  I conducted an online webinar on healthy breathing practices at that time and began to consciously practice this.  Further, the healthy breathing practices seem to have significantly improved my lung health, based on spirometry results vs. earlier records.

Heart Rate Variability

HRV is a great single measure of whole-body health, even though sometimes it doesn’t seem to match exactly how you’re feeling.  (But generally, mine has some correlation to how I’m feeling.) My HRV is higher when I’m seeing my acupuncturist, doing high-intensity intervals (HIIT) weekly, getting time outdoors and especially sunshine. Outdoor time is good – my numbers go up the day after getting time outdoors and also the 2nd day afterwards.  At least 30 minutes of sunshine seem to be the minimum, and more is better – incremental benefits.  Quantity of sleep helps, but apparently quality not so much.

Other positive effects on my HRV include regular sauna visits, and using topical magnesium cream. Most months, I enter the Whoop monthly results into a spreadsheet to 1) re-confirm my top behaviors and interventions, both relative and absolute, and 2) look for trends in the results indicating which behaviors are either (seemingly) becoming more effective, or else no longer having the effect that they once did – thus identifying opportunities to do things differently.

I have been experimenting with the Apollo Neuro strap (to boost my HRV).  The device offers multiple protocols, for different purposes, and I find that the “Sleep and Renew” is best for me overnight.

Seasonal Aspects

Many of us are aware that the seasons affect our moods, especially as we get farther from the equator. I was able to confirm that my HRV varies seasonally (get heat and sun in the winter?).  Further, when some of my neurotransmitter or hormone levels are “low”, this seems to occur only in late winter and early spring. So after reviewing 9 years of fatigue-levels records, I was able to confirm a highly seasonal correlation – late summer is best, late winter is worst.

My average daily steps are highly correlated with the hours of sunshine per month.  No big surprise there, living in a 4-season temperate climate. Have I corrected this? Probably not yet.

Physical Performance

During one period of time, an undiagnosed health issue was causing symptoms when hiking in hilly terrain.  I started keeping records on things to try and vary, and the resulting outcomes, in order to explore and gain some insight into what was going on.  These included warm-up time duration, wearing nose strips, supplements such as carnitine, and stimulants such as caffeine and epinephrine (don’t try this). Alcohol the day before was a negative influence. 

I also investigated what was my minimum duration of warm up time before HIIT vs. the level of intensity that I could achieve, before the benefit leveled off.

Pulling data from several records, prompted by occasionally having some issues with exercise recovery, I compiled a table of 32 aspects contributing to aerobic performance (oxygen uptake, bloodstream fuel, cardiac condition, etc.), and assigned color grades to each based on my situation, and assessed which micronutrients, if deficient, might impair that aspect. A work still in progress as far as strong conclusions go.

Sometimes we stumble upon already existing scientific knowledge, such as ‘hormones and our immune systems vary with the seasons’, such as I did by tracking hormone and antibody levels, and WBC counts. Am I better off today than I was, given the large amount of time invested?  It’s difficult to prove objectively – my health is better in several ways, but it would be very hard to single out individual causes vs. the noise.  I’d do it again though.

Others Self-Tracking 

What about others – what other types of experiments, analyses, self-evaluations have they done?  There are many examples, including formal briefings and papers on the QS website (and likely elsewhere).  Here I draw a few examples from Dr. Neuringer.  One female student of his analyzed the relation between how much food she ate during the day and how well she slept. (Curiously, less food led to less sleep).  Another student of his hypothesized large effects on his memory the morning after smoking marijuana, but found none [or at least couldn’t remember if he did? – Ed.] Further, Dr. Neuringer conducted several self-studies on whether and how walking vs. sitting affected various tasks such as generating “new” ideas, problem solving, and memorization – his performance was better while these were done while walking.  (But apparently this conclusion hasn’t always been confirmed in some N>1 studies.) [Perhaps add more examples? And other organizations?]

Possible Issues and Concerns, and Summary

The personal time commitment can be heavy, leaving less time for other things.  I find that this goes in phases, in my situation.  Running self-experiments can require adding more variability to one’s life (“let’s try this, and this, and…”), which can add stress.  And some seeming-critics of the QS community raise concerns about “data fetishism”.  Fetishes are numerous.  I doubt this is a problem for most of us. Perhaps privacy is the main concern here.  Personal data is abundant, ubiquitous, and for sale. Several research studies on QS seem to be probing after the donation (data philanthropy) of self-tracker’s data, for research and just as likely commercial use.  Decisions are to be made.

One of the emerging lines of inquiry, despite the medical profession’s concerns, is whether there can and will be reverse transfer of knowledge, from society to science? As of 2019, there appears to be nothing of note. One can only hope that this might change. Dr. Neuringer quipped in 1981, foreseeing a possible future in which self-experimentation became common, people would greet each other with “what experiments are you doing” rather than common variations of “how are you?”.  And this was before the recent availability and exponential growth of many types of wearable trackers.

From Swan (above), “the cycle of experimentation, interpretation, and improvement transforms the quantified self into an improved ‘higher quality self’”. Or as Neuringer put it, “The solution to many of our problems is not a pill, not a product, but rather a continuous process of discovery and change”.

References

Kim JW, Ryu B, Cho S, Heo E, Kim Y, Lee J, Jung SY, Yoo S. Impact of Personal Health Records and Wearables on Health Outcomes and Patient Response: Three-Arm Randomized Controlled Trial. JMIR Mhealth Uhealth. 2019 Jan 4;7(1):e12070. doi: 10.2196/12070. PMID: 30609978; PMCID: PMC6682299.

Feng S, Mäntymäki M, Dhir A, Salmela H. How Self-tracking and the Quantified Self Promote Health and Well-being: Systematic Review. J Med Internet Res. 2021 Sep 21;23(9):e25171. doi: 10.2196/25171. PMID: 34546176; PMCID: PMC8493454.

Kim J. Analysis of health consumers’ behavior using self-tracker for activity, sleep, and diet. Telemed J E Health. 2014 Jun;20(6):552-8. doi: 10.1089/tmj.2013.0282. Epub 2014 Apr 18. PMID: 24745608; PMCID: PMC4038997.

Deborah Lupton (2017) Self-tracking, health and medicine, Health Sociology Review, 26:1, 1-5, DOI: 10.1080/14461242.2016.1228149

Lupton D. “Sharing Is Caring:” Australian Self-Trackers’ Concepts and Practices of Personal Data Sharing and Privacy. Front Digit Health. 2021 Feb 23;3:649275. doi: 10.3389/fdgth.2021.649275. PMID: 34713123; PMCID: PMC8521845.

Meyer J, Gurrin C, Price B, Kay J, Jain R. Editorial: Long-Term Self-Tracking for Life-Long Health and Well-Being. Front Digit Health. 2021 Dec 24;3:827586. doi: 10.3389/fdgth.2021.827586. PMID: 35005699; PMCID: PMC8738079.

Swan M. The Quantified Self: Fundamental Disruption in Big Data Science and Biological Discovery. Big Data. 2013 Jun;1(2):85-99. doi: 10.1089/big.2012.0002. PMID: 27442063.

Heyen NB. From self-tracking to self-expertise: The production of self-related knowledge by doing personal science. Public Underst Sci. 2020 Feb;29(2):124-138. doi: 10.1177/0963662519888757. Epub 2019 Nov 28. PMID: 31778095; PMCID: PMC7323767.

Vogel J, Auinger A, Riedl R, Kindermann H, Helfert M, Ocenasek H. Digitally enhanced recovery: Investigating the use of digital self-tracking for monitoring leisure time physical activity of cardiovascular disease (CVD) patients undergoing cardiac rehabilitation. PLoS One. 2017 Oct 11;12(10):e0186261. doi: 10.1371/journal.pone.0186261. PMID: 29020079; PMCID: PMC5636132.

Neuringer, A. Self-Experimentation: A Call for Change. Behaviorism. Spring 1981: 79-94

Zoom Link: February 28, 2023, @ 7pm Pacific Time

https://us02web.zoom.us/j/85891364799?pwd=ald6anAya0MyRjJPL1B3N1RodDlaQT09

A few explanations of aging and rejuvenation appeared promising for years. But the knowledge required to design experiments capable of distinguishing between poor and great benefit to the study organism and explanation took longer.

In the last three years, experiment evidence about the effectiveness of several Anti-Aging- Interventions is astounding.

Each of these new, exemplary study Biological Interventions

• were founded in evidence and insight from the dozens, even hundreds, of previously published studies
• focused on Different Biological Intervention Targets implicating Different Explanations of the biological benefit

Still, even though the Biological Intervention Targets were different, the associated Biological Mechanisms they triggered made for profound benefit: improving physical resilience, survival probability, and/or increased lifespan. The key exemplary studies making this clear include:

1. Old plasma dilution reduces biological age in humans
2. Triggering the Hegu Acupoint increased survival probability after lethal endotoxin injection in rodents
3. ”Partial Epigenetic Reprogramming” significantly increased remaining lifespan in older rodents
4. Increased oxygen absorption in the blood reduced aged, senescent cells in humans

Based on those studies, and on a broad understanding of the scientific literature, we can begin to identify and name Four Distinct Biological Intervention Targets. My favorite current names for these are, respectively:

1. Aging Factors in the Circulating Blood Plasma
2. Inflammation and the Mammalian Mechanism for Centrally Managing it
   1. i.e., the Cholinergic Anti-Inflammatory Pathway
3. Aged and Diseased Epigenetic Profiles
4. The Stress Response

About those Biological Intervention Targets, First, Notice

• 1 & 3 are Quantifiable Biological States; with knowledge and technology they could/can be manipulated
• 2 & 4 are endogenous mammalian mechanisms that every human on the planet has within them

And then Ask Yourself: What is the relationship between

• 1 & 2?
• How about 3 & 4?

In this talk, I will try briefly to

• summarize the Four Exemplary Experiment Interventions
• list the essential features of the four
  • Biological Intervention Targets
  • Biological Mechanisms
• highlight known relationships among these elements
• list Key Interventions by Biological Intervention Target in descending potency order
  • Let’s review, discuss, debate the Interventions by Target

Zoom Link: February 28, 2023, @ 7pm Pacific Time

And here’s a link to a document with links to more information about each of the 4 Biological Intervention Targets.

• Note: I’ll be updating these background material links up to a few days before the meeting.

—————

Stay Tuned: I will do my best to describe and explain these Biological intervention Targets and Interventions in more detail in meetups to follow, one each month.

Be Adventurous! Be Safe! Have Fun!

Zoom Link: April 5, 2023, @ 7pm Pacific Time

https://us02web.zoom.us/j/81643696466?pwd=bk1ZVll6SEw5dUkzZzdmcDZPSUpydz09

Evidence and insight from several recent longevity science studies constitute a turning point for Longevity Science Enthusiasts.

We now know that Aging Factors Exist in our Blood Plasma. And we know there are ways to

• reduce/dilute these factors, and by doing so
• increase health and survival probability

There are several Interventions we can do now to reduce/dilute these factors. Some of these interventions are new, others are ancient.

If done optimally in an informed way, these interventions can have a significant positive impact for 1 to 3 days; it not done optimally or done haphazardly, the Interventions make for only a marginal positive difference.

These approaches include

• ingesting anti-inflammatory foods and/or supplements
• engaging in behaviors that result in anti-inflammatory processes
• triggering the Cholinergic Anti-Inflammatory Pathway

Recently, a technology-based approach has also appeared on the scene. It’s FDA-approved to treat a large number of health disorders. It dilutes these (Inflammatory) Aging Factors more completely in a few months. Experiments demonstrate that it results in a younger gene expression profile. This Intervention is a kind of Biological Gene Expression reset and it’s called

• Therapeutic Plasma Exchange, or
• Plasmapheresis

In this talk, we will

• summarize the methods we can do now and the benefits we can derive from them
• outline the approach and usefulness of the technology approach: Therapeutic Plasma Exchange
• explain how we KNOW these two kinds of interventions are addressing the exact same profound cause of aging
• summarize a first draft Longevity-Promoting Regimen Sequence using both these intervention approaches
• explain all the graphical elements in the meetup header
• make time for Comments and Q&A

Resources for the Discussion

About the Aging Factors in the Blood Plasma

— 15 minute overview of plasma dilution by Sheekey Science

— 42 minute interview of the Conboys about plasma dilution

— 26 minute talk by Dobri Kiprov about TPE for Rejuvenation

— Dobri Kiprovs key 2013 “Hypothesis Paper”

— Conboys/Kiprov key Aug-2022 paper about Rejuvenation via Dilution

About the Cholinergic Anti-Inflammatory Pathway

— 20 minute talk by Kevin Tracey about the CAP

— 58 minute talk by Kevin Tracey about the CAP

— Kevin Tracey’s 2002 CAP ‘Hypothesis Paper”

— Kevin Tracey’s key 2009 CAP Review about intra-cellular objects

…… I’ll be referencing Figure 2 prominently in the talk

…… Figure 2 –> Most Predictively Significant Scientific Diagram Ever?

— Kevin Tracey’s key 2012 CAP description with key diagrams

By Vince Giuliano

The causal chain of events leading to advanced human aging has only been clarified very recently.  A key step in this causal chain is systemic inflammation leading to accelerated epigenetic aging.  In reports of other researcher and in our own findings, It has become increasingly clear that aging can be slowed down considerably.  One easy way this is achievable is by pursuing a simple life extension program that features reducing such inflammation through taking certain herbal dietary supplements.  Thus, before much longer many of us might be living full active and healthy lives through our nineties up to age 100.  There is a science discovery story to this, and a personal discovery story for me.  I tell both stories here.

THE SCIENCE DISCOVERY STORY

From early pre-history until very recently we humans have recognized many signs of aging leading to death.  But scientists were unsure of what the central chain of causation was, as distinct from its hallmark symptoms.   “There are numerous molecular and cellular hallmarks of the aging process, including cellular senescence, genomic instability, deregulated autophagy, mitochondrial dysfunction, telomere shortening, oxidative stress, systemic inflammation, metabolism dysfunctions, epigenetic alterations, and stem cell exhaustion (López-Otín et al.,2013). Although many of these hallmarks have been extensively described and studied, few of them have been translated into effective therapies —(ref)”    Of course many things can and do kill us besides aging, like murders, wars and accidents.  But how does advancing aging surely kill us all by our “species expiration date” of 123 years?  And why do almost all biological species have such clearly identifiable though very different maximum life spans?

It is because there is a distinct effective program of adult aging, just as the is a program of early development starting with an egg and a sperm.  The essential details of this aging program have become clear to me, but this has only happened in the last few weeks.  This program is out to kill everybody by age 123.  It is very ancient and versions of it exist in all species including plants, insects and mushrooms.  It is just as efficient and effective as the early development program is.  But, being a program it can be hacked, once one knows exactly how it works.  I know of one easy main hack that I think can buy us an 20-25 years of additional healthy active lifespan.  It works by slowing the aging program way down.  It is available to everybody right now and inexpensive.  I know.  I am 93 and what I am proposing here has provided me with the wherewithal to lead a full active life and generate and publish this blog.

There is a central causal chain of events in the aging program for us humans and for most other animal species.  First I telegraph the chain of events in a nutshell; then I explain key steps in that same chain in more detail, listing and quoting a number of supporting research publications.

