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[ImmInst]

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.

View the full article at Anti-Aging Firewalls