The work of George Church combines a broad knowledge of science with an ambitious imagination. Our world needs visionaries, and Church is one of a kind. His Harvard laboratory is at the cutting edge of several key areas of biochemistry. Please construe the following criticism narrowly. There’s just one of his ideas that I think is dangerous enough that I am moved to speak out against it. Changing the genetic code is a really, really bad idea.

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I’ve heard Dr Church speak three times in the last month, and each time he has mentioned a technology to make humans resistant to all viruses. He has already done a proof-of-concept experiment, creating a strain of E coli that uses a different genetic code from all other life on earth (including, of course, all viruses). Since viruses use the host cell’s machinery for translating their own genome, the virus won’t be able to replicate in a host with a modified genetic code.

Changing the genetic code is not the same as “gene editing” or “gene therapy”. Gene therapy involves changing one gene (perhaps throughout the cells or a particular organ, perhaps in every cell in the body). Changing the genetic code is a global search-and-replace in the entire 3 billion base pairs of the human genome. It’s a hundred million changes, all of which have to go just right, together with a change of instructions about how to interpret the new code.

What is the Genetic Code?

Roughly speaking, DNA is an information molecule and proteins are service molecules. Most of the functions of a cell are performed by proteins, including signaling, energy transduction, locomotion, filtering, promoting beneficial chemical reactions and inhibiting others — essentially all the functions of metabolism are accomplished by proteins.

A protein molecule is a chain of (usually) thousands of amino acid units strung together in a particular order. There are 20 amino acids to choose from, and they have differently shaped fields of electric charge around them that make them attract or repel other amino acids. So a string of amino acids that is a protein wants to fold into a unique, characteristic shape, and the shape determines its function in the metabolism.

DNA lives in the cell nucleus and is copied and passed from mother to daughter when a cell divides in order to clone itself. One of the functions of DNA is to carry information about how to build proteins. (In fact, this was the first and primary function of DNA that was discovered in the 1950s.) DNA is constructed of millions of four nucleic acid subunits strung together in a particular order. (Note that a nucleic acid is not an amino acid.) DNA is built from only 4 nucleic acid subunits (usually abbreviated A, C, T, and G) compared to 20 amino acids subunits used to construct proteins.

The “genetic code” is a mapping between DNA and proteins. Each sets of 3 nucleic acids specifies a particular amino acid. A “gene” is a stretch of DNA that contains instructions for making a particular protein. So, for example, a stretch of DNA that is 30,000 base pairs long may contain instructions for creating a protein of length 10,000 amino acids. Only about 3% of our DNA consists of genes. To “read” these instructions is the function of a ribosome. Ribosomes are organelles, little chemical factories, millions in every cell, where proteins are made.

The genetic code constitutes a language through which DNA (mediated by messenger RNA) tells the ribosome what amino acids to string together in what order. The messenger RNA copies a gene and then leaves the nucleus to look for a ribosome. The ribosome reads the message. Every time it sees the 3 nucleic acids GCT, it adds an amino acid called Alanine. If it sees GGA, it adds a Glycine, and so on. A combination of 3 DNA units specifies each protein unit, with some redundancy. Redundancy means, for example, that TCT, TCC, TCA, and TCG all correspond to the single amino acid called Serine.

(U is another way of saying T in this language. DNA uses T, while RNA uses U for the same meaning.)

The association of a particular triple with a particular amino acid is thought to be mostly arbitrary. It’s just a language that DNA uses to talk to the protein factory.

One of the deepest truths about biology is that this arbitrary language, this same language, is shared by all living things. All living things, from the toadstool to the bowhead whale, use the same language to communicate between the DNA and the ribosome.

This means that all life can exchange DNA with all other life. From bacteria to baboons, we all speak the same language

This is also powerful evidence that all life is related. Life arose once, and differentiated on a vast tree over the course of 4 billion years. You and I and the toadstool and the bowhead whale are all cousins.

How does Dr Church propose changing it?

This is the article in which Church proposes the project.

We might imagine that we have to reprogram millions of ribosomes in each of trillions of cells in the body to change the genetic code. That would be correct about reaching trillions of cells, but maybe incorrect about the ribosomes. As it turns out, all the ribosomes are reading from the same hymn sheet, and we can change the hymn sheet with standard genetic engineering.. The genetic code is itself encoded as proteins, and the proteins are made from a nuclear DNA template. So for example, there’s a particular protein that has a slot for the GCA combination and another slot that attracts Leucine. This one protein is responsible for one pairing in the genetic code. If this one protein is deleted from the genome, then no ribosome in that cell will be able to read GCA. The ribosome will choke when it gets to GCA and abandon work on the protein it started to make.