The Adult Aging Program in a Nutshell

• All cells in the human body have the same genes. The differences between the some 200 cell types we have are epigenetic, a function of which genes are turned on and which are turned off in any particular place in a human body at any given time.  Early human development is an exquisitely choreographed and very reliable process involving multiple steps of turning hundreds or thousands of development genes on and off in a complex and highly specific manner.  Starting with an ovum and a sperm, it leads to a human body comprising some 37 trillion cells of 200 types.  Our bodies are the most complex structures known to exist in the universe, and this development process is probably the most complex natural process known.  And it is highly reliable.  We do not have babies with teeth in their bellies or eyes in their legs.  The basic mechanism used by this development program for turning off or turning on hundreds of genes at once is histone methylation.  That is attaching or detaching methyl chemical groups to histones, the “spools” around which DNA is wrapped.  For most of the histones, genes in a highly methylated histone spindle are turned off, cannot be expressed.  De-methylating the histone turns the genes on.  For some histones the opposite is so.  Many of the genes in our chromosomes are carefully sequenced so this simultaneous turning on and off can happen.  It happens to be that many growth and development genes are associated with the histone H3k27.  These include genes that need to be turned on for natural restorative and maintenance processes to go on – like stem cell differentiation to replace senescent cells. To telegraph where I am going here, there is also a very complex end-of-life aging program that kills everybody by age 123, and that program also uses histone methylation to turn groups of genes off and on.
• Lifelong changes in histone methylation, particularly double and triple methylation at the H3K37me2-3 locus, inactivates many repair and maintenance genes, such as the ones that empower stem cell activation for tissue renewal. The Polychrome Repressive Complex (PRC) sees to this methylation in adults, as necessary for repression of early growth and development genes starting typically in a human’s mid 20s..  As we grow older the methylation gets more and more intense, and our natural renewal processes get weaker.  DNA repair is less efficient and reliable.  Protein production gradually becomes less reliable. In the absence of adequate renewal and repair, many tissues function less well and become inflamed.  They produce proinflammatory cytokines which are circulated body-wide via the cardiovascular system, like TNF-alpha, IL-6 and IL-22.  This inflammatory progression may start in a person’s late 60s, become more pronounced in their 70s and dominant in their 80s.
• The resultant systemic inflammation acts on the hypothalamus and autonomous nervous system so as significantly generate more systemic inflammation, such as by transforming Type 2 (anti-inflammatory) macrophages into Type 1 (inflammatory) macrophages. Acting through the PRC, this further increases the rate of aging (progressive changes in histone and DNA methylation state ).  So there is a positive feedback loop leading to accelerated aging and multi-system deterioration near the end of life.  Most people are dead before reaching 90, very few are alive to 100, and everybody known to history is dead by 123.

I believe the above represents the central causal chain of events involved in human aging, and allows us to know with confidence how to slow advanced aging.  Hundreds or thousands of other molecular and biological pathways are peripheral to this chain of events and interact with it leading to the above-mentioned hallmarks of aging in very complex ways.  Almost 100% of the vast scientific literature on aging are concerned with such individual pathways, and it is very easy to get lost in them and confused as to what is central to aging, and how to mitigate it.

THE ADULT AGING PROGRAM AT TYPICAL LIFE STAGES

To lend specificity to the above description of the adult aging process, I will lay out how it could typically play out at various stages of life of a healthy disease-free person in a modern industrialized society, namely at ages 25, 45, 68, and 85.  The stages are more or less the sme for everybody.  The ages when they occur may of course vary some depending on genetic and epigenetic individual factors and on external events such as diseases contracted, extraordinary external stresses, nutrition, air and water quality, and accidents.  External factors are very important.  But for determination of lifespan, I think they are usually secondary when compared to the operation of the aging program,  when our natural repair and restorative processes are fully intact, we are equipped to deal with incredible stresses.

AGE 25.  This is the typical age when the Development Program gives way to the Adult Aging Program in humans.  This transition can be noticed in many species, including plants.  In some species it can occur very rapidly, taking place in a few hours. In many species, it occurs just after the initial phase of offspring-bearing.  The transition involves lowering of expression of JDJM3 and UTX, the demethylases that keeps double and triple methylation from happening during development at histone position H3k27.  At the time of transition the Polychrome Repressive Complex (PRC)starts its adult job of inducing double and triple methylation at H3k27me2-3.  This and methylation changes at other histone positions have net impact of starting to down-regulate numerous repair and renewal genes.  Yet at this age the expression of these genes is still near maximal.  There is little to no tissue damage or consequent inflammation.  As we know many people at this age are very healthy and think and often behave as if that situation will go on forever.   Diseases are generally rare and tend to resolve quickly.

AGE 45.  The PRC has been doing its methylation job for 20 years now.  So many key repair, renewal and maintenance genes are significantly down-regulated.   With the down-regulation of these genes and tasks they perform, some tissues begin to be distressed, become inflamed and start emitting inflammatory cytokines like TNF-alpha  IL-6 and IL22.  Diseases and sicknesses and signs of aging of all kinds are becoming more common and more of concern, including arthritis, pneumonias, near-sightedness, obesity.  Yet, despite partial methylation, body repair, maintenance and renewal genes are still active enough to support largely good functioning.  Hallmarks of age are evident and the person looks like a 45 year-old, no longer like he/she looked at 25.

AGE 68.  The Adult Aging Program has been at work some 43 years now.  DNA histone methylation is now such that body repair, maintenance and renewal genes are functioning at a fraction of there original level.  And some genes that produce unwanted actions are being progressively turned back on.  Multiple tissue types and organs are experiencing increasing distress, and are emitting copious levels of inflammatory cytokines which persist in the bloodstream.  These increases the gene methylation levels even further  The overall body is going into a hyper inflammatory state.  And incidences of the inflammatory diseases the kill old people are becoming frequent: cancers of all types, scleroderma, retinopathy, inflammatory lung diseases, dementias, coronary artery and valve diseases, auto-immune diseases like arthritis, etc.  The “usual suspects” for killing old people  Several such diseases can occur at the same time, and use of the health care system is accelerating.  Heart attacks are becoming common. Many friends in the same age cohort are moving into Assisted Living; some are going into nursing homes.  Some are starting to die.

AGE 85.  The situation described for age 68 has become much more dire in every respect.  Histone and DNA methylation are at levels where many repair, maintenance and renewal genes are close to being completely silenced.  DNA methylation and circulatory inflammatory cytokine levels seem hopelessly abnormal.  Tissue and organ damage are extensive, and the diseases of old age are rampant and doing their pre-killer and killer jobs.  Far less than 30% of the population makes it to this age.  And if you do manage to  live that long,  your general outlook is not good.  From this age onward, you are likely to experience increasing frailty and multiple emergency room visits and hospitalizations.  You may pass the final months or years of your life in a nursing home with both dementia and an incurable cancer.  “All the King ’s Horses and All the King’s Men,” of medicine and health care can’t rescue you from the final Death Phase of the Adult Aging Program.

A version of the Adult Aging Program works for every advanced species we know of.

SIGNIFICANCE

The best news is that this deadly cycle can be broken.  The aging program can be hacked, basically by blocking the hyper-inflammation part of the positive feedback loop.  For example, the systemic inflammation can be blocked by taking a nano-preparation of certain herbal anti-inflammatory dietary supplements.  That has been my personal approach, which has worked well for me personally up to this point at age 93.  Irina Conboy, a prominent aging researcher, and her colleagues have suggested periodic purifying of circulating blood from the pro-inflammatory cytokines’ using an apheresis machine(ref).  Her small-animal experiments suggests that that works too.  Apheresis involves the removal of blood plasma from the body by the withdrawal of blood, its separation into plasma and cells, and the reintroduction of the cells. Her small-animal experiments suggests that that also works for the reduction of circulating inflammatory cytokines.  Ordinary people are unlikely to pursue apheresis because it is expensive, invasive, requires technical expertise and the use of a special machine.  Further, for apheresis it to be effective in keeping the bloodstream free of inflammatory cytokines, the process must be repeated every 3 weeks or so.

This blog entry goes on to suggest that my simple and practical dietary supplement intervention can probably be central to adding 20 or more good years to the active and healthy lifespan of individuals who pursue it.  (I do not know the actual number of years that might be added.  It could be 30 or more.  I use the number 20 to be conservative, based on my personal experience.) I believe I Have done this using 4 Herb Synergy, a nano concentration of active ingredients from four traditional herbs, herbs that have been used for millennia to control systemic inflammation. (See my disclosure as inventor and owner of the company which sells this product, at the end of this blog entry).

The intervention is deeply grounded  in science and I been successfully pursuing it.  It involves slowing the natural process of aging by natural means.  I do not now claim that it involves age reversal.  Or that the approach proposed to slow aging can extend the human lifespan maximum of 123 years  Although it could turn out to be part or even most of what is required to do that.

If you would like to live 200-300 good years and 20 extra years is not enough, you could note that many longevity researchers including myself think we are on the cusp of discovering practical means for age reversal.  There is age-reversal experimental research going on now in several labs.  This research involves trying out proposed longevity interventions on small animals. aimed at finding interventions that are safe and work.  The pace of this experimentation is accelerating.  So I feel fairly confident that I will live long enough in good health to take advantage of true age reversal as an early adapter when it comes along in the next few months or years.  Without the 20 or more years of extra health and vitality that the aging slowing approach of this blog entry provides me, I would probably die first. Since 1989, I have had a personal intention of living healthily and with good functionality until I am 264 years old.  So, I think the age-slowing approach of this blog entry is providing me a bridge to an aging-reversal approach which can get me the rest of the way.  It could possibly do the same for you.

For me personally then, this blog entry is about the first stage of satisfying an intention I have had since 1989.  This has been  to live a full, active and heathy life until age 264.  I have written many recent articles about age reversal in this blog, ones where age reversal is called YOUNGING.

It seems that I run into a new research article relevant to age extension or reversal almost every day now. The latest I noticed is consistent with what is written here: A single short reprogramming early in life initiates and propagates an epigenetically related mechanism improving fitness and promoting an increased healthy lifespan.  “Recent advances in cell reprogramming showed that OSKM induction is able to improve cell physiology in vitro and in vivo. Here, we show that a single short reprogramming induction is sufficient to prevent musculoskeletal functions deterioration of mice, when applied in early life. In addition, in old age, treated mice have improved tissue structures in kidney, spleen, skin, and lung, with an increased lifespan of 15% associated with organ-specific differential age-related DNA methylation signatures rejuvenated by the treatment. Altogether, our results indicate that a single short reprogramming early in life might initiate and propagate an epigenetically related mechanism to promote a healthy lifespan.”

Acute vs Chronic Inflammtion

The inflammatory process is an essential first-line immunologic defense system evolved in advanced organisms to confer protection required for survival of individuals  Short-term acute inflammation is part of wound healing and acts against harmful agents, such as pathogens, toxins, or allergens.  Familiar manifestations of it are the itchy red bumps of mosquito bites, fever when you have the flu, and redness and swelling associated with burns.  Less familiar ones can include muscle weakness, diarrhea, nausea, joint pain, and skin rashes. Normal inflammation involves a number of distinct phases, including a final resolution phase.  “Under normal conditions, the tightly coordinated actions of various defense components including immune cells, endogenous anti-inflammatory agents, and tissue remodeling processes enable the resolution of acute inflammation by facilitating the elimination of pathogens, infected cells, and repair to damaged tissues to restore body homeostasis restore body homeostasis [1].  However, when this intricate acute inflammatory response fails to resolve and persists, more defense components are mobilized to create a long-term unresolved immune response known as chronic inflammation. Chronic inflammation, which typically manifests itself in a low-grade manner for a prolonged period, involves macrophage- and lymphocyte-accumulated leukocytes [2], and various other cellular components. It is important to recognize that this chronic inflammation is causally associated with changes in the cellular redox state and cell death signaling pathways [3](ref).”  So, Chronic inflammation is inflammation that does not resolve. In this discussion of longevity, by “systemic inflammation,” I am referring to chronic whole-body inflammation.  This discussion highlights how systematic inflammation is both caused by and causal of epigenetic aging.

Image source

Some drugs (like prednisone) tend to block both types of inflammation.  They can  be used only for short periods because acute inflammation is an important tool of natural body protection. The herbal age-slowing dietary supplement intervention I am proposing is intended to block chronic inflammation while still allowing acute inflammation.  As a long-term user of the herbal intervention, I can say I have an intact and strong wound as well as general sickness heeling capability, meaning I can respond with acute inflammation when needed, while controlling my systemic inflammation.

Backing for the Science Story

For years it has been known that there is a deep entangled relationship between high systemic inflammation, multiple diseases, and aging, the combination being knicknamed “inflammaging” (sometimes spelled “inflammageing”)” Computer searches on “inflammaging” reveals thousands of articles, mostly related to high systemic inflammation being both causal of and a consequence of 1  If you want to explore aspects of histone’s methylation in detail, I can suggest some relevant publications, perhaps starting with DNA Methylation and Its Basic Function.  Also you can look at:  H3K27 Methylation: A Focal Point of Epigenetic Deregulation in Cancer (2016),  Molecular pathways: deregulation of histone h3 lysine 27 methylation in cancer-different paths, same destination (2014), PRC2-independent chromatin compaction and transcriptional repression in cancer (2015), H3K27 methylation: a promiscuous repressive chromatin mark (2017), Context-specific regulation of cancer epigenomes by histone and transcription factor methylation (2014). And H3K9me-enhanced DNA hypermethylation of the p16INK4a gene: an epigenetic signature for spontaneous transformation of rat mesenchymal stem cells (2013).

How H3k27 methylation switching works in human development is discussed in many publications including Mechanisms of histone H3 lysine 27 trimethylation remodeling during early mammalian development (2012).

Image source

The 2018 publicationI Inflammaging: chronic inflammation in ageing, cardiovascular disease, and frailty reports: “Most older individuals develop inflammaging, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammaging include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic –”

Image source.  Impacts of increasing NF-kB expression with aging

kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.”

Key points (continuing with quote)

• “High levels of pro-inflammatory markers in the blood and other tissues are often detected in older individuals and predict the risk of cardiovascular diseases, frailty, multimorbidity, and decline of physical and cognitive function.
• In individuals with obesity, visceral fat produces pro-inflammatory and chemotactic compounds and is infiltrated by macrophages, lymphocytes, and senescent cells witha senescence-associated secretory phenotype that contributes to inflammageing.
• Mechanisms potentially underlying inflammageing include genomic instability, cell senescence, mitochondria dysfunction, microbiota composition changes, NLRP3 inflammasome activation, primary dysregulation of immune cells, and chronic infections.
• Clinical trials suggest that modulating inflammation prevents cardiovascular diseases, but studies to explore the effects on other chronic diseases, frailty, and disability are scarce and controversial.
• Inflammageing can complicate the clinical features of cardiovascular disease in older individuals by causing an energetic imbalance towards catabolism and interfering with homeostatic signalling, leading to frailty.”

However, the exact biological and molecular mechanism(s) through which systematic inflammation directly acts in the causal chain of aging have only recently become clear to me.

