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

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