Part of what makes this feasible is that, besides GCA, there are other combinations that code for Alanine. So the plan might be to eliminate this one protein that translates GCT into Alanine, and then to go through the entire genome — billions of bases — and do a “global find and replace” operation. Every time there is a GCT, replace it with GCA, which also codes for Alanine. These two changes would put the cell aright again, so Alanine would appear in all the same proteins as before. But an invading virus wouldn’t know that the code had been changed. The virus might sometimes use GCT for Alanine, and it wouldn’t work. The ribosomes would be able to decode native DNA, but not the virus’s DNA.

Of course, while we’re genetic engineering, we could change that one protein in a way that makes CGA translate into Tyrosine instead. That change would be global. We would change the genetic code for all of the DNA in that cell that is engineered in this particular way.

The global find and replace function is called multiplex base editing, and it is already (the last decade) a developing lab technique. There are several ways to do it. For example,

A base editor is a fusion of catalytically inactive CRISPR–Cas9 domain (Cas9 variants) and cytosine or adenosine deaminase domain that introduces desired point mutations in the target region enabling precise editing of genomes. [ref]

In other words, CRISPR is used to locate particular sequences wherever they occur on the genome, and an enzyme called a deaminase is used to modify all of the copies of one particular nucleic acid base in that stretch of DNA. For example, deamination of T turns it into U, and the next step is to add a reagent that will change the U into something else, perhaps A in the example above.

Suppose humans were engineered with a different genetic code

We would still be able to eat food, because our bodies ignore the DNA in the food we eat. The DNA is de-activated but not digested. The proteins in the food we eat would be available just as before, because the body recognizes those proteins, irrespective of what genetic code was used to ake them.

However, the human body with changed genetic code could not be infected by viruses that use the old, standard genetic code. Viruses don’t have ribosomes of their own, but count on the host’s ribosomes to translate their genes into the proteins they need. Humans that were engineered to have a different genetic code would play a trick on the virus, translating its DNA (or RNA) into the wrong protein, or failing to translate it at all.

What could go wrong?

• Our bodies contain hundreds of trillions of viruses. Western science has not begun to study these relationships, and we don’t know which are helpful, which are harmful, which are neutral. We cut off all symbiosis with viruses at our peril.
• We do know that our gut microbiomes and skin microbiomes harbor thousands of species of bacteria, most of which are beneficial. Would they still be able to work with us if we used a different genetic code? (The known interactions all involve proteins, so that, presumably would be unaffected if the change in code went off without a hitch.)
• A man and woman who have genomes that are coded differently could never have children together. Does Dr Church imagine switching over everyone’s genetic code in the same year so that such couples would never occur?
• Horizontal Gene Transfer = exchange of genes between organisms that have no parent-child connection. We know little about it, except that HGT plays a major role in evolution, in the long run. Is HGT important in the space of a single lifetime? No study has asked that question.
• We know that all of us are exhaling exosomes all the time, and that they send signals that are picked up by other humans and other animals and plants in the vicinity. Exosomes contain snippets of DNA. How would a person with a modified genetic code read these signals? How dependent are we on these signals? We don’t know.
• DNA has other functions than coding for proteins. In fact, more than 97% our our DNA does not code for proteins. (This was once called junk DNA by people who theorized that it was just leftover debris from the past and silenced viral infections.) We have some ideas about what this DNA does for us. An obvious role is in epigenetics. It determines how DNA folds and unfolds, and so the 97% is important for gene expression. Would a change in the genetic code affect gene expression? We don’t know. What other roles are there for DNA? We don’t know. How would a global modification of DNA affect a living human? We don’t know.
• There are therapies based on matching radio frequencies to a resonance of a chromosome. Don’t scoff— a brilliant Nobel laureate named Luc Montagnier spent much of his later life working on this stuff. Humanity would be foolish to bet the farm on his being all wrong.
• The whole purpose of this exercise is to confer viral resistance. What if the viruses are on to us, and they evolve to adapt to our new genetic code? The rate of viral evolution ranges over 5 orders of magnitude and is a poorly understood. Viral adaptation to a new genetic code might never happen, or it might happen very quickly.
• Changing the genetic code must be done in most cells of the body to stop a viral infection. Must the change reach every last cell? If the body becomes a chimera with the new genetic code in 90% of cells but 10% retaining the old code, will conflicts arise and the cells begin a civil war? In theory, mRNA does not pass between cells, so this should not be a problem, but we really don’t know.

The big picture

I have advocated approaches to aging based on signaling. Aging is centrally orchestrated at the system level. We don’t have to reach into every last cell and fix the damage; we need only to restore the body to a young epigenetic state, and all the innate mechanisms of repair and renewal will be once again available.