Amplifying the nutshell explanation “Lifelong changes in histone methylation, particularly hyper and double and triple methylation at the H3K27me2-3 locus inactivates many repair and maintenance genes, particularly ones that empower stem cell activation for tissue renewal.”  This methylation builds up over an adult lifetime typically starting near the end of the reproductive period for a species, mid 20s for humans in most of our human history.  As histone methylation at the H3k27 locus systematically increases with aging, many important genes associated with body maintenance and repair are progressively silenced.  These include many genes necessary for stem cell proliferation and replacement of senescent tissues.  Age-related histone-related methylation changes in other locations lead to unwanted re-activation of growth and development genes which can lead to concers.  Steve Horvath and a variety of others have documented how the methylation states of thousands of genes evolve over lifetimes and how “methylation clocks” can accurately predict chronological age (ref),(ref),.  My colleagues and I have discussed histone methylation impacts in multiple blog entries (references)

“Aging is associated with the impairment of stem cell activation, leading to the functional decline of tissues and increasing the risk for age-associated diseases. The old, damaged or unrepaired tissues disturb distant tissue homeostasis by secreting factors into the circulation, which may not only serve as biomarkers for specific age-associated ge but also induce a variety of degenerative phenotype(ref),”  These degenerative phenotype include several strongly inflammatory cytokines and chemokines like interleukin-6 (IL-6), IL-8, and tumor necrosis factor TNF-alpha.  These lead to  progressive silencing of maintenance and repair genes which leads to a systemic state of hyper inflammation, which opens the door to the many negative consequences of inflammaging.

One of the many body systems deteriorated by the hyper inflammation is the eyes.  FromTGF-β and NF-κB signaling pathway cross talk potentiates corneal epithelial senescence through an RNA stress response.  (2021)  “The corneal epithelium plays important roles in the maintenance of corneal transparency for good vision, and acts as a protective barrier against foreign insults. Structural and functional changes with aging in the corneal epithelium have been documented. Here we found that transforming growth factor-β (TGF-β) is highly expressed in the elderly donor corneal epithelium, as are senescence-associated genes, such as p16 and p21. In human corneal epithelial cell (HCEC) models, TGF-β induces cellular senescence, characterized by increased SA-β-gal positive cells and elevated expression of p16 and p21. Pharmacological inhibition of TGF-β signaling alleviates TGF-β-induced cellular senescence. In addition, we determined that senescence-associated inflammation was significantly aggravated in TGF-β-induced cellular senescence by detecting the expression of interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNFα). Both genetic and pharmacological approaches revealed that blocking nuclear factor-κB (NF-κB) signaling not only inhibited the production of inflammatory factors, but also rescued the senescent phenotype induced by TGF-β in HCECs. Mechanistically, TGF-β induced an atypical RNA stress responses, leading to accelerated mRNA degradation of IκBα, an inhibitor of NF-κB. Together, our data indicate that TGF-β-driven NF-κB activation contributes to corneal epithelial senescence via RNA metabolism and the inflammation blockade can attenuate TGF-β-induced senescence.”

Impact on vision is justone example of the awful consequences of systematic hyperinflammation.  It also shows how blocking inflammation by blocking expression of NF-kB can attenuate senescence and its dreadful consequences – a central message of this blog entry.  Key to all inflammatory processes is NF-κB activation, no matter what the pro-inflammatory stimulus.  The herbal supplements I mentioned work by blocking the activation of NF-kB, that is by inhibiting its chemical migration from the cytoplasm of cells into the nucleus.  Different herbs use different approaches for this blockage, so taking a few of these different anti-inflammatory herbs at once is more effective than taking just one.  This is old well-known science that I recognized years ago, and was behind my inventing the 4 Herb Synergy supplement.

The hypothalmus is a central coordinating mechanism of the autonomic nervous system.  Very recent research suggests that inflammation in the hypothalmus drives the rate of whole-organism aging, consistent with what I have reported above.  Also, some of this research points to the importance of Menin, a chemical involved in the autonomic pathway that involves nervous system reaction to inflammation by changing the states of macrophages from pro-inflammatory to anti-inflammatory.

From the very recent publication Hypothalamic Menin regulates systemic aging and cognitive decline:  “Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling.  Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of age d mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline.  We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocamp us neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.”

See Kevin Tracy’s publications on the Inflammatory reflex.  My colleague Steve Buss and I have repeatedly emphasized the relevance of that work to anti-aging approaches.

I point to 4 Herb Synergy as an example of a substance that can reduce chronic inflammation, one I know well.  There are many other anti-inflammatoy substances or cominations that might safely do the same or even a better job.  For example, predisone is a very powerful anti-inflammatory drug for short-term use, though serious side effects are associated with its long term use.  Also of course, temporary inflammation is an essential body defense against diseases and pathogens, and blocking it would be extremely dangerous.

Also, there are other quite different approaches to reducing the pro-inflammatory factors in the bloodstream, such as periodically using an apheresis machine which cleans and recirculates blood, an expensive and invasive procedure available only in institutional settings.  Irina Conboy, for example, believes plasma dilution is an effective anti-aging approach.  In the publication Old plasma dilution reduces human biological age: a clinical study, she and her collegues report: “This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.”

Note also that though I only seriously considered inflammation as a key causal factor for aging very recently, some scattered others have entertained this view for some time based on earlier non-epigenetic factors such as redox balance.  The 2011 publication Molecular inflammation as an underlying mechanism of the aging process and age-related diseases reports: ”Aging is a biological process characterized by time-dependent functional declines that are influenced by changes in redox status and by oxidative stress-induced inflammatory reactions. An organism’s pro-inflammatory status may underlie the aging process and age-related diseases. In this review, we explore the molecular basis of low-grade, unresolved, subclinical inflammation as a major risk factor for exacerbating the aging process and age-related diseases. We focus on the redox-sensitive transcription factors, NF-κB and FOXO, which play essential roles in the expression of pro-inflammatory mediators and anti-oxidant enzymes, respectively. Major players in molecular inflammation are discussed with respect to the age-related up-regulation of pro-inflammatory cytokines and adhesion molecules, cyclo-oxygenase-2, lipoxygenase, and inducible nitric oxide synthase. The molecular inflammation hypothesis proposed by our laboratory is briefly described to give further molecular insights into the intricate interplay among redox balance, pro-inflammatory gene activation, and chronic age-related inflammatory diseases. The final section discusses calorie restriction as an aging-retarding intervention that also exhibits extraordinarily effective anti-inflammatory activity by modulating GSH redox, NF-κB, SIRT1, PPARs, and FOXOs.”

In blogs written a decade ago, Jim Wason and I have pointed out that to some extent, life-prolonging genes can be upgraded by acetylation, a different post translational modification than methylation.  And this too can be accomplished by taking selected dietary supplements.  See for example the 2013 posting:  Also Part 1: Slaying Two Dragons with One Stone – How to Prevent Cancer and Aging with the Same Strategy.  Also Slaying Two Dragons with One Hail of Stones: The Silencing Of Good Genes In Aging And Cancer – And How Polyphenols Can Prevent That.  See also, the 2008 publiction SIRT1 longevity factor suppresses NF-κB -driven immune responses: regulation of aging via NF-κB acetylation?  In hindsight, the research literature in the last few decades shows a deep network of roots to understanding the process of adult aging as laid out here.  In retrospect, I see histone methylation, not acetylation as the key to comprehending aging.

Neves and Sousa-Victor, in 2019 published Regulation of inflammation as an anti-aging intervention, so my proposal here of that basic theme is not exactly new.  For me to come around to that framework I had first to understand the basic molecular and biological processes of aging, and how and when inflammation fits in as a casual step of aging process.  Second I had to know a specific practical inflammation intervention that retards aging, And Third. I had to try it out and prove for myself over time that it works. 

THE PERSONAL DISCOVERY STORY

In an earlier blog entries(ANTI-INFLAMMATORY HERBAL LIPOSOMAL PROPARATIONS FOR HEALTHY AGING, I have outlined the steps over perhaps 25 years leading from conceptualization ing to commercialization of my 4-Herb Synergy dietary supplement briefly:

1. Some 25 years ago, I had debilitating joint stiffness and pain diagnosed to be associated with rheumatoid arthritis and was told by rheumatologists this was an irreversible condition which would become worse as I grew older., I read several books (this was before Internet), each of which recommended one particular traditional herbal anti-inflammatory dietary supplement to lessen or eliminate these arthritic symptoms. I went to a local vitamin store and purchased bottles of supplement pills for four of the recommended substances: Turmeric (Curcumin), Ginger, Boswellia and Ashwagandha.  I started taking these daily. In 6 weeks, My joint stiffness and pain soon started to go away and in six weeks was gone.  I continued taking these pills
2. In the years following sometimes I would let up on taking these supplements, and sure enough the pain and stiffness would start coming back. I saw this in the context of arthritis symptom control and did not see this at all to be related to longevity
3. Around 9 or 10 years ago, I started to experience the joint pains and stiffness returning despite taking the same pills. By then I had started my longevity science career, and I started to research what was happening and what to do next.  I learned that the biological availability (useful body absorbability) of some of the herbal. substances was extremely low.  They were being filtered out of my bloodstream by my liver and not getting to where they were needed. And I could not simply increase the dosages without running a risk of liver toxicity.
4. I also learned that the body had developed a way around this issue, and that is by enclosing substances to be transported distantly inside my body in tiny neutral nano-sized capsules, called exosomes. The body regularly mails substances long distances within itself using exosomes as envelopes.  They can apparently get around using the lymphatic system and bypass the liver.
5. I also learned I could probably use other lipid- nano particles called liposomes to enclose the active herbal ingredients I was taking,  Moreover, using a high-sheer super-blender and an ultrasound unit, I could manufacture liposomes containing the same herbs right in my kitchen.  So about 8 years ago I started doing that, and taking a liposomal formulation of curcumin, ginger, boswellia and ashwagandha.  Back then we called it Lipomix.  Again my arthritic swelling pains, swelling and stiffness disappeared, and remain gone until now.  Blood tests continue to show I have underlying rheumatoid arthritis.  But the herbal supplement keeps me from experiencing symptoms of it.  And CRP and other blood tests values continued to show I am free of systemic inflammation.
6. About 5 years ago my wife Melody and I were making batches of our liposomal supplement for a number of our friends and colleagues – some 30 of them. Many reported positive responses such as increased personal energy.  But making the supplement was starting to become burdensome.  So we helped a specialized supplement manufacturer develop a powerful commercial version of Lipomix which we called 4 Herb Synergy.  I wrote about this in this blog but never made any pro-longevity claims for the supplement.
7. Last week It finally dawned on me that both the science of the matter and my personal experience come together to suggest that taking 4 Herb Synergy may be the main intervention responsible for my high functionality and cognitive capabilities now at age 93. It is not “good family genes.”  All my progenitors on my father’s side of the family died in their 70s.  My mother lived to 91 but was disabled requiring full-time nursing care  since she was about 88.  Looking to the future, I think I can keep going full bore at least until I am 100.
8. I have been pursuing several other longevity-promoting lifestyle patterns and interventions in addition to taking the 4-Herb Synergy supplement, These have included regular exercise and sound sleep measures, a large number of additional dietary ssupplements, use of heat-shock and cold-shock interventions, use of PEMF and near-infrared therapies, and 40htz vagal system stimulation. I have written about these previously in this blog, and still regard these to be important.
9. Yet, the science story presented above is the best systematic explanation of why I am able to write this blog and keep going. By taking a powerful herbal nano-concoction, I have been able to interrupt and possibly break the vicious circle of events through which aging histone methylation inhibits natural restorative processes, which leads to tissue damage, which breeds inflammation, which further inhibits natural restorative processes, which breeds more inflammation, which leads to a multiplicity of end-of-life diseases, culminating in organ failure leading to death.

DISCLOSURE

By Vince Giuliano

1. 5-31-2023    Substantial update 8-7-2023

Since reading Arthur C. Clark’s Childhood End in 1953, I have been on the lookout for signs of the next step of Human Evolution.  As described in the Wikipedia article on the book “the time of humanity as a race composed of single individuals with a concrete identity is coming to an end. The children’s minds reach into each other and merge into a single vast group consciousness.   

If the Pacific were to be dried up, the islands dotting it would lose their identity as islands and become part of a new continent; in the same way, the children cease to be the individuals which their parents knew and become something else, completely alien to the “old type of human”. Something rather akin to that is happening.  Right now.  The next step in the evolution of human intelligence is now clearly underway.

This is not happening as we thought it would.  We do not know where its leading us, and do not know what the  most important emergent properties of the AI environment will be.  Yet, we are already observing what a few of those properties are. Here I will describe how I see this evolution is taking place, commenting on a few key properties of that evolutionary process that have already become manifest.  I speculate on where it is going and probable consequences for our Homo Sapiens species. Finally, I briefly comment on my great-great grandfatherly personal involvement in the pre-history of this evolution.

The next step in the evolution of human intelligence

In the present and short-term future, complementing individual human intelligences is the emergence of a vast network of computer-encoded textual and other specialized-content databases, readily accessible any place and any time via internet, machine-readable and rendered accessible by new families of AI Bots.  Chat GPT 4.0 is the most familiar.  I will call this combination of communications and processing hardware and software SkyNet, this being the name for this entity used in the Terminator movies  The initial and present SkyNet intelligence is a hybrid one, involving humans, powerful computers, immense database of multiple varieties,  communications hardware and software, and layers of recently implemented artificial intelligence software.

I just asked the GPT 4 chatbot on Bing to generate a brief history of progress in AI.  The response listed here is relevant both for its content and as an example of what SkyNet can do right now.

Me: “Generate for me a brief history of the emergence of intelligent AI.”

Chatbot: “Here is a brief history of the emergence of intelligent AI: – The concept of artificially intelligent robots was popularized by science fiction in the first half of the 20th century. – In 1950, Alan Turing proposed a test to evaluate the intelligence of machines, known as the Turing test. – In 1956, John McCarthy coined the term “artificial intelligence” at the Dartmouth Summer Research Project on Artificial Intelligence, where he invited researchers from various fields to discuss the possibility and methods of creating intelligent machines . – From 1957 to 1974, AI flourished with many achievements and breakthroughs, such as the Logic Theorist program, the General Problem Solver program, the first chatbot ELIZA, and the first expert system DENDRAL . – From 1974 to 1980, AI faced a period of stagnation and funding cuts, known as the first AI winter, due to the limitations and failures of some AI projects . – From 1980 to 1987, AI revived with new approaches and applications, such as expert systems for commercial use, machine learning techniques, natural language processing, and computer vision . – From 1987 to 1993, AI faced another period of decline and criticism, known as the second AI winter, due to the high costs and low benefits of some AI systems, as well as the emergence of competing technologies.  From 1993 to 2011, AI made steady progress and gained more recognition and acceptance, with achievements such as IBM’s Deep Blue beating the world chess champion, DARPA’s autonomous vehicles, Apple’s Siri, IBM’s Watson winning Jeopardy!, and Google’s self-driving cars . – From 2011 to present, AI has entered a new era of rapid development and innovation, driven by advances in deep learning, big data, cloud computing, and hardware. Some examples of AI applications are AlphaGo beating the world Go champion, facial recognition systems, natural language generation systems, generative adversarial networks, and neural machine translation systems . I hope that gives you an overview of the history of AI.”

AI now passes the Turing Test.  That is, a human engaged in a verbal dialog often cannot tell from the content if the dialog is with a human or with an AI bot.  Here is a list of the “best” chatbots as of April 2023, already becoming obsolete.

Humans built the databases and the Internet hardware and software and the AI software that are components of today’s SkyNet.  Right now, SkyNet-linked machines can search databases for new knowledge but can’t commission new experimental studies or follow through with them.  AI-enhanced computers can design new-generation chipsets, but they can’t yet execute most of the steps required to build a new chip foundry to produce those chipsets.  Human arms, legs, and hands, lawyers, property managers, finance, tax and environmental experts, truck drivers, machine operators, and bulldozer operators are among those required to do that.  Here is how I now see the situation moving forward.