Repair at the cellular level is more invasive. There is much opportunity for things to go wrong. I believe that this kind of approach is unnecessarily exacting and difficult.

Changing the genetic code is a cell-level therapy, which, in my calculus, is a strike against it. Furthermore, it goes beyond restoring the cells to a youthful state; it creates an artificial state with unknown consequences.

And why? People in the prime of life with young immune systems almost never die of viral infections. If we can achieve rejuvenation of the immune system via any of the means now on the drawing board, then changing the genetic code will be unnecessary.

George Church is a giant in the field of biochemistry. His visionary ideas and research projects are moving science and technology in many good directions. But he doesn’t think in terms of ecology. It’s true in general that biochemical science has advanced explosively in recent decades, leaving the study of ecology in the dust. Biochemistry has benefited from computer analysis. Ecology requires intensive field observations. But ecology is just as important to the understanding of life as biochemistry.

We can be confident that humans are intimately connected to the ecosystem that spawned us. There has been exactly one experiment in which a small group of humans tried to live in an artificial ecosystem for a year. It ended disastrously in just a few weeks. No one has begun to catalog the ways that we are dependent on the earth’s biosphere, or to ask how those connections would be changed if we used a different genetic code from every other plant, animal, fungus, microbe, and virus on the planet.

For the foreseeable future, changing the genetic code in the human body — even if it proves to be feasible — would be a reckless step into unknown territory for our species.

Rebalancing proteins in the blood is the single most promising strategy for age reversal in the present environment. There are two competing schools for how to approach this. I’m calling on both to put their heads together and develop a strategy that combines their insights.

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<rant>
Please forgive me while I rant for a paragraph before beginning this column in earnest. Len Hayflick demonstrated that senescence in many animal species, probably including humans, is promoted by lack of a simple, cheap enzyme (telomerase) that every cell knows how to produce. To anyone who hasn’t been indoctrinated into the selfish gene dogma, this would be a sure indication that the body is trying to kill itself. But fifty years on, Len is still saying that aging = entropy catching up to a body’s chemistry. An equally powerful discovery came from Irina and Mike Conboy, who have been at the forefront of experiments demonstrating that aging is centrally coordinated through signal molecules in the blood. In every context but this one, the Conboys will acknowledge that these molecules are subject to directional selection and are tightly regulated in the metabolism. But when the blood plasma fills up with pro-inflammatory cytokines during aging, the Conboys insist that this is an accident. The body made a mistake. They call it “deregulation”. And in case anyone misses the point, they add in parentheses, “(noise)”. These are exactly analogous to the directed changes that cause growth, puberty, cessation of growth, onset of menopause, etc. In those other context, the change in balance of plasma proteins are signals, but in the context of aging, they must be “noise”. 

And even more incomprehensibly, the “noise” to which they refer always goes in one direction, and that is producing too much of some signal molecules, and the “noise” always manages to emphasize exactly those signals that bring the body down in a hailstorm of inflammation. 

Evolution is a many-splendored thing, and natural selection is perfectly capable of producing well-regulated, interdependent communities. This has meant selection for Goldilocks rates of reproduction balanced artfully against death rates that are also well regulated under evolutionary control. 

And YES, it does matter whether you think of aging as signal or noise. (I apologize again as my rant spills into its fourth paragraph.) It matters because if aging comes from a set of signals, we know well how to block those signals, e.g., with drugs that jam their receptors. But if it’s noise, the task is so much more difficult because it unfolds differently in every individual. 

If you want to hear more of this kind of thing, please read my book, or just refer to the dusty archives of my blog.
</rant>

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It’s no secret to readers of this column that I think altering the balance of signal molecules in blood plasma is the most promising road to anti-aging in humans. There are now two competing approaches to this project. The Katcher school says that there are youthful factors missing in the blood of old animals, while the Conboy school says that there is an excess of pro-aging factors. Both are quick to say that yes, it is a balance of pro-aging and anti-aging factors in the blood that ultimately determines the animal’s fate. But Katcher says that if you deliver the right combination of youthful factors, they will reprogram the epigenetics so that the pro-aging factors retreat as a side-effect; while the Conboys claim that if you dilute the blood, removing equal proportions of pro-aging and anti-aging factors, that dilution is sufficient to reset the aging clock, and stimulate new production of the youthful factors. 

Problems with the Katcher protocol

Until last week, Katcher had the more compelling data (IMHO), because he demonstrated dramatic epigenetic age reversal in rats. But last spring, the disappointing results in a small lifespan trial (8 rats) makes us wonder if his protocol needs a lot of fine tuning before it’s ready for prime time. And another weakness in his protocol is that he doesn’t know what is in the blood-derived E5 elixir that does its magic. He tells me there are efforts underway to identify the active components of E5. I think this determination is a high priority with global implications for health, so, by my lights, the analytic work on E5 should be a top priority. But there is a financial incentive not to know what are the active components of E5. This is because Katcher’s Yuvan Research has a patent on the process of extraction, but the components themselves are natural proteins, and thus they cannot be patented. So as soon as the information about the active components of E5 become public, his process patent risks becoming worthless. Other, larger laboratories than Yuvan will be able to synthesize the chemicals and sell them. I fear that research is being held back, and for what? I don’t even believe that the strategy of secrecy can secure the patent rights for Yuvan, because the knowledge will inevitably leak out, and Yuvan doesn’t have the resources to pursue multi-million dollar court battles over patent rights.

Human trials of plasma dilution

Now there is a new article from the Conboys analyzing results of plasma dilution in three human subjects. They show improvements suggestive of rejuvenation in several biomarkers. They do not report methylation age. They do begin the analysis process, and offer suggestions about what may be the most important pro-aging components of blood plasma that must be removed or inactivated.

Why don’t they measure methylation age using any of the available clock algorithms? There is a short statement why they don’t believe in methylation clocks, and they express the opinion that another biomarker of aging, one not based on “machine learning or large data sets” is urgently needed by the community. I believe that methylation clocks are the best means we have at present to evaluate the effects of anti-aging interventions, and in this one respect I find myself (for a change) aligned with the majority view in the field. The Conboys owe us a better explanation why they have gone to such great lengths to report other biomarkers of aging, but they don’t offer us the simple one that most researchers rely on.

Accumulated DNA damage triggers genetic aberrations, senescence [26], and loss of cell function and leads to age-related diseases [24].

It’s a popular theory aging that DNA damage is an important driver of aging , but I don’t believe it.

Interestingly, the procedure of small animal plasma exchange to dilute the circulating factors in plasma effectively reset the age-elevated systemic proteome and restored youthful healthy maintenance and repair of muscle, liver, and brain, without any added young blood, young plasma, or young factors [15–17].

This is a crucial point. How strong is the evidence? The three references are all previous publications from the Conboy lab. Ref 15 describes results of delivering young blood into old mice, an experiment which cannot tell us whether dilution alone rejuvenates gene expression. Ref 16 is about plasma dilution in mice and humans. This study establishes that something in old blood inhibits satellite (stem cell) growth, necessary for healing and repair, and that dilution is sufficient to restore youthful activity of these cells. Some evidence is noted of changes in the global proteome toward a more youthful state. Ref 17 establishes that plasma dilution is sufficient to enhance cognitive performance and reduce inflammation in old mice.

There is a section of the paper documenting “proteome noise”, which the Conboys propose as an important biomarker of aging. I disagree, of course. I see the directed changes in gene expression as the important drivers of aging, and the random changes are secondary. Much of the Conboys’ paper is devoted to analyzing noise in the proteome of subjects, and interpreting this as an aging biomarker which moves in the direction of youthfulness after plasma dilution. I admit much of the biochemistry is above my pay grade. I can’t comment on the merits of their proposed components of a new proteomic clock. But from the vantage of scientific methodology, developing appropriate biomarkers of aging should be a separate endeavor, done in advance. Criteria for successful rejuvenation should be established ahead of time, and not developed on the fly with results of the experiment already in hand.

I would have liked to see methylation age before and after treatment. I understand that the Conboys have reasons for not giving credence to the methylation algorithms. But how about A1C or CRP? These are measures of insulin resistance and inflammation, respectively, that are standard blood tests, but are not mentioned in the Conboy paper. How about any measures of cognitive or physical performance? There are no phenotypic aging markers in the Conboy paper.

Breaking new ground

The Conboys identify two proteins, TDP43 and TLR4, that were previously unfamiliar to me, but are markers of an aging proteome. The former is associated with cancer, the latter with dementia, and both increase with age. Both are attenuated with the Conboys’ plasma dilution protocol. I recognize that it is labor-intensive work to identify specific protein targets and test them individually, but this is the kind of work I think is most valuable going forward.  

How I think about aging

My (tentative) model:   “Old” and “young” are always in the body’s repertoire of behaviors, and the body will choose according to the signals it receives. The age state of the body is stored in the epigenetic state of cells, and communicated through hormones and other signal molecules in the blood. Some of these molecules also act as transcription factors, and they can feed back to affect the epigenetic state of dispersed cells. This is the reason for hope that a younger environment in the blood can effect long-lasting rejuvenation.

The great task before the Conboys and Katcher and other researchers in plasma rejuvenation is to identify which of the hundreds of proteins that change with age are the few transcription factors that are capable of reprogramming expression of the rest. 