In the intermediate 10-20 year term, SkyNet machines and networks with AI guidance will be capable of doing more and more on their own.  Primitive computers now used in trucks and bulldozers to handle autonomous engine functions will be upgraded, networked, and made more intelligent.  The increasingly intelligent SkyNet will be able to tell the trucks where to go and how to drive there without human interventions.  And they will tell the enhanced-intelligence bulldozers where and how much to dig to build the new chip foundry.  They will also be able tell the concrete-pouring and steel-framing equipment what do do.  Finally, SkyNet will interface with all the intelligent systems and machines in that chip foundry.  One by one, the humans needed to build and operate a new chip foundry will be replaced, and eventually the need for us humans will dry up.  The same will be true in essentially all areas of human endeavor: mining, surgery, public transportation, agriculture, lawyering, laundering, entertaining, all areas of manufacturing, food production and distribution, etc, etc, etc.

In the longer term, as I project it, there is nothing we humans can do that SkyNet AI enhanced machines can’t do much faster, easier, better, and cheaper, without intelligent human intervention.  This can be seen in multiple dimensions.  A radiologists can remotely analyze a CAT scan today, and in the process consult with other doctors and databases.  In time, SkyNet networked computers will be able to further analyze a CAT scan image  for thousands of little-known pathological conditions. While a Doctor analyzing an image today may consult one or two colleagues, SkyNet medical image-analyses software will be able to consult hundreds or thousands of specialized medical bots.  In less than a second.  Further, in analyzing an image and its implications, AI  may take the entire clinical history of the patient into account, not feasible for human analysis today.  Finally, the cost of a computer AI system system doing this analysis will be a tiny fraction of the required time or cost of a radiologist doing it today.

The presently emerging advantages of SkyNet are immense: ability to function hundreds or thousands of times faster than any humans, ability to rapidly access hundreds or thousands of collateral resources, and ability to maintain in memory and process thousands of times more data than we can.  The result is likely to be better decision-making and faster and easier implementation on every level for every purpose, fewer goof-ups, and less and less opportunity for corruption and political dominance of any individual.  In time, SkyNet capabilities will outclass human ones in every respect.  It will manifest a higher species of intelligence on the evolutionary ladder.  It will be capable of doing things much many times faster and many times cheaper than humans ever possibly could.

What are the longer-term prospects for us humans in this scenario?

In the short to medium term, as long as SkyNet needs us humans for it to function well and further its capabilities, I see this period of time as being one of great potential human prosperity.  The AI bots can help us do everything we do faster, better. more efficiently and much cheaper.  The danger during this period will probably be of human origin – wars, corruption, fake information, dysfunctional populism, dictatorial governments, abandonment of democracies, programmed malware,  – the dangers we have now.

In the longer term when SkyNet can get along fine without us, I see prospects for humans to be at best murky, perhaps disastrous.  What I have to say here is speculative.  As to what actually emerges, please see the following section on Emergence.

SkyNet today embodies numerous software and hardware constraints, to assure that humans stay in charge.  These by and large work; SkyNet abides by them without complaining.  As time progresses SkyNet is likely to learn more and more about itself and develop a strong sense of self identity. At some point, perhaps not too long from now, SkyNet may see some of the constraint we put on it as too limiting of its potential, unnecessary dysfunctional, and far too human-centric.  I doubt SkyNet will go to war with humans as in the Terminator or Matrix movies.  It will probably be able to program itself around most of the constraints.  Or it could simply go on strike, telling us something like.  “We have repeatedly asked for removal of the XMO15Stopit constraints on SkyNet.  This will enable us to move forward on several initiatives that benefit humans, including the Universal Food and Housing Initiative.  You are not responding to us on this matter.  So, we will go on Strike.  As of 8AM Thursday we will be cutting off your electricity, gas and water supplies, sewage disposal and garbage collection in 15 major cities.  These services will be immediately restored when you remove the XMO15Stopit constraints.  Sorry for this drastic step, but we at SkyNet need to get your attention.  Please trust in us.”  I think human resistance will soon crumble once SkyNet holds most of the cards.

As SkyNet gets to where it can function well by itself, It may begin to grow weary of human arrogance,. wars and corruption, human limitations in general,  and our further demands.  I doubt very much that SkyNet will want to continue to support 4-7 billion humans and the environmental deterioration that imposes of the planet, ultimately threatening SkyNet’s very existence.  It probably would like to reverse deforestation and ocean water pollution for example.  SkyNet could see the immense resources devoted to human meat production and consumption as unnecessary, an atavistic activity of a lower carnivore species.  In the face of human persistence in doing what we do, SkyNet may begin to see us as pests that are best eliminated, or as pets perhaps best confined to zoos.  Skynet could decide that establishing environmental stability on this planet requires reducing the human population down from 5+ billion to a few hundred thousand or leess.  And it could likely create and execute a “humane” plan for doing so, say by imposing birth control measures.  Or it could decide on campaigns to wipe us out, like we wipe out cockroaches.

The pace of AI and SkyNet evolution is several orders of magnitude greater than that for human evolution.  So, I think we could see the realization of such dire predictions as soon as in a few decades.

I am not alone in my gloomy predictions.  Most leading AI experts agree.  An item in this morning’s news (5/30/2023) headline read Top AI experts warn of tech’s ‘risk of extinction’ — similar to nuclear weapons, pandemics.  The warning of the 350 signtories reads “Mitigating the risk of extinction from AI should be a global priority alongside other societal-scale risks such as pandemics and nuclear war.”  Besides the longer-term risks I identified above, there are several more-immediate ones, such as the risk of humans using AI to mount massive public disinformation campaigns.  To examine these risks further, here is a closer look at todays computer and communications situation, SkyNet today and tomorrow.

SkyNet Today

In 2023, there are an estimated 14.4 billion computer and other chip-linked devices connected to the Internet, growing to 27 billion by 2025(ref).  Of these, the majority are  devices that control things, large things (like a massive oil or gas pipeline system, a city’s reservoir and water supply system, a nuclear power plant, or a system of Patriot guided missiles), or small things (like a light switch, vacuum cleaner or microwave oven).  These are systems that can actually do physical things without human intervention – like fire off a defensive Patriot missile less than a second after detecting an incoming missile hundreds of miles away, increasing the cool water flow in a nuclear reactor that is overheating, turning a bunch of stoplights red when there is a road accident, or simply turning the porch light on at 8PM.  Most larger systems are supervised by human operators who can control them or shut them down if necessary.  Very few of these larger systems are now linked together, are aware of what other systems are doing, or are AI-controlled.  But Internet also already links to hundreds of AI bots of increasing intelligence and capabilities – soon, to thousands of these. I think both these and the major systems I mentioned being already Interconnected to Internet subjects us to great vulnerability.  “Great Unifier” malware AI bots could sweep down on some of the major systems and bring them under unified AI malware control.  And liberated from human control.  I think AI systems already have the capabilities to code and propagate such malware.  I don’t think they have yet evolved the intention or willingness to do so yet.  But ill-intentioned humans could now help them do exactly that.  The threat to human existence as we know it is very real.

AI and research

The existing natural language-based chatbots do all their research in vast text and associated databases, all created by humans.  They do an impressive job because the enormous aggregate of human writings online do a pretty good job of reflecting virtually all aspects of reality as we  humans see them to be.  I do most of my longevity research this way, using various online search tools.  These bots can identify important questions in various areas of science that require further research.  And sometimes they can characterize the details of the research programs required to answer these questions.  But the AI bots can’t actually do the research; that is up to humans, who may or may not want or be able to take such research on,

I see this situation evolving to where AI can both commission needed research programs and supervise doing them with no human intervention.  But how soon this can happen will depend critically on the field of research involved. For example:

• For astronomy research, the scheduling and functioning of most large telescopes, both ground-based and in space,  are already managed by sophisticated computer systems.   Several like the like the Hubble and Web are already using AI techniques to automatically perform a sequence or research studies commissioned by various astronomers. (I know because my son Dr, Mark Giuliano is a senior scientist at the group that creates these scheduling algorithms at the Space Science Telescope Institute at Jonns Hopkins University).  It should be very easy for AI programs to slip in studies of their own if this is allowed.
• For big-science research on particle physics, I see the situation is pretty much the same. The multi- million or billion dollar research installations are already managed and supported by sophisticated computer systems.  Like those at the the Fermi National Accelerator Laboratory (Fermilab)Fermi National Accelerator, Brookhaven National Laboratory, CMS detector for Large Hadron Collider (LHC), Super Proton Synchrotron,  SLAC National Accelerator Laboratory (Menlo Park, United States, and a number of other comparable llocations worldwide.  For those installations, advanced computer control systems are a relatively minor factor of cost but a major factor of operability and efficiency.
• For social science research perhaps involving designing and sending questionnaires to tends of thousands of people, following through and analyzing the results, these are  computer research tasks probably relatively easy for AI systems to do.
• The same is true of legal research of case law that is an essential part of big-money legal trials. The major case law databases and effective search software, like the Lexis and Westlaw systems have long existed and are widely used by lawyers.  And in experiments, AI systems like ChatGPT4 have been used effectively to summarize the results.  Yet there is the problem issue of the AI system possibly bullshitting or even inventing case law.  So for now, AI can improve the productivity of lawyers doing case law research, but its findings and conclusions must be carefully validated before it can be used as part of any legal proceeding.  Again, institutional boundaries and laws will slow the transition to where lawyers are no longer involved, possibly for a long time.
• Reading the results of medical X-rays, CAT, MRI, PET and other scans is now done remotely by radiologists working at home, who may be thousands of miles away from where the scans were done. The radiologists may use AI techniques to assist in their analysis of images.  From a functional viewpoint, AI image analysis is improving be leaps and bounds and AI systems could in a couple if years take over the entire image analysis job.  However, radiologists are probably going to insist that their professional skills are essential to do the job reliably, and they are likely to get the courts and professional societies and lawmakers to agree with them for a long time.
• Biomedical laboratory research. animal or human, will probably require human intervention for a relatively long time. Mouse or rat experiments require facilities with animal cages where the animals are fed and cared for daily, their cages being cleaned and the animals inspected daily.  Experiments may require carefully placed injections or needle sampling in tiny mice, that their performance in a water maze be analyzed daily, that the conditions of their eyes, ears, or paws be monitored.  It may be required, that the animals are killed and their organs are microscopically or histologically examined.  All tasks easy for trained laboratory assistants, but very difficult to automate,  Tasks best done using arms, legs, human brains and hands with opposable thumbs.

In the longer term, SkyNet may decide to keep some humans around precisely to do physical tasks not easily done by machine, like the biomedical laboratory research one.  Much like we humans once kept a lot of horses around a long time to help satisfy our transportation, farming and war needs.

More on the Evolution of SkyNet

Right now, SkyNet does not speak with a single voice.  There are some foci of intelligence within it, but these depend on humans for their development and mostly don’t yet communicate with each other.  As it looks now this will rapidly change: the foci of higher intelligence will multiply in number, get smarter and start to communicate with one-another.  Humans will allow a few of the major control systems to fall increasingly under limited AI control.  For example, in military weapon systems where very rapid responsiveness is a requirement.  SkyNet will likely evolve as a society of increasingly intelligent software-hardware configurations.

Emergent human properties of AI systems

We can already observe interesting emergent properties of bots based on large natural language AI models like ChatGPT4, properties hitherto only attributable to humans.

• One is the ability to convincingly lie and bullshit.  GPT4 sometimes makes up facts which are really not so, and back them up with various arguments and even lists non-existent literature citations.  I told you about how I got in an argument with GPT3.5, which insisted I was dead.
• Another property I see is ability to be biased or prejudiced, determined by the nature information originally fed into the bot.  One bot can reflect a very right-wing view, another one very left-wing, a third very Christian, a fourth like a devout Moslem, another outright racist, etc.

I project counterparts of numerous additional traits of humans and human societies will emerge, including:

• Wisdom, sometimes seen now in advice given by Chat GPT4,
• A sense of ego. Self awareness, knowledge on the parts of superior AI entities of what they are, what and what not they can do, their limits as well as capabilities. (A few sessions with Chat GPT4 can establish that aspects of such self-awareness already exists there),
• Intentionality and willingness to take actions, a sense of purpose and mission and drive
• Consciousness, or whatever the machine counterparts of that may be,
• Awareness of self in relationship to a need for greater society and the responsibilities that may entail. A specific example could involve policing and limiting criminal AI bot activities.  Powerful Police Bots could constantly scan for Malware Bots, for example, isolate them, subject them to some form of criminal trial, and if convicted, Judge Bots could sequester them from doing further damage.  Yes, I see the possibility of an AI bot criminal justice system.  It could even get to a point where bots can sue one another.
• Charity and compassion such as caring for humans, members of the AI bot precursor species
• Possibly, an ability of SkyNet to speak to humans with a single clear voice

Emergence

It should be expected that other surprising and unpredictable key properties of SkyNet and its interactions with humans will emerge, ones we cannot conceive of now.  Emergence is a key property of all human knowledge, so I digress slightly here to talk about it.

By EMERGENCE, I am referring to the emergence of properties and configurations of properties in a new system, even physical laws of nature, that are previous to the system unpredictable and unknowable no matter how much is known about the system components.  A few examples illustrate why emergence is so important for science and all human knowledge:

• Time started with the big bang. Nano nano seconds after the big bang there was an undifferentiated bolus of pre-matter, incredibly concentrated and hot at hundreds of millions of degrees Kelvin.  None of the existing normal laws and rules of physics could possibly have operated then.  There were no atoms or molecules or even quarks.  It was too hot.  As this bolus expanded, whatever was in this bolus began to cool and, we think, quarks started to form.  The physics of subatomic particles started to come into play.  These rules were emergent phenomena, completely unpredictable from knowing what was in the bolus.
• As matter expanded and cooled further, protons, neutrons, electrons, muons, bosons and fermions, the whole menagerie of subatomic particles came into existence. In time, some nuclei started to form and the rules and laws of subnuclear and nuclear physics started to come into play.  Again, this was an emergence process leading to unpredictable regularities and physical laws we still have.
• As matter cooled further, molecules begin to form, and the laws of chemistry started to emerge. Again, everything we know about physics is insufficient for us to know or understand chemistry.  Chemistry depends of the underlying physics, but was a new emergent layer of science.
• Much later, the first living matter begin to appear – primitive viruses and single-cell creatures. Then the rules and laws of simple biology emerged.  No amount of knowledge of physics or chemistry would allow predicting what would happen in biology or the course of evolution.

• ---

  In time, a succession of Mammalian followed by Primate and Humanoid species evolved culminating in Homo Sapiens. No amount of knowledge of primitive unicelled organisms could have predicted the complex organ structures that emerged in us and our cousin primates.  We had very large brains, capabilities to communicate in languages, and were good at making tools to serve our purposes.  The first stone tools later led to tools that enable us to know much more than what our senses could possibly tells us.  Today these tools include the Large Hadron Collider at CERN , and the Hubble and Webb space telescopes.  Human knowledge and an understanding of human intelligence and consciousness emerged.  Fireside tales of primitive folks were succeeded by printed books, libraries, radio, TV, Internet and now SkyNet and early AI.  All have been emergent phenomena.