Risks: 

• There is no guarantee that a small subset of proteins exists that can do the job, but we won’t know until we look. 
• And there remains the possibility that a central clock in the hypothalamus is able to override records of biological age in the epigenetics of dispersed cells. If this turns out to be the case, then we have to find ways to breach the blood-brain barrier and reprogram the hypothalamus.

A modest proposal

Harold Katcher, Mike and Irina Conboy are at the forefront of anti-aging technologies today. Both labs are very close to having an effective treatment for humans, close in the sense that there remain no conceptual hurdles, but only the predictable quotidien work of expert lab biochemists. In other words, a lot of work remains to be done, but the map is drawn.

Aging is not a cell-autonomous function, but happens under system-level control, with information about the body’s age communicated by signal molecules in the blood. This is the key insight on which Katcher and the Conboys agree.

To those of us watching from the outside, it is clear that a rebalancing of young and old plasma components will have a dramatic effect on health and lifespan. The remaining task is to identify a minimal set of those factors that must be removed (or neutralized) and those that must be added to the blood of an old person in order to trigger a global resetting of the epigenome toward full youthful gene expression.

We, the consuming public, would benefit greatly if the Conboys would hire Katcher to come work in their lab. Their two conceptions need not be antithetical. Let’s call on them to work together to identify that minimal set of blood factors, resetting of which can accomplish robust rejuvenation.

The importance to humanity of this research agenda must override the personality differences, the philosophical differences, the legal and IP problems that must be overcome to make this collaboration possible.

Sickening by John Abramson, MD. Mariner Books, 2022, ISBN 978-1328957818

This book describes the top-to-bottom control over medical research and its dissemination exerted by large drug manufacturers. Of course, they have their own research staff, paid to test their patented drugs and make sure those tests come out favorably. In addition, they are the largest sponsors of research at all the major medical schools, their reprint purchases from medical journals supply 40% of total journal revenue, and they are the largest advertiser in mainstream media, newspapers and TV, assuring that the most influential purveyors of science news know where their bread is buttered.

Thus “science-based medicine” has become tilted toward science that is curated and supported by the companies that profit from a particular approach to medicine, and toward exaggerating the benefits and minimizing the risks from the most recent and most expensive medicines.

Sickening, yes. But the actual situation is even worse than the bleak picture Dr Abramson paints. Big Pharma is not just cheating us, their approach to medicine has had disastrous effects on public health in the West, especially the USA.

For example, why would anyone believe that the same companies that defrauded the FDA and paid billion dollar fines would be telling us the truth about safety trials of their vaccines?

This book describes the scandalous state of healthcare in America, and traces the problems to financial domination by the pharmaceutical industry. The story is told with numbers. It’s a book only a statistician could love.

I’m a statistician. What’s my problem?

Limited hangout def : A piece of journalism that covers a scandal, often with breathless intensity, but focuses on lesser crimes, and thereby diverts readers’ attention from the worst excesses. See also controlled opposition.

We call it “healthcare”, but of course this word ranks with “Ministry of Truth” and “Re-education center” as an Orwellian deception. So much can be done to protect our health, starting with exercise, social support, organic vegetables, and clean air. But “healthcare” in America has nothing to do with these things, and it’s all about waiting until you develop symptoms, then suppressing those symptoms in the most expensive way possible. The US ranks first in the world in high-tech medicine, first by a long shot in medical expense per capita, and 68th in healthy longevity.

“Only about 20% of a population’s health is determined by medical care; most of the rest is determined by these external factors [including] interaction between individuals and their social, cultural, and physical environment.” 

40% comes from social factors and wealth disparities; 30% from diet, exercise, and individual behaviors; 10% from pollution and other environmental factors. A compelling theme of this book is that we spend an outsized portion of our national income on the 20% and have utterly neglected the other 80%.

A generation ago, Dr Abramson was a pioneer in muckraking from the inner bowels of the Pharma industry. To a large extent, this book is based on research he did in the early 2000s when he served as consultant to plaintiffs and expert witness in court cases against drug companies. Missing is the story of how much worse the situation has become since then, with an explosive rise in deception during the COVID pandemic.

In the intervening decades, Big Pharma has captured the regulators at FDA and CDC and has solidified its control over the mainstream media. Without these two institutions reliably in their camp, the great deceptions of 2020-22 could never have been accomplished.

Abramson barely mentions vaccines, but when he does so it is with the understanding that, of course, vaccines are safe, the best thing Western medicine has to offer, also the best tools we have for preventive medicine. This bias is my largest beef, and I will say more about it after describing what the book does well.

“The uniquely high revenue generated by prescription drugs in the United States creates a self-generating cycle. High prices create surplus funds, which are used, in part, for advertising and lobbying, which maintain the manufacturers’ control of the knowledge and pricing, which increases profits to fund the next round of even more expensive new drugs, and so on.” 

There you have it. The Pharma industry is so profitable that they can pay off the research institutions, the doctors, the regulatory agencies, and the Congress to maintain their profitability. Controlling the flow of medical knowledge is the linchpin of their business strategy, and they do it so well that most health professionals have no idea that what they read in the medical journals is high-falutin advertising copy.

“Under our current system, it is more profitable for large pharmaceutical companies to commit crimes and pay the fines than to obey the law.”

In case after case, Abramson describes how companies have been convicted of defrauding the FDA and other corporate crimes. Humans are jailed if they are convicted of such crimes; but for  companies the equivalent of jail would be putting the company in receivership or forbidding the company to do business for a period of years. This never happens. Instead the companies pay fines which are always a fraction of the profits they reap from the very fraud they have committed. Thus “crime pays” if you’re a drug company.

“We can’t be in the business of policing every piece of data we put out.”
— Editor of the New England Journal

The most prestigious medical journals have become the least reliable. Precisely because of the respect they command, they have been targeted by the drug companies for capture. When an article is published that demonstrates the benefits of a new drug, the manufacturer will buy hundreds of reprints, which salesmen then distribute to doctors in their offices. Journals have become addicted to sales of reprints. Britain’s best-respected journal, The Lancet, gets 40% of gross revenue from selling reprints to drug companies, while the Journal of the American Medical Association and New England Journal of Medicine (JAMA and NEJM) refuse to reveal their revenue from reprints.

Summary

Chapter 1 revisits Abramson’s old haunting ground and reminds us of medicine’s most famous scandal: Vioxx. Merck had been one of the most highly-regarded companies in America before its executives made an economic decision to (statistically) kill tens of thousands of its customers, so long as the lawsuits were costing less than the profit margin.

Chapter 2 is about the epilepsy drug Neurontin, which was repurposed and illegally marketed for pain control. (It is legal for physicians to prescribe any drug off-label, but it is not legal for the manufacturers to talk to doctors about off-label applications.) “There is no other drug being used to treat so many different conditions with so little benefit.”

In the older cases of Merck’s Vioxx and Pfizer’s Neurontin, Abramson did the right thing, and patiently pored through the data from company trials of the drugs, demonstrating that the data told a different story from the companies’ summaries to the FDA. But in the case of Pfizer and Moderna’s clinical trials for their mRNA vaccines, the data were even more damning, yet Dr Abramson does not review them. In fact, he scolds the companies for charging so much for their vaccines that they are unaffordable in Third World countries. But there is good evidence that the mRNA vaccines are doing more harm than good.

For example, when you read that the Pfizer trials showed they are 95% effective, you might be excused for thinking that 20 people died in the placebo group for every 1 person who died in the group that got the vaccine. The truth, from Pfizer’s own FDA submission, is that more people died in the vaccinated group than the placebo group [FDA doc, p 23]. Wouldn’t you think that this vaccine should be dead in the water the moment that this information was known? But FDA found excuses to ignore this most significant of all indicators, and sleep-walked to fast-track emergency authorization of the vaccine.

The theme of Chapter 3 is that statin drugs lower risk of heart attacks for those who have already had one, but are being marketed to a great many more people who are judged to be “at risk”. Certainly, statin drugs are among the most over-prescribed in history, but I would like to see Abramson address the deeper controversy about their mode of action. Usually, they are prescribed to lower cholesterol levels in the blood, but many medical researchers today believe that the link between cholesterol an CV risk has been discredited. The alternative view is that the benefit of statins comes exclusively from their anti-inflammatory effect. If this is true, then inflammation can be lowered far more safely and with fewer side effects by natural herbs (curcumin), omega 3s, and NSAIDs.

Chapter 4 is about insulin. Until reading it, I didn’t know that most insulin sold today is not natural insulin but a synthetic protein, slightly modified from human insulin, that arguably provides improved performance for some Type 1 diabetes, and inarguably costs hundreds of times as much. Many diabetics can’t afford the more expensive drug and don’t know about the less expensive version, so they scale back dosage to save money and they pay with their health. I wonder if synthetic insulin doesn’t cause other long-term health problems as well. The corporate motive to “improve” on human insulin is that natural hormones cannot be patented, so they must compete on price. But insulin is literally billions of years old and has multiple metabolic functions, including regulation of lifespan in yeast cells and lab worms and humans, too. Yes, insulin has a direct impact on aging itself. Before we modify a hormone that has co-evolved with diverse aspects of our metabolism, we should be doing whole-life studies to establish long-term benefits. Synthetic insulin has been improved based on short-term, narrowly-focused studies that demonstrate marginal improvement in control of blood sugar only.