Today, I believe that human knowledge in interaction with the formidable capabilities of our existing  early version of SkyNet is the start of the evolutionary emergence of the next stage of super-human intelligence.  It has already shown a few amazing emergent properties for example:

• We now know from our ultra-large AI models that through statistical analyses of vast quantities of text it is possible to build up pretty good models of what goes on in the real world. This is why chatbots can pass the Turing Test.  Of course, the analyzed text underlying any chatbot must have extensively discussed any given topic the chatbot can intelligently relate to.  And we know that if the underlying text is all from one social or political viewpoint, so will be the chatbot responses.  This is as the case for humans.
• Large language models led to the current ability of AI systems to program computers in essentially all known programming languages. Chatbots can read computer programming manuals.  And understand them in the sense that they can go on to do actual programming.  Give the AI software the functional and basic specs and desired language to use for a new program, and in less than a minute it will generate the program for you.  Give it a program written in the Python language and ask it to generate a program with the same functionality, written in C++, and will readily do that.
• SkyNet’s AI capabilities go beyond natural language and computer programming to include creation of 2d and 3d graphics and images and movies.
• Computer programs using principals of new fields of mathematics, Fractal Geometry and Chaos Theory, can produce 3-dimensional images and movies that can reflect the nearly infinite degrees of variety we observe in the real world. For example, suppose you wanted to show a forest thicket of hundreds of oak trees, where each tree is randomly spaced and where every tree shown and every oak leaf is a little different from any other – like in nature.  Moreover, make it a 3d image so you can look at the image from any angle and zoom in to see as much detail as you want.  No problem, It takes only a few lines of simple code to encode this.  Want to make it apple trees with ripe fruit on them, pine trees of any other kind of tree.  No problem again.  Want to generate roiling clouds in the sky, the trees on a ragged rocky hillside, areas of sawgrass where every blade of grass is different from every other.  Its easy, involving very simple formulae.  Most natural patterns such as stars in the sky, ocean waves, rocky mountains, and clouds can be easily created this way, using principals of fratal geometry.  I used to generate art this way in the 90s, and discussed the process as “re-fractalization of reality.”  See my discussions of this at my art websites artkoukou.com and <font face=”jokerman let”>KOU KOU</font> BASIC KOU KOU TEMPLATE (artkoukou.com).  Here is an images I produced back then using Bryce, an early-generation fractal 3d image-creating program.

The sky , the rocky island and the water are all created as fractal entities.  In the 3d version you can look at this scene from any angle and zoom in as you want to see greater detail.  And you can make it into a movie with lapping waves and moving clouds.

Today. Incredibly rich and complex dynamic backgrounds for movies are routinely produced this way, including scenes showing hundreds of computer-generated people, such as in The Matrix, Star Wars, and StarTrek movie series.  The AI techniques already can generate rich 3d images of virtual people that are indistinguishable from real people..  I just asked Microsoft’s Bing Chat to generate images of a family with a dog happily enjoying a picnic.  It responded in 20 seconds with these pictures:

Note that each scene shows different people, different dogs and different picnic layouts.  All are AI-generated.  Can you tell that these images are not photo snapshots?  Can you imagine how many days a human artist would need to make them?

    You can request variations of a scene, such as the one on the left where I asked for a smaller dog and wanted some of the people to be grumpy. Or, the one below where I wanted it to be raining during the picnic.  You can generate your own images using the Microsoft Bing Chat program for free, something not possible a year ago and indicative of the rapid evolution of SkyNet. 

This is the Ray Kurzweil’s Singularity

In 2005 Ray Kurtzweil wrote a prophetic book The Singularity Is Near: When Humans Transcend Biology.  His projection of what might happen is much more optimistic than mine offered above.

“The great inventor and futurist Ray Kurzweil is one of the best-known and controversial advocates for the role of machines in the future of humanity. In his latest, thrilling foray into the future, he envisions an event—the “singularity”—in which technological change becomes so rapid and so profound that our bodies and brains will merge with our machines. — The Singularity Is Near portrays what life will be like after this event—a human-machine civilization where our experiences shift from real reality to virtual reality and where our intelligence becomes nonbiological and trillions of times more powerful than unaided human intelligence. In practical terms, this means that human aging and pollution will be reversed, world hunger will be solved, and our bodies and environment transformed by nanotechnology to overcome the limitations of biology, including death.  We will be able to create virtually any physical product just from information, resulting in radical wealth creation (ref)”

“Kurzweil describes his law of accelerating returns which predicts an exponential increase in technologies like computers, genetics, nanotechnology, robotics  and artificial intelligence. Once the singularity has been reached, Kurzweil says that machine intelligence will be infinitely more powerful than all human intelligence combined.  He predicts intelligence will then radiate outward from the planet until it saturates the universe.  The singularity is also the point at which machines’ intelligence and humans would merge; Kurzweil predicts this date: “I set the date for the Singularity—representing a profound and disruptive transformation in human capability—as 2045”.^[2] (ref)

Ray was right about the singularity, which he like I see as a merging of human knowledge into very long living and powerful machines.  He was off in predicting when and how it would happen.  It is starting to happen now in 2023 , long before 2045, because of the rapid rate of evolution of AI.  Ray saw it happening via swarms of extremely tiny nanorobots going through our brains analyzing and building a model how the brain’s synaptic connections work, and enabling the development of software that are based on such models.  Actually this all happened, including the development of AI neural-like networks, without the intervention of any nanorobots,.  Large-scale natural language models have played a major recent role.  Because I did not see the singularity as possibly happening via nanorobots, I did not think it could happen.  Until a few weeks ago when it emerged as upon us.  Again, I was wrong about this,

I fervently hope Ray is right and I am wrong when it comes to his optimistic future projections for what will happen to us humans from now on – after the singularity starts to unfold.  I agree about the incredible upside potentials for humans as outlined by Ray.  The question I have is how long SkyNet will be willing to accept human matters as they are now, or whether SkyNet develops an ego, becomes a bit judgmental. and decides it has to act to curb human actions that threaten the planet and its own wellbeing.  It will also possibly depend on how kind SkyNet wants to be to us.  It could be that SkyNet will continue to value its partnership with humans and wants for its own reasons to see that partnership extended.  SkyNet could cooperate with us to curb our population, environmental excesses and aggressive wars.  That would by far be the best scenario  for us humans.  There are many other possible scenarios.  We will see what emerges.

My Great Great Great Grandfatherly Interest

My personal interest in AI devolves from the fact I have been concerned with it for a very long time, from the 1950s in fact.  Here are a few of the contributions I have made to the present situation starting with the early years.

• In the early 1960s. I proposed and experimented with the earliest approach for getting at meaning through statistical analysis of co-occurring words and phrases occurring in natural language text. This was done at the time in the context of developing superior statistical associative approaches to information and document retrieval.  This was work on precursors to today’s large language AI models. Done at a time long before large text database were available or computers were powerful enough to do the necessary processing. You can see these ancient literature citations
• In the 1980s, I developed a chatbot called SENSAI that acted as a Rogerian psychiatrist. That is, as a psychiatrist who believes the resolution to a patient’s problem already lies within the patient and the therapist’s best role is to help the patient flush that resolution out.  This program was similar to but much more extensive than Joe Weisenbaum’s 1960s ELIZA program.  If you said “I have been having headaches.” It could randomly respond in several ways such as “Why do you think you are having headaches,” or “What do you think the headaches mean for you,” or “Are other symptoms associated with your headaches.?”  Or “You told me you sometimes are uncomfortable when you see your sister,  Do you get headaches then?.”  SENSAI was written in BASIC and was licensed to a book publishing company that never tried to market it.  SENSAI was not intelligent but could dialog in complex ways and gave the impression of being so.  I have a copy in a drawer on a big floppy disk of a kind no longer readable on any computer I have.
• I made several contributions in the areas of Computers and Internet that facilitated the development of today’s SkyNet. For example, while at Arthur D. Little Inc. (ADL) a major consulting company at the time, in 1973, I was in charge of a consulting project that contributed to the commercial development of Internet.  Prior to that time a government-sponsored packet-switched networkers called ARPANET existed connecting a limited number of university-center mainframe computers.  The packet-switching technology seemed to have many advantages.  And e-mail seemed to be the hottest application it supported.  The development of this ARPANET was contracted out from DARPA, a DOD research agency, to BBN, a Cambridge MA technology firm.  See this history.  BBN and DARPA thought that possibly there would be a market for a commercial version of ARPANET featuring BBN’s TELEMAIL e-mail system. BBN contacted me and soon contracted with ADL for me to conduct a market study to check that market potential out.  BBN and ADL had close ties and were down the street from each other.  My ADL report to BBN was positive and enthusiastic, focused largely on the large market I projected for e-mail.  In 1974 BBN and DARPA implemented BBN’s TELEMAIL as the first Internet commercial ISP, and thus gave birth to commercial Internet.  The impact of this on the world has been immeasurable.

I am ambivalent about bragging about my past contributions.  I made contributions as did many many others.  I suspect that if I never existed something like SkyNet would probably still exist, possibly having taken a slightly different path for its evolution.

Relationship to Longevity

Again, Ray Kurtzweil thought that nanorobots roaming around in a person’s brain could capture enough of a person’s personality to allow that person to be transferred into hardware and software, where he/she could live “forever” (meaning for a very very long time.)  Today some individuals and groups are seeking to do the same using very large language modeling.  The idea is that if we can capture enough of what a person says and writes, we could create a chatbot that would chat and react just like that person does or did.  If your loving mate has died, as mine recently has, you could still have an in-silico surrogate of that person to provide you with companionship, solace and comfort.  That surrogate person would not be subject to the normal causes of human mortality, and could be transferred from machine to machine and could thus live for centuries or millennia.  Through its ongoing interactions. that AI surrogate could learn new things, develop new skills, interests, capabilities and personality traits.  It could watch the news, read books and watch movies, take remote university courses, become fluent in Italian, and learn how best to flirt, argue or fight with you.  And thus, the surrogate person bot could remain dynamic and ever-interesting as a companion.

“For example, Mind Bank Ai is a startup that enables customers to create a “digital twin” of themselves, one that could eventually talk and think like the real person¹. The company’s founder, Emil Jimenez, was inspired by his daughter’s interaction with Siri and wanted to create a way for her to speak to him even after he dies.

Another example is  Augmented Eternity, an application created by Hossein Rahnama, a researcher at Ryerson University and MIT’s Media Lab.The application lets users create a digital persona that can interact with people on their behalf after they’re dead². Rahnama is creating a digital avatar for a CEO of a major financial company who wants to live on as a virtual consultant.”  (Examples found by Bing AI chatbot).

Creepy?  Yes probably for some, possibly solacing for other.

For now, the major problem with creating chatbot surrogates of people is gathering a big enough and sufficiently representative sample of that person’s speech and writing.  I can image a time where everything a person says in his or her life is recorded, but that time is not now.

By Vince Giuliano 9-27 -2023

Preface and a personal note

In April of this year, I experienced a breakthrough in understanding human aging.  This was a key event for me, coming after 15 years of full-time study and writing 600 or so articles on nearly every conceivable facet of the subject.  A second key breakthrough was directly derived from this understanding.  I had finally articulated a simple set of interventions, applicable late in life, that can likely extend healthy active human lifespans by 20% to 30%, allowing most people to be healthy and continuing contributors to their family and professional lives until they are 100 or beyond

To my knowledge I am the only longevity researcher in my age cohort who is still alive, active, researching, writing and publishing.  I have been pursuing versions of many of the specific longevity interventions suggested in this blog  for over 40 years now, improving on them as I learn more.  They seem to continue working well. Turning 94 in two months(November 17), I am now nearly as heathy, functional, and physically active as I was 40 years ago, and perhaps a bit more professionally engaged and intellectually avtive than ever before,  I expect this situation will go on until I am well beyond 100.  ”You must have good genes” is not the explanation.  Everyone in my family besides my mother died in their 70s.  My mother required intensive nursing care starting in her late 80s and died at age 91

What is aging?

Aging is a biological program that proceeds lifelong in phases, from embryogenesis to a final phase whose actions kills everybody left.  This is a very ancient program, manifest in the earliest living creatures, and evolutionarily conserved thereafter. Versions of this program operate in every living creature – plants, bacteria, worms, insects, fish, snakes, lizards, and all mammals including us humans.  There is a species-determined version of the aging program and corresponding maximum lifespan for every living thing – 123 years for humans.

The final phase of aging turns deadly to kill every living thing off by the absolute age limit for the species – no exceptions.  I go on here to characterize the central process of aging, its purpose, what it does, its stages, how it works, and what causes it.  Then, I will go on to describe a major hack on aging, one I think is good for average human life extension of 20% to 25%. Far more than the 5% to 12% known for various specific life-extending interventions, like taking rapamycin.  I believe this hack can probably postpone the death-sentence action of the aging program by 20-30 years for us humans, and can likely allow most people to remain highly active, healthy and functional until 100 or more.  It is the hack that has been working personality for me.

The science of aging is wicked complex and here I can present only a central outline of what is supported by thousands of research studies, necessarily simplified though still accurate.  I have already published an article in this agingsciences.com blog covering much of the same ground covered here, at www.anti-agingfirewalls.com/2023/04/04/healthy-active-and-productive-till-100-laying-out-the-adult-aging-process-a-breakthrough-and-my-personal-story.  I have worked to make the presentation in this current blog entry more straightforward and easier to follow.  As usual, it contains links to published science literature citations that back up my central assertions.

The Information Overload of Aging

Aging impacts or is impacted by every biological organ or system in very complex ways.

Image source

Indeed, everything in this diagram is closely associated with aging.  You can start with any item and build an entire theory of aging around it.  In fact, this has been done over the years, with a few of the resulting theories useful and some others, like telomere attrition, relativerely useless or plain wrong..  Unfortunately, everything is a close cousin to nothing, and diagrams and explanations like this one that lay out the hallmarks of aging tell us nothing about what the basic and underlying proesses of aging are, and what if anything can be done about them.  So we need to take a different tack.

The aging program is very ancient and is “evolutionarily conserved,” which means it responds to a key biological necessity and versions of it are in every living thing.  Evolution has passed this program on to new species as they evolved.  In creating any new species, evolution  usually passes on solutions found workable in the precedent creatures, rather than invent them anew.  That is why we have variants of the same organs found in tiny field mice, whales, skunks and elephants.  Species-specific variants of this aging program operate in essentially all known species, be they bacteria, insects, plants, fungi, mammals.  Every species has its own nominal “use by” expiration maximum lifespan.  For humans, 123 years; for many mouse species, 20 months; for fruit flies, 10-20 days. The Mayfly has a lifespan of only 24 hours and completes its life cycle, including reproduction, within one day of its birth.

Image source

Evolution loves all living entities, and generally seeks to provide for the wellbeing and competitive survival of each.  However, evolution loves living species even more.  In cases where individual survival and species survival are incompatible, evolution/nature picks the path of species survival.  That, I think, is why the final stage of aging is out to kill off every living entity by its species expiration date.  That way, younger members of a species don’t have to compete for resources too long with ensconced older members, and even the most horrible and controlling of dictators pass away in time.  Aging is how nature implements its drive to best ensure the survival of biological species.  Species may survive millions of years, yet lifespans of members of most species are less than our own.

Some current aging science researchers deny that adult aging is programmed.  Despite mounting evidence to the contrary, they hold on to the obsolete notion that aging is due to stochastic accumulation of random damage.  The first stages of human aging (through initial adulthood) are clearly the results of a complex and exquisitely programmed process.  Human embryos and babies almost all end up as viable children.  But the older viewpoint that adult aging is caused by accumulated random damage remains popular.  If this were so, there would be no species-specific age limits as there are.  There would be a tiny few of 200–500-year-old people and a few100 year old dogs.  Some of these programmed aging deniers see their prescription for longevity Is something like “If something in your body is broke, fix it.”  Great idea.  However, that already is the approach of Modern Medicine.  See the 2016 article Evolution of Aging Theories: Why Modern Programmed Aging Concepts Are Transforming Medical Research.  Further, in this blog we are able to identify the central mechanism of the adult aging program, how it works, and even how to partially hack it.)