Chapter 5 is mostly about income disparities being the deep cause of bad health in America. Amen. I wish he had fingered our dysfunctional economy as being the reason for most antidepressant prescriptions.

In Chapter 6, he tells the story of a meta-analysis review of relevant data on the antiviral drug Tamiflu, signed by the prestigious and once independent Cochrane Collaboration. The review was modified after discovery that the most compelling evidence in its database was provided by the manufacturer, Hoffman-Laroche, data which had never been peer reviewed and never made public before the “review article” was written. The revised article found that Tamiflu had minimal benefit, and no impact on severe outcomes or deaths, but this revision came only after US  Homeland Security had purchased a $1.3 billion stockpile of the drug for emergency use.

Since 1975, the Federal office of Health Technology Assessment provided independent evaluation of what was working and what was cost effective. Under the Clinton Administration, HTA was defunded. To save money. There was, at one time, a Federal Clearing House, a project of the Agency for Healthcare Research and Quality that vetted healthcare information. AHRQ was shuttered during the Trump Administration. To save money.

In Chapter 7, Abramson lays out the story of Prilosec’s replacement by Nexium, which is in fact no more effective than Prilosec, but which enabled Pfizer to effectively extend patent rights on a bestselling drug. What he doesn’t say is that both Prilosec and Nexium are deeply flawed strategies for countering stomach acid reflux (GERD). Both products are Proton Pump Inhibitors, which act by interfering with the body’s acid-generating mechanism. But the stomach requires acid to digest food, and the body chemistry quickly learns to compensate. People taking a PPI drug adapt to it by upregulating the enzymes that produce acid; the result is that PPIs are highly addictive, as discontinuation of use results in a painful surge of excess stomach acid. Older and cheaper antacid strategies don’t have this problem.

Chapter 8 is theoretical: Why we can’t rely on the free market to fix our problems. Why aren’t honest drug companies producing better products able to crowd out the parasites? The reason involves control of information that doctors and consumers need to make medical decisions.

Chapter 9 is about Obamacare. He describes how the bill faced stalwart opposition in Congress, and in the end it achieved an increase in percentage of insured Americans from 80% to 88%. But passage was possible only because both Big Pharma and Big Insurance were solidly behind the bill; and this, in turn, was because the Obamacare plan posed no public competition for private healthcare, regulation of the industry was not included, and bargaining for price breaks on drugs was explicitly forbidden. Obamacare added to the profitability of both the insurance industry and for-profit hospitals. In the story that Abramson tells, the President fought valiantly for the “public option” that might have held down costs, but in the end the combined political clout of the drug and insurance industries defeated the reforms he had promised during his campaign. I’m not so sure that Obama was not in on the fix from the beginning.

Chapters 10 and 11 describe the political conditions that maintain our state of high prices and low quality research. I think Abramson is correct in focusing on data transparency as the key reform that is needed. The central cause of dysfunction in our medical system is that we rely on for-profit corporations to summarize for us the science that supports the benefits of their own products, while raw data remains proprietary. This is not madness, it is fraud. Abramson rallies us into the coalition that will be necessary to break the stranglehold that Pharma has on government. He has more faith in America’s democracy than I have, but I hope he’s right.

Quibbles and suggestions:

He mentions in passing the advantage of polyunsaturated fats for lowering cholesterol. This is badly out of date. I assume that the reference slipped through Abramson’s careful editorial pen because it was part of a quote that was intended for other purposes. Nevertheless, it should be flagged for readers so they don’t take it as a recommendation to increase intake of polyunsaturated fats. Recently Dr Mercola has inveighed against polyunsaturated fats.

Is it right that Ivermectin needs only one dose a year to prevent river blindness? This study from 2014 that twice yearly works much better. Still, this is impressive testimony to a Nobel prizewinning drug that has had enormous benefits for people whose environments routinely expose them to parasites. Abramson doesn’t mention the propaganda war that disparaged of Ivermectin as “horse paste” during the COVID pandemic. In reality, dozens of clinical trials and observational studies have indicated that IVM is the best preventive and probably the best treatment we know for COVID (see also). The story of Uttar Pradesh in India is eye-opening.

Abramson notes several times that life expectancy in the US has improved in recent decades. He fails to mention that the increase is almost entirely for men. In 1980, men’s lifespans were 8 years shorter than womens’. Now, men have nearly caught up, while women’s lifespans have barely improved. Surely, neglect of research on women’s health is a scandal in its own right.