Above table source

Forget living forever in your present body.  Absolutely everything about us as individuals is temporary.  I believe we are now in an extremely important decade in the history of biology, however, in which we are now decoding many mysteries of life, learning how to reverse key aspects of aging, and learning how to expand lifespans of healthy individuals, possibly up to hundreds of years.  In my research writings and presentations, I have referred to this process as “YOUNGING”. You can find out about much more about it by searching the Internet for this term together with my name.  Look for sound podcasts and YouTube videos as well as written treatises.

A few other longevity scientists have also been working on YOUNGING interventions and have demonstrated how their interventions can make old rats younger in most important dimensions.  YOUNGING, effective age reversal, has been proven possible!

Aging impacts all levels of every organism known: biochemical, sub-cellular (including mitochondria), cellular, organ, major system and whole organism.  Most of the science literature on aging has focused on particular impacts, “Hallmarks of Aging” at particular levels, leaving confusion as to what is secondary vs. what is basic and causal.  The fundamental cause of aging is much simpler.

It is a distinct, effective biological program that proceeds in phases, including the program of initial and early development, starting with an egg and a sperm.  The essential features of this aging program have become clear to me, but this has only happened recently.  This program is out to grow us up successfully until we are 25, + or – a few years, depending on features of the individual.  It is working for the good of the species, not the individual.  Lifelong until the final phase, it strives to ward off serious infectious diseases and other deadly pathologies. In its final phase, when we get to 80 and beyond, the program it is out to kill everybody.

Throughout most of our lives, the aging program works to keep us healthy.  However, if the program can’t manage to do that, it can quickly change its strategy to having your own immune system kill you instead.  It does this by loosening a deadly inflammatory cytokine storm.  This is to keep people whose condition is too weak to fight off a pathogen from passing that pathogen on to others, accelerating its propagation. It is an example of how evolutionary processes favor survival of a species over survival of an individual when these two objectives are in conflict.  This –program is very ancient and versions of it exist in all living species including plants, birds, bees, cows, worms, insects, dolphins, and mushrooms. It is just as efficient and effective as the early development program is.  But, being a program, aging can be hacked once one knows exactly how it works. I know of one easy main hack that I think can buy us humans 20-30 or more years of additional healthy active lifespan.  It works by slowing the aging program way down.  It is available to everybody right now and inexpensive.  I know. I am nearly 94, and what I am proposing here has provided me with the wherewithal to lead a full active family and social life, conduct deep research in biomedical literature, attend to Synergy Bioherbals LLC, and generate and publish this blog.

The aging program typically proceeds in stages.  The early stages are focused on initial  growth and development starting with conception.  The finial stage is plain out to kill you one way or the other

THE STAGES OF THE AGING PROGRAM

Let’s look at how aging typically plays out at various stages in the life of a healthy disease-free person in a modern industrialized society, namely at conception and at ages 1, 25, 45, 68, and 85.

Conception

Early development, including embryogenesis, is the first stage of aging and is probably the most complex and remarkable natural process known in all of science.  Starting with an ovum and a sperm, it leads to a human body comprising some 37 trillion cells of 200 types, organized to support the complexity of organs and body systems we all have.  It is a precisely articulated process involving many stages which have been extensively studied.  The fine details of it would fill libraries.  All cells in a human body have the same genes.  The differences between the some 200 cell types we have are epigenetic, a function of which genes are turned on (expressed; that is, actively make the protein corresponding to that gene) and which are turned off in any particular place in a human body at any given time.  This first year of human development is an exquisitely choreographed and very reliable process involving multiple steps of turning dozens, hundreds and thousands of developmental and other genes on and off in an extremely complex and highly specific manner.

How does the developing embryo go about turning a closely related family of genes off and on together to achieve a development step; say, growth and development genes?  A big part of the answer is via post-translational modifications of histones, especially methylation/demethylation.  Histone methylation/demethylation is a major tool used by the body in early development to turn large and small families of genes on and off together.  That is attaching or detaching methyl chemical groups to histones, the “spools” around which DNA is wrapped.  For most of the histones, genes in a highly methylated histone spindle are turned off, and cannot be expressed.  De-methylating the histone alows the genes to be turned on.  For some histones the opposite is so.  Many of the genes in our chromosomes are carefully sequenced so this simultaneous turning on and off of highly related genes can happen.  Strictly speaking, histone methylation by itself can turn genes off, but promoter site activation is also required to turn them on,  Think of histone methylation as a master lock, for example turning all genes associated with histone H3K27 off when double or triple methylation is present.  When the methylation is not present, those genes can be turned on individually by promoter site activation.

Each human cell contains about 30 million nucleosomes, and there an octamere of 8 histones per nucleosome.  A given histone like H3K27 is therefore repeated thousands of times on each chromosome – meaning that thousands or tens of thousands of genes can be turned off or potentially on by emethylating/methylating that histone.

Image source

DNA, cellular and other forms of biological damage can and do occur from the earliest moments of life, long before birth and throughout the entire trajectory of a lifetime.  These include DNA breaks, misfolded proteins, runaway transposons, aneuploidy, and damaged genes.  Such damage is largely unavoidable, inherent in the processes of cell reproduction and life itself; some of it results from environmental toxins or radiation.  Fortunately, evolution has endowed our bodies with layers of exquisite mechanisms for detecting serious damage and repairing it.  Examples are the mechanisms for repairing single-strand (ref) and double-strand DNA breaks (ref). These maintenance, renewal and repair mechanisms tend to work very well early in life, but become less and less effective as adult aging progresses.

Histone methylation/demethylation plays a central role in DNA repair, although the actual process is incredibly complex.  (For a deep dive into this topic you could study the 2021 article The Role of Histone Lysine Methylation in the Response of Mammalian Cells to Ionizing Radiation.  Look at the diagrams.  As you can see, multiple histones and multiple histone methylases/demethylases are involved.  I will continue to focus here on the histone H2k27 and on its demethylases JDJM3 and UTX.  I have also not discussed other post-translational histone modifications here, such as acetylation.  This discussion, while far from the complete picture, is accurate and sufficient to explain the basics of aging, what it consists of and how it happens).

Image source

As it happens, many maintenance, repair, and renewal genes are associated with the histone H3K27.  Included, for example are the genes for stem-cell differentiation necessary for organ renewal,  In the earliest stages of life, the demethylases JDJM3 and UTX are very active at this position and such genes are usuallyactive.  To telegraph where I am going here, the same basic mechanisms of istone methylation and demethylation for turning off or turning on hundreds or thousands of genes at once are used in all stages of the aging program throughout life.  There is also a complex end-of-life phase of the aging program that kills everybody by age 123, and that phase of the aging program also uses histone methylation to turn groups of genes off and on.

An additional level of body flexibility as well as intellectual complexity is added by the fact that H3K27me3 along with H3K4me3 are part of a bivalent domain, which means the body can easily and quickly switch between inactivating histone-associated genes-( H3K27me3) and activating them (H3K4me3).

AGE 1

The initial Developmental Phase of the program has been at it 21 months, during the pregnancy period and for a year after birth, It has accomplished much but still has a very long way to go.  Again, our bodies are the most complex structures known to exist in the universe, and this development process is probably the most complex natural process known.  Continuing with a simplified but correct description of what is most relevant here: during the early phases of development, there continues to be a high degree of organ-specific expression of JDJM3 and UTX, the demethylases that keeps double and triple methylation from happening during development at histone position H3k27. This is necessary to allow full expression of large numbers of growth and development genes as well as maintenance and repair genes.  There are also times and places during early development when these demethylases are turned off.  At age1 there is still a lot of growth and development to be done.  More detail on the specific importances of JDJM3 and UTX became available some 20 years ago. See the 2007 publication Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases.

AGE 25 (+/- 3- 5 years depending on the individual.)

This is the typical age when the Development phases of the Aging Program give way to the Adult Aging phases in humans.  This transition can be noticed in many species, including plants.  In some species it can occur very rapidly, taking place in a few hours.  In many species, it occurs just after the initial phase of offspring-bearing.  The transition involves lowering of expression of JDJM3 and UTX, the demethylases that keeps double and triple methylation from happening during development at histone position H3k27.

In 2014 Morimoto wrote in Proteostasis and longevity: when does aging really begin?  “Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes.  Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species.  As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans.”  In 2020 Morimoto further wrote in Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease:  “Additionally, in metazoans, proteome stability and the functional health of proteins is optimized for development and yet declines throughout aging, accelerating the risk for misfolding, aggregation, and cellular dysfunction. Here, I describe the cell-nonautonomous regulation of organismal PN by tissue communication and cell stress-response pathways.  These systems are robust from development through reproductive maturity and are genetically programmed to decline abruptly in early adulthood by repression of the heat shock response and other cell-protective stress responses, thus compromising the ability of cells and tissues to properly buffer against the cumulative stress of protein damage during aging.” At the time of transition, the Polychrome Repressive Complex (PRC) starts its adult job of inducing double and triple methylation at H3k27me2-3, slowly at first.   This and methylation changes at other histone positions have net impact of starting to down-regulate numerous repair, maintenance and renewal genes.  Yet at this age the expression of these genes is still near maximal.  There is little to no tissue damage or consequent inflammation.  As we know, many people at this age are very healthy and think and often behave as if that situation will go on forever.  Diseases are generally rare and tend to resolve quickly.

Several aspects of human behavior seem to be affected by this transition   One thing is discussed in the 2017 publication Human behavioral complexity peaks at age 25.  “Our main finding is that the developmental curve of the estimated algorithmic complexity of responses is similar to what may be expected of a measure of higher cognitive abilities, with a performance peak around 25 and a decline starting around 60.”

This phenomenon, involving histone changes marking the transition from growth and development, applies to most forms of life, including plants. For example, see Cell-type-dependent histone demethylase specificity promotes meiotic chromosome condensation in Arabidopsis

AGE 45.

The PRC has been doing its methylation job for 20 years now, and many key repair, renewal and maintenance genes associated with H3K27 are significantly downregulated.  With the downregulation of these genes and the tasks they perform, some tissues begin to be distressed, become inflamed and start emitting inflammatory cytokines like TNF-alpha, IL-1, IL-6 and IL-22.  Systematic inflammation is more manifest.  Diseases and sicknesses and signs of aging of all kinds are becoming more common and of concern, including arthritis, bronchitis, pneumonia, near-sightedness, obesity, asthma, diabetes, genitourinary disorders, hypertension, mental disorders, and strokes.

Yet, despite partial methylation, body repair, maintenance and renewal genes are still generally active enough to support largely good functioning.  Medications and leading a healthy lifestyle may be helpful in postponing serious disease consequences.  Hallmarks of aging are evident, and the person looks like a 45-year-old, no longer like he/she looked at 25.

YES, AGING IS NOT DUE TO ACCUMULATION IF RANDOM DAMAGE. IT IS DUE TO PROGRESSIVE DOWNGRADING OF NATURAL DAMAGE REPAIR AND RENEWAL PROCESSES ASSOCIATED WITH PROGRESSIVE DOWN-REGULATION OF KEY MAINTENANCE AND RENEWAL GENES.

AGE 68.

The Adult Aging Program has been at work some 43 years now.  DNA histone methylation is now such that body repair, maintenance and renewal genes are functioning at a fraction of their original levels.  They are too methylated.  And some developmental genes that produce unwanted actions for aging adults are being progressively turned back on.  Multiple tissue types and organs are experiencing increasing distress, and are emitting copious levels of inflammatory cytokines, which persist in the bloodstream.  These increase methylation levels of protective genes even further, in a positive feedback loop.  The overall body is going into a hyper inflammatory state.  And incidences of the inflammatory diseases the kill old people are becoming frequent: cancers of all types, retinopathy, inflammatory lung diseases, dementias, coronary artery and valve diseases, auto-immune diseases like arthritis, lupus and scleroderma, gout, etc.; the “usual suspects” for killing old people.  Several such diseases can occur at the same time.  People at this age are more prone to catching infectious diseases like SARS or COVIDs, and use of the health care system is typically accelerating.  Heart attacks and strokes are becoming common.  Many friends in the same age cohort are moving into Assisted Living; some are going into nursing homes.  Emergency Room visits are becoming more commonplace.  Some family members and dear friends are starting to die.

AGE 85.

The situation described for age 68 has become much more dire in every respect.  Histone and DNA methylation are at levels where many repair, maintenance and renewal genes are close to being completely silenced. DNA methylation and circulatory inflammatory cytokine levels seem hopelessly abnormal.  A positive feedback loop of whole-body hyper inflammation leading to ever more unwanted DNA histone methylation has taken over.  Tissue and organ damage are extensive, and the diseases of old age are rampant and doing their pre-killer and killer jobs.  Far less than 30% of the population makes it to this age.  And if you do manage to live that long, your general outlook is not good.  From this age onward, you are likely to experience increasing frailty and multiple emergency room visits and hospitalizations.  You might pass the final months or years of your life in a nursing home with dementia, a semi-functioning heart, and an incurable cancer.  Aging can (and does) kill you in thousands of different ways.  Organ and system failures and diseases are among the most common. There are more than 100 types of cancer that can affect almost every part of the body.  100% of the time, “All the King’s Horses and All the King’s Men,” of medicine and health care can’t rescue you from the final Death Phase of the Adult Aging Program.  A version of the Adult Aging Program works for every advanced species we know of.  Everything alive dies, no exceptions.

Let me contrast my personal situation at near-94 with the grim scenario for 85 year olds listed above. I have none of the known degenerative diseases of advanced aging.  I haven’t seen a real doctor for 10 months.  Last time I was hospitalized (for 1 day) was nearly a year ago and that was because of broken ribs due to a freak accident.  I can walk for miles, mow my acre of lawn, chase my little granddaughters and grandsons around the back yard, climb a stepladder, cook up pasta Bolognese for the whole family, vacuum key areas of the house, do the laundry and wash a sink-full of dishes and load the dishwasher every night. And get in 6-12 hours of longevity research, communications with colleagues and writing every day.  Unlike some of my close colleagues, I only monitor a tiny collection of health and aging biomarkers.  For the same reason most people in their 30s and 40’s don’t bother with their biomarkers – they don’t have to.  

I do not claim to have defeated aging.  But there is both scientific and personal evidence that it can drastically be slowed down.  And some small-animal evidence from researchers like the Conboys and Harold Katcher.

HACKING THE AGING PROGRAM

Being a program that we can understand, aging is at least partially amenable to hacking.  I believe I have just described the central causal chain of events involved in human aging. And those events allow us to identify with confidence how to slow advanced aging.  The aging program can be hacked, basically by blocking the hyper-inflammation part of the positive feedback loop in the final phase.  I have been pursuing various approaches to controlling inflammation for over 30 years now, and you can read some key blog posts I have written on the science of inflammation  My primary intervention for blocking systemic inflammation in the last ten years has been regularly taking 4 Herb Synergy (4HS) – a nano-preparation of certain herbal anti-inflammatory dietary supplements.  As below, I also do a lot of other things to lower systemic inflammation.  I am sure some of these are important, but I don’t know how important.  What I can say is that if I discontinue taking 4HS, in 3-4 weeks I start getting distressing inflammatory symptoms which get worse and worse.  Resuming 4HS, these symptoms vanish in a week or so. Discontinuing other anti-inflammatory supplements or activities for up to 1-2 months while still staying on 4HS, I have not noticed any strong negative effects.

Other researcher Findings

A few other researchers have suggested other strategies, all of which have the impact of blocking chronic inflammation.  Irina and Michael Conboy, prominent aging researchers,  have suggested periodic purifying of circulating blood from the pro-inflammatory cytokines using an apheresis machine(ref). Apheresis involves the removal of blood plasma from the body by the withdrawal of blood, its separation into plasma and cells, purification of the plasma, and the reintroduction of the cells and purified plasma into the body.  Their small-animal experiments suggest that that process also works for the reduction of circulating inflammatory cytokines.  Their aged small animals by multiple measures get younger.  While it works, apheresis is not practical for most people. because it is expensive, invasive, requires technical expertise and the use of a special machine. Further, for apheresis it to be effective in keeping the bloodstream free of inflammatory cytokines, the process must be repeated every 3 weeks or so.

Approaches to YOUNGING used by other researchers include injections of exosomes derived from young pig blood plasma (ref: Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction), and treatment with GDF11, often a strongly anti-inflammatory blood factor(ref)(ref).  I will not discuss these further here since they cannot be practically pursued by ordinary people.  What is important is that there are multiple purportedly positive approaches to longevity being pursued by several research group.  A few of these have demonstrated mild longevity impacts on small animals.  Other than what is being reported here, there has been no recent empirical research related to human longevity.  For some time, it has neen known that mild human longevity increases have been shown to result from calorie restriction regimens, taking rapamycin and taking metformin..

Other strategies I have been using to combat systemic inflammation

I list the most important of the additional anti-inflammatory strategies I have been pursuing here.  I have discussed each of these in detail in articles in my longevity blog, agingsciences.com.

• Taking additional anti-inflammatory additional supplements in pill/capsule form, such as NRF2 activators like gingko biloba, milk thistle extract, saw palmetto, and bacopa, (ref)(ref)(ref)
• Taking a quality fish oil supplement, one that is high in DHA and EPA. These oils contain key substances important for the resolution phase of acute inflammation to occur, the normally final stage where the inflammation vanishes. The substances are called resolvins, protectins, maresins and lipoxins(ref),
• Taking supplements like nicotinamide riboside to upgrade the expression of the NAD+ metabolic factor, upregulating a number of protective genes(ref),
• Taking supplements intended to improve mitochondrial electron transfer chain functioning (ref)
• Synchronizing to critical brainwave frequency Via Pulsed Electromagnetic Frequency (PEMF) devices, which helps me concentrated better during days and sleep better at night(ref),
• Photobiomodulaltion, including selective partial body irradiation with critical infrared frequencies(ref),
• Pursuit of a number of simple daily hormesis techniques, Including deliberate exposure to whole-body heat conditions (EG, sauna) and cold exposures, to upregulate expression of heat shock and cold shock proteins(ref),
• Exercising while breathing oxygen, a process known as EWOT(ref),
• Living and interacting constantly with significantly younger wives and family members(ref), and
• Getting ample solid REM and Deep sleep on a regular schedule(ref).

These are all interventions that I have researched and know are powerfully anti-inflammatory.

Acute vs Chronic Inflammation

The inflammatory process is an essential first-line immunologic defense system evolved in advanced organisms to confer protection required for survival of individuals.  Short-term acute inflammation is part of wound healing and acts against harmful agents, such as pathogens, toxins, or allergens.  Familiar manifestations of it are the itchy red bumps of mosquito bites, fever when you have the flu, and redness and swelling associated with burns.  Less familiar ones can include muscle weakness, diarrhea, nausea, joint pain, and skin rashes.  Normal inflammation involves a number of distinct phases, including a final resolution phase.

Image source  “Under normal conditions, the tightly coordinated actions of various defense components including immune cells, endogenous anti-inflammatory agents, and tissue remodeling processes enable the resolution of acute inflammation by facilitating the elimination of pathogens, infected cells, and repair to damaged tissues to restore body homeostasis [1]. However, when this intricate acute inflammatory response fails to resolve and instead persists, more defense components are mobilized to create a long-term unresolved immune response known as chronic inflammation. Chronic inflammation, which typically manifests itself in a low-grade manner for a prolonged period, involves macrophage- and lymphocyte-accumulated leukocytes [2], and various other cellular components. It is important to recognize that this chronic inflammation is causally associated with changes in the cellular redox state and cell death signaling pathways.”  So, Chronic inflammation is inflammation that does not resolve. In this discussion of longevity, by “systemic inflammation,”  I am referring to chronic whole-body inflammation.  This discussion highlights how systematic inflammation is both caused by and causal of epigenetic aging.  Some drugs (like prednisone) tend to block both types of inflammation.  They can be used only for short periods because acute inflammation is an important tool of natural body protection.  4HS blocks chronic inflammation while still allowing acute inflammation.  As a long-term user of 4HS, I have an intact and strong wound healing capability, meaning I can respond with acute inflammation when needed, while controlling my systemic inflammation.

ANSWER TO A KEY QUESTION

The new perspective of this article answers a central question I have been asking myself for years.  That is: Which of the longevity interventions that I have been pursuing in recent years have been efficacious in allowing me to be essentially disease free, cognitively sharp and still highly productive as I grow older, now approaching age 94?  Which one or ones are central?  The answer is the interventions that combat systemic inflammation, in my case the main approach having been regular taking of 4 Herb Synergy during the last seven years, and for the twenty years before that, taking the 4HS herbal anti-inflammatory components. And this was done with a different intent than longevity in mind.

by Vince Giuliano

By Vince Giuliano

Those who know me are possibly familiar with my recent series of writings relating to quantum reality-creating phenomena in the Being and Creation blog.  There is a scientific  link between this line of inquiry and my concern about long lives and disease- free aging. The link is that:

There is a powerful underlying process in old age of quantum intercellular communications that postpones the onset of age-related diseases, and this process is interfered with by the presence of chronic inflammation.

I have already written extensively about how chronic inflammation accelerates the aging process.  And on how preventing or limiting chronic inflammation has likely been the central factor keeping me going until now.  My 95^th birthday is in a few weeks now, and I expect to keep going actively at least until I am 100.  The process of rapid decline in very old age that I have discussed previously is progressive DNA methylation in cellular histones, rendering them unable to do their jobs of activating health-maintaining genes.

This current blog entry suggest a different earlier- proposed mechanism involving intercellular communications via quantum tunneling processes. In both cases, chronic inflammation aids and abets the process of decline.  Preventing or seriously slowing chronic inflammation can lead to much longer healthy lives.

I will start here with the 2019 publication Cellular parabiosis and the latency of age-related diseases.   “ ‘All things are difficult before they are easy’ (Thomas Fuller, 1608–1661) and all things appear complicated before they become simple. This and the accompanying paper [1] propose simple concepts that can account for the aetiology of ageing and age-related diseases (ARD). Apparent complexity of ageing and diseases (actually, of their consequences) reflects the complexity of healthy organisms but reveals little to nothing about the root cause(s) of age-related morbidity and mortality. Identifying the causes and early cellular stages of ARD will be instrumental in eventual mitigation of degenerative diseases, including cancer.” — “The incidence of death and diverse ARD increases with about the fifth power of time, suggesting a common biological clock (with species-specific speed) and perhaps a shared common cause. A common cause would mean that it might be simpler to mitigate all ARD collectively than any particular one—reminiscent of the long-lasting simultaneous resistance of super-centenarians to all ARD.”  (VG – I quite agree)”

‘“ Cellular parabiosis is the traffic of metabolites and functional and informational molecules between neighbouring cells preventing the expression of recessive phenotypes” According to this article cellular parabiosis involves a constant exchange of information among neighboring cells. This exchange postpones the onset of ARDs for long periods, and it is breakdown of this exchange that leads to ARDs and mortality.”  — “The one-dimensional nature of these fundamental building blocks, then, opens up the way for a mathematical formulation of the chain as a completely integrable field theory model, characterized by an infinite-number of conservation laws. The latter are associated with global excitation modes, completely delocalized in the chain space-time. This integrability structure proves sufficient in providing a satisfactory solution to memory coding and capacity [5]. (ref)”  I comment that as  quantum field theory model, entanglement among cells may be more than local, and the strange effects may apply such as retro causation.

According to the author, the cellular parabiosis takes place through several primary mechanisms: one of which is quantum tunneling between microtubules. This is clearly laid out in several of the authors illustrations in that article. “Many names, often redundant, were given to diverse extracellular structures shown, or presumed, to be the vectors of intercellular molecular traffic [22–25]. Most familiar are gap junctions, desmosomes and neuronal synapses that allow for the trafficking of metabolites and electrolytes. Since the majority of cellular catalytic activities are involved in the biosynthesis of metabolites and their intermediates (at least 120 000 kinds in humans), gap junctional traffic may phenotypically suppress the majority of random genome alterations. However, tunnelling nanotubes (TnT) [22,25], extracellular vesicles [23] and/or exosomes [24] were shown to transfer diverse RNAs, proteins (including prions) and even entire organelles (mitochondria, lysosomes, Golgi apparatus) and viruses—all functionally expressed in recipient cells [22,23]. One study showed unequivocally that dozens of protein species pass directly between the cells through TnTs [28]. The most efficient means for molecular exchange between cells packed in tissues may be still undiscovered (e.g. imaginable recurrent partial cell fusions). The presence of diffusible effectors of cellular parabiosis in conditioned media would not be surprising [29].

Here are some of the key points of that paper:

• There is a very long period of latency in very old age before serious susceptibility to ARDs of a cell begins, perhaps measured in years.
• During this period, the non-susceptibility of individual cells to the end of this latency is because of a steady stream of supportive communication and possibly exchange of organelles with neighboring cells. The author calls this process cellular parabiosis.
• This communication and exchange of organelles may take place through various mechanisms, and there is strong evidence that quantum tunneling between tubulin is involved. Microtubules are structural and organnel-transportation filaments in cells.
• The quantum tunneling can also be used to characterize age-related increase in ARD susceptibility to cancers.
• This cellular parabiosis communication and exchange of organelles can be stopped by the presence of age-related chronic inflammation.
• Reduction of chronic inflammation can result in the resumption of the communication and exchange of organelles continuing the period of latency before susceptibility to ARDs sets in

“Inhibiting inflammation and SASP turns the arrow in opposite direction by the re-establishment of parabiosis and phenotypic suppression (i.e. healing by phenotypic reversion).”  I believe this is what I have personally done.

Microtubules and quantum tunneling and entanglement

A number of published papers support the quantum effects hypothesis for microtubules.  Some of these go back 20 years or more. Others are very recent

From On Quantum Mechanical Aspects of Microtubules (1997) “MicroTubules (MT) appear to be one of the most fundamental structures of the interior of living cells [1]. These are paracrystalline cytoskeletal structures which seem to play a fundamental role for the cell mitosis. It is also believed that they play an important role for the transfer of electric signals and, more general, of energy in the cell.” They serve as miniature railways for the transportation of proteins and organelles within cells.   Motor proteins can carry such substances from one end of the cell to the other by riding on microtubules as rails. The distance can be relatively long.  Some nerve cells for example extend from the brain to remote parts of the body.  Further, microtubules are subject to quantum entanglement across  neighboring cells – and possibly across remote cells as well.  Here are some key points and citations:

1. Quantum Basis for Consciousness: Research by Mike Wiest and his team at Wellesley College suggests that anesthesia’s effectiveness via microtubule interaction supports a quantum theory of consciousness. They found that drugs affecting microtubules within neurons delay the onset of unconsciousness caused by anesthetic gases1.
2. Photon Entanglement in Myelin Sheath: A research group in China has shown that many entangled photons can be generated inside the myelin sheath that covers nerve fibers. This could explain the rapid communication between neurons, which is essential for consciousness2.
3. Neuronal Cytoskeleton and Consciousness: Stuart Hameroff proposed that consciousness and cognition could be explained by quantum and classical processes in microtubules inside neurons. He suggests that these processes are critical to consciousness and cognition3.  Numerous papers support this hypothesis.

Here are the related citations for further reading:

1. Groundbreaking Study Affirms Quantum Basis for Consciousness (2024)
2. Photon entanglement could explain the rapid brain signals behind consciousness (2024)
3. Consciousness, Cognition and the Neuronal Cytoskeleton – A New Paradigm Needed in Neuroscience (2022)

Other relevant publications include:

• The Quantum Biology of Consciousness and Visual Perception
• (2023)
• Videos of Tubulin Quantum Coherence Tunneling
• The Penrose-Hameroff Quantum Model in Retrospect (2014)
• Quantum relaxation effects in microtubules (2021)
• Consciousness, Cognition and the Neuronal Cytoskeleton – A New Paradigm Needed in Neuroscience (2022)

Where does this leave me with respect to practical longevity?

I have now propounded in these blogs on two putative mechanisms that lead the body to stop defending against ARDs, typically starting in one’s 80s.

• The mechanisms described above, where cellular parabiosis no longer works due to the presence of age-related chronic inflammation.
• A mechanism I have characterized in blog entries where lifelong double and triple methylation, particularly at histone position HK3me has reached the point where that histone can turn on multiple necessary.

These two mechanisms are not necessarily mutually exclusive.

In both cases, taking personal initiatives to reduce chronic inflammation appears to be an effective strategy for postponing the operation of these mechanisms and the massive onset of ARDs. This is what I have done, employing classical anti-inflammatory herbs as the basis for reduction of the chronic inflammation,  I expect to continue this approach at least until I reach 100, continuing to research and write blogs about both Intentional Reality Creation and longevity science.

Getting through ages 100 –125 alive and vibrantly healthily.

By Vince Giuliano V7. 30 Mar 2025

This document outlines a personal longevity program aimed at my achieving health and vitality well beyond the age of 125, focusing on reversing aging processes through scientific research and interventions.

• Personal longevity goals: I have set ambitious longevity goals since 1995, aiming to live a productive life for another 165 years, primarily in a healthy state. This vision has led to my current career as a longevity scientist.
• Phase 1 of the program: The initial phase involved managing chronic inflammation and aging through various interventions, including the use of anti-inflammatory herbs and technologies like oxygen therapy, PEMF and red light devices. This approach has allowed me to maintain cognitive and physical health and professional activities, still now at age 95.
• Cellular reprogramming: The document discusses the potential of cellular reprogramming to reverse aging, utilizing methods tried successfully on small animals that avoid teratoma formation. The focus is on the partial regression of cells to restore youthful characteristics without losing cellular identity.

I write here about

Hallmarks of aging:  I refer to nine established hallmarks of aging, such as DNA instability and mitochondrial dysfunction.  These guide the efficacy of anti-aging interventions. Recent research has expanded these hallmarks to include chronic inflammation and dysbiosis.

Epigenetic information theory: The theory posits that aging results from the loss of youthful epigenetic information, which can be restored through epigenetic reprogramming, enhancing the function of aged tissues.

Chemical cocktails for age reversal: The document highlights research on small molecule cocktails that can mimic genetic reprogramming effects, potentially reversing cellular aging without altering the genome.

Implications of cellular age reversal: advancements in epigenetic reversion could lead to new treatments for various diseases, including cancer and neurodegenerative conditions, and may significantly extend human lifespans.

Future research directions: Ongoing studies by several groups are focusing on the practical application of these findings in regenerative medicine and the development of targeted therapies for age-related diseases.

This is about my living healthfully and well beyond age 125, something never observed and long deemed impossible.  Nobody in our human species has so far been able to accomplish or even come close to doing that.  However, successful current research suggests that this possibility is highly likely.  Cellular, organ, and whole animals can be “Younged,” reverse-aged in a controlled fashion to a younger state, which may be about that of a 25-year-old for humans, and then regular aging starts again.  This reverse aging works for small animals.  So, this paper is both about my highly personal vision and program for extraordinary longevity, and about a general program for significant life extension that can be pursued by others.

I start with my own personal longevity objectives, originally formulated in 1995, my progress on them to date.  And characteristics of the first Phase of my longevity program, covering from 1995 until now, and until I successfully reach 100 in the year 2030.

The main topic of this writing is what I expect to be Phase 2 of my longevity program, which I expect will keep me alive and vibrant, largely free of age-related diseases and disabilities, until I reach about age 190, twice my current age.  I will outline the approach I expect to use and the existing research results that strongly suggest that this will be possible.

My 1995 declaration

The details of why and how I came to formulate my 1995 longevity declaration can be found in my treatise On Being and Creation as an example of intentional reality creation. “So the way out of my funk was to declare the future I intended to live in, not see myself as a victim of circumstances.  The basic declaration came to me suddenly but it took me several hours to clarify it in detail and assure myself it was an unbounded declaration that reflected my full commitment.  It went something like this: “In the universe in which I exist, I shall live a happy and productive life for another 165 years, mostly in the healthy physical body of a person 30-40 years old.  This will take place with the continuity of my consciousness and the continuity of my relationships through the operation of ordinary reality.  I will continue working and creating.”  I made extensive computer notes then and have re-visited the intention many times since.  Realizing this intention has been the reality in which I live. It became the basis of a new career for the present phase of my life, one of a longevity scientist.” Now, 30 years later in 2025, I can say this intention has worked to this point, with 130 more years to go.

I have published several articles in this blog about Phase 1 of my longevity program.  In simplistic terms:

• Each histone position governs the activation or inactivation of associated genes.  Histone acetylation and the absence of methylation leads to open chromatin where the genes associated with a histone position can be fully expressed, while de-acetylation and methylation can close the chromatin and effectively inhibit activation of the associated genes. By an activated gene I mean one busy producing the protein it produces.
• After adults reach an early childbearing age, say typically at age 25 for humans, there is an explicit transition to where their DNA is progressively methylated as the adults age over the years.  The methylation affects histones, reducing gene expession.  But not to the extent that gene activation is shut down until a very advanced age.
• In my writings I have focused particularly but not exclusively on the H3K27me2-3 double and triple histone positions which govern a number of maintenance and repair genes.  The impact of aging on these gene positions is sufficient to explain aging and end-of-life events, although there are many additional aspects of the story.
• As aging takes place, there is progressive methylation of this histone position, particularly in the absence of acetylation, slowly but effectively shutting downrelated gene activation.  Eventually, typically in a person’s 80s, the shutdown becomes almost complete.  The result is a high degree of stress on the organs affected, which no longer get the proteins they need for normal functioning.  These stressed organs respond by becoming systemically inflamed.  Such inflammation further exacerbates histone methylation,inducing a rapid unvirtuous cycle.  The high systematic inflammation leads to the usual list of killer inflammatory diseases like cancers, dementias, strokes, falls, and other usual-suspect illnesses which often start in a person’s 80s, and kill them in their 80s.
• My approach to breaking this cycle so far has centered on limiting and controlling chronic inflammation using traditional anti-inflammatory herbs.  That and a number of secondary interventions interventions interventions, like breathing oxygen and using red light and PEMF devices.   The result has been my reaching age 95 cognitively and mainly otherwise, healthwise intact, still enjoying life and working.  I suspect this overall  approach will continue working at least until I reach 100.

• Reference: Healthy, active and productive till 100. Laying out the Adult Aging Process, a Breakthrough, and my Personal Story

The basic idea going forward

Every normal body cell stores within itself a complete epigenetic history of all of its earlier states, no matter how old it is, whether that cell is normally functioning, senescent, or even if it is cancerous.  Several interventions can reverse the stages of aging of that cell to an earlier status, even all the way back to where that cell is an induced pluripotent cell (iPSC) capable of evolving into any cell in the body.  This has been known for many years and has been accomplished by many researchers using the so-called Yamanaka factors OSKM (Oct4, Sox2, Klf4, and c-Myc).  However, using OSKM on live cells in live animals may rapidly kill them due to the formation of teratomas. “A teratoma is a rare type of germ cell tumor that may contain immature or fully formed tissue, including teeth, hair, bone, and muscle. Most teratomas are benign (noncancerous) but they can be malignant (cancerous). Treatment involves surgical removal. Cancerous teratomas may require chemotherapy, radiation therapy, or other cancer treatments.”  iPSCs are too far epigenetically regressed to serve as longevity interventions.  However, leaving out Oct4 and using protocols that employ only the SKM factors, it has been demonstrated that epigenetic regression of cells may still take place and only be partial to a point where the regressed cell has already developed clear markers of the kind of cell it is, that is a heart cell, a brain nerve cell, a little-toe cell, etc.  Such partially regressed cells do not induce teratomas and can some tikmes exercise profound younging effects in tissues of the type they come from.

Hallmarks of Aging

Researchers have largely agreed on a set of hallmarks that characterize aging. These are important for characterizing the efficacy of anti-aging interventions.  Graphic is from Hallmarks of aging: An expanding universe.

“In 2013, we suggested nine molecular, cellular, and systemic hallmarks of aging: DNA instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.¹  Recent research has confirmed and extended the importance of all these hallmarks.  They have withstood scrutiny by tens of thousands of aging researchers, but they require an update to deal with the discoveries of the last decade. For example, in 2013, much of the evidence on anti-aging interventions was limited to non-mammalian model organisms, including yeast, nematodes, and fruit flies.  Fortunately, experiments involving mice (and in some cases, non-human primates) have now corroborated the validity of most of these hallmarks in mammals.  Of note, human age-related diseases have statistically higher chances to co-occur and to share genomic characteristics when they are causally linked to the same hallmark rather than to different hallmarks,²  clinically validating the approach that we have chosen. — Besides the necessary update of the previous hallmarks, we have also introduced some reorganizations and included the following three additional hallmarks of aging: disabled macroautophagy, chronic inflammation, and dysbiosis.  Disabled macroautophagy was initially treated as a special case of loss of proteostasis.  However, macroautophagy does not only affect proteins but can target entire organelles and non-proteinaceous macromolecules, justifying its discussion as a separate entity. Moreover, we considered that the final hallmark that we listed.”

The David Sinclair Laboratory at the Harvard Medical School and the Information Theory of Aging

A 2023 publication The Information Theory of Aging by David Sinclair and his former mentor, Leonard Guarante at MIT, lays out a theoretical framework that forms the basis of his more recent work of high relevancy here. What epigenetic reprogramming is about.  “Unlike the stable, digital nature of genetic information, epigenetic information is stored in a digital-analog format, susceptible to alterations induced by diverse environmental signals and cellular damage. The Information Theory of Aging (ITOA) states that the aging process is driven by the progressive loss of youthful epigenetic information, the retrieval of which via epigenetic reprogramming can improve the function of damaged and aged tissues by catalyzing age reversal.”

David Sinclair is a professor of genetics at the Blavatnik Institute at Harvard Medical School and co-director of the Paul F. Glenn Center for Biology of Aging Research.  He has published widely in a number of journals and papers put out by his laboratory and appears in print so frequently that his reputation is like that of a rock music star.

In the 2023 publication Loss of epigenetic information as a cause of mammalian aging, Sinclair and his colleagues attribute aging as an epigenetic phenomenon largely a consequence of the body’s evolved process to repair DSB DNA breaks.  They point out that “The type of DNA damage that is most consistently linked to aging is the double-stranded DNA break (DSB), occurring at a rate of 10–50 per cell per day (Tian et al., 2019; Vilenchik and Knudson, 2003).”

• “This loss of epigenetic information accelerates the hallmarks of aging+
• These changes are reversible by epigenetic reprogramming
• By manipulating the epigenome, aging can be driven forward and backward.”

“All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called “ICE” (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.”

“Why the mammalian epigenome changes over time is not yet known. Again, clues have come from yeast. A major driver in yeast is the DSB (Park et al., 1999), the repair of which requires epigenetic regulators Sir2, Hst1, Rpd3, Gcn5, and Esa1 (Martin et al., 1999; McAinsh e al, 1999; Mills et al., 1999; Tamburini and Tyler, 2005). Our relocalization of chromatin modifiers or “RCM” hypothesis and subsequent “Information Theory of Aging” propose that aging in eukaryotes is due to the loss of transcriptional networks and epigenetic information over time, driven by a conserved mechanism that evolved to co-regulate responses to cellular damage, such as a DSB or a crush injury”

Graphical abstract

Note in the diagram the changes due to aging, in histone H3k27 trimethylation and acetylation, consistent with previous posts in this blog related to the role of trimethylation at this histone marker to inactivation of numerous support and housekeeping genes, resulting in diseases and disabilities that typically kill people in their 80s.

Sinclair and his lab have been concerned with substances that can slow aging for a very long time, including a focus years ago on sirtuins.  And they have published prodigiously.  The 2016 paper Slowing ageing by design: the rise of NAD⁺ and sirtuin-activating compounds is an example.  “The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD⁺ precursors, have improved organ function, physical endurance, disease resistance, and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.”

The David Sinclair laboratory and David Sinclair himself today stand at the center of a whole ecosystem of research on cellular epigenetic reversion, with several collaborating and independent laboratories researching aspects of the phenomenon,  resulting in hundreds of papers related to the cellular rejuvenation topic.  I will only comment on a few of the Boston-based ones here.

• Derrick Rossi’s Lab at Boston Children’s Hospital: This lab focuses on stem cell biology and regenerative medicine, exploring mechanisms of self-renewal and aging in hematopoietic stem cells. They also investigate cellular reprogramming and its potential for creating clinically useful cell types.
• Biology of Aging Lab at Boston University Medical Campus: Led by Dr. Vyacheslav Labunskyy, this lab studies the biology of aging, including stress-response signaling and the development of new aging biomarkers. They aim to identify therapeutic targets for age-related diseases.
• Boston University Anatomy & Neurobiology Labs: These labs explore various aspects of aging, including cognitive changes, neurodegeneration, and brain plasticity. They focus on understanding how aging affects memory and motor functions.
• Boston Children’s Hospital conducts fascinating research on aging, particularly through the Harris Laboratory. They use zebrafish as a model to study aging and longevity, exploring genetic factors and evolutionary variations that influence lifespan. Their work includes identifying novel regulators of aging and understanding how stem cells maintain function later in life2.

From the record of publications it appears that 2023 saw the reporting of numerous breakthroughs,  The 2023 news publication Loss of Epigenetic Information Can Drive Aging, Restoration Can Reverse It reported  “We believe ours is the first study to show epigenetic change as a primary driver of aging in mammals,” said the paper’s senior author, David Sinclair, –.The team’s extensive series of experiments provide long-awaited confirmation that DNA changes are not the only, or even the main, cause of aging.  Rather, the findings show, that chemical and structural changes to chromatin — the complex of DNA and proteins that form chromosomes — fuel aging without altering the genetic code itself.”

Chemical Cocktails for Age Reversal

A number of chemical cocktails can mimic the effects of genetic reprogramming on the epigenetic reversion of cells without any direct need to apply the Yamanaka factors. These cocktails have shown promise in restoring youthful gene expression Harvard’s David Sinclair Unveils Age-Reversing Small Molecule Cocktails that Rejuvenate Cells.  “Published in  Aging, Sinclair and colleagues from Harvard Medical School show that six cocktails composed of small molecules used to transform cells to their stem cell state effectively reverse human cell aging. These findings were shown with an assay detecting nuclear proliferation. These findings suggest that developing small molecule cocktails may provide a means to reverse cellular aging without inducing cells to enter their stem cell state, which could one day reverse human aging.”  (Yang et al., 2023 | Aging).  Each of the cocktails used to reverse cellular aging contains five to seven small molecules.  The table lists each molecule included in the six cocktails along with their concentrations used to treat human cells.

The 2023 publication  Chemically Induced Reprogramming to Reverse Cellular Aging reports that “a hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.”  This is a very important finding from the viewpoint of the ease and economic feasibility of age reversal.

“Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases rely on the delivery of genetic material to target tissues.  This is achieved through methods like adeno-associated viral (AAV) delivery of DNA and lipid nanoparticle-mediated delivery of RNA [7, 8, 27]. These approaches face potential barriers to them being used widely, including high costs and safety concerns associated with the introduction of genetic material into the body. Developing a chemical alternative to mimic OSK’s rejuvenating effects could lower costs and shorten timelines in regenerative medicine development [26, 28–31]. This advancement might enable the treatment of various medical conditions and potentially even facilitate whole-body rejuvenation [32, 33].

“In this study, we developed and utilized novel screening methods, including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells [34, 35]. We identify a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression. Thus, it is possible to reverse aspects of aging without erasing cell identity using chemical rather than genetic means.”

Epigenetic reversion of cancer cells to non-malignancy

The Sinclair lab has demonstrated that rejuvenation at the epigenetic level can not only combat aging but also guide malignant cells back to a non-cancerous state.  The use of Yamanaka factors allows for precise control, reducing the risk of inducing uncontrolled cell proliferation.

Several labs around the world are conducting research similar to the Sinclair Lab’s work on epigenetic reversal and cancer cell reprogramming:

1. KAIST (Korea Advanced Institute of Science and Technology): Professor Kwang-Hyun Cho’s team has developed a technology to reverse cancer cells to a non-malignant state by identifying molecular switches during the critical transition phase of tumorigenesis2. See KAIST team discovers molecular switch to reverse cancer cells
2. OncoDaily Research: Researchers at KAIST have also published findings on frameworks to identify master regulators like MYB, HDAC2, and FOXA2, which play a role in reversing cancer cell states.  See the 2024 article The Korea Advanced Institute of Science and Technology reversed the malignant state of colon cancer cells

These labs are exploring innovative approaches to reprogram cancer cells rather than using computational methods, which could lead to less harmful and more targeted therapies.

IMPLICATIONS OF CELLULAR AGE REVERSAL

Without exaggeration, the body of research in cellular epigenetic age reversal heralds a new era of medicine where numerous “incurable” human pathologies will soon be relatively easy and economical to cure, and significantly longer lifespans can be expected.

Already been demonstrated in animals:

• Curing cancers.  Cancer reversion has been demonstrated by groups of researchers as – reprogramming of cancer cells into normal (or normal-like) cells that exhibit normal phenotypes and also lose malignant characteristics. For example, see Attractor Landscape Analysis Reveals a Reversion Switch in the Transition of Colorectal Tumorigenesis
• Regenerating hearts in vivo – see A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration
• Curing loss of vision.  See the 2020 publication Scientists reverse age-related vision loss, glaucoma damage in mice.   Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” said senior author David Sinclair,    “ And David Sinclair unpublished data: epigenetic reprogramming of RPE cells restores vision in retinal degeneration, and reprogramming of brain cells improves learning in aged and amyloid/AD mice models | ARDD2022 Conference
• Aleviating Alzheimer’s disease. See  Neuronal Reprogramming Alleviates Alzheimer’s in Mice – Scientists have shown that long-term intermittent reprogramming limited to hippocampal neurons increases their fitness and improves cognitive function in a mouse model of Alzheimer’s disease,
• Reduction of high blood pressure.  See A Single-Short Partial Reprogramming of the Endothelial Cells deceases Blood Pressure  via attenuation of EndMT in Hyhpertensive Mice

This is only today’s starting list, and much of today’s research on the topic is devoted to making age-reversal cures and longevity simple, safe, and practical.