Why doesn’t he explore the relationship of insurance companies to the problem? Insurance companies’ financial interest is opposite to the interest of drug companies, and they have used their market power to demand discounted drug prices. But they have rarely gone to bat for the health of their patients, doing their own research to determine which drugs are actually benefiting their customers’ health and reimbursing those at a higher rate than more questionable drugs.

He might have told the story of antidepressants, sold based symptoms that reflect patients’ despair about the state of American culture and the economic pressures that come from wealth disparity. Two generations of Americans have grown up numbing themselves in response to problems that are far larger than their individual depression. He might have told how frequently side effects of drugs are treated with more drugs, which have their own side effects in an escalating, profitable spiral that is devastating to patients’ health and lucrative for the medical establishment.

Why are vaccines a sacred cow, untouchable in the press?

It is a remarkable public relations coup. The Pharma industry has surpassed Big Tobacco as the #1 industry hated by the American public. But this same public believes that vaccines are life-saving preventatives, and never questions their safety. The vaccines, of course, are sold and tested largely by the same companies that they hate, and the public never connects the dots. Why should we think that companies that have repeatedly been convicted of criminal fraud would honestly report the benefits and the risks of their vaccines?

The truth is that some vaccines have saved hundreds of millions of lives, while others are actually doing more harm than good. Vaccines have general, long-term effects on the immune system, and these can either increase or decrease risk of diseases other than the one for which the vaccine was targeted. (Refer to the work of Christine Stabell Benn.) Vaccines have communal as well as individual benefits, but they also have communal costs; so discussion of any particular vaccine must be nuanced, taking account of wide-ranging social factors. This analysis is never, never done — not by the press nor the epidemiologists nor the journals, certainly not by the FDA. Instead, the world is divided into pro-vax and anti-vax. The latter are disparaged as “enemies of science”. One of the Orwellian triumphs of the vaccine industry is that anyone who asks for vaccines to submit to the same testing regimen as every other drug category is tarred as an “anti-vaxxer”.

There are five reasons why Big Pharma is so jealously protecting its fiefdom, marketing vaccines without public or regulatory opposition.

1. Childhood vaccines are actually mandated by most states for school children, guaranteeing a market among people who don’t even have any present health problems.
2. Vaccine manufacturers enjoy legal immunity and cannot be sued in America when their products cause harm in vaccinated people.
3. Vaccines bypass most tests for safety and efficacy. In “placebo-controlled” trials for vaccines on the childhood schedule, the “placebo” is usually a previously approved vaccine, rather than a harmless saline solution. This practice has masked an escalating spectrum of side effects, growing as the number of vaccines expands.
4. Childhood vaccine injuries, mostly unrecognized as such, feed a pipeline of lifelong customers for other drugs, especially stimulants and antidepressants.
5. As a result, vaccines were already the most profitable sector of any drug company’s portfolio before vaccine profits went through the roof in 2021.

I won’t pretend to any comprehensive history of vaccines and their discontents, but I want to tell two stories with which I have some personal familiarity.

The childhood vaccine schedule

Dr Paul Thomas is a pediatrician in Portland Oregon. His practice is rooted in standard Western medicine, but he believes in informed consent. So every time a child comes up for a scheduled vaccine, he explains in detail to the parent the trial results, the pros and the cons, the benefits and the risks as far as they can be known from the medical literature. As a result, his patients have become a diverse sample of vaccination status, with some accepting the full vaccine schedule and some others having no vaccines at all, and most of his patients selective about which vaccines they accept. A few years ago, he worked with statistician James Lyons-Weiler to study the histories of these patients over 10 years of follow-up. How did the fully vaccinated, the less vaccinated, and the unvaccinated fare in the subsequent years of their childhood?

They wrote up their study and published it (2020) in the International Journal of Environmental Research and Public Health. In every measure of health, the unvaccinated children did better. One sixth as many allergies and anemias. One fourth as many asthmas and colds. Zero cases of ADHD among 561 unvaccinated children; nationally, the rate of ADHD is 9.4%. The article presents a graph demonstrating a positive relationship between the number of vaccinations a child receives and the number of future medical problems s/he experiences.

Fig caption: The horizontal axis divides Dr Thomas’s juvenile patients into 20 groups from the least to the most vaccinations received. The vertical axis is the normalized number of office visits. Green bars show that the number of routine check-ups was about the same across the board. Red bars show that showing up in the office to deal with fevers of any kind was much more common among the heavily vaccinated.

It is well-known that vaccines have long-lasting effects on the immune system, affecting susceptibility to multiple diseases, but the mix of benefits and risks is impossible to predict without a study of this kind. Remarkably, this is the first such study ever attempted published. Had no one ever asked the question, “are vaccinated children better off overall?” Or had they asked the question and didn’t like the answer they found?

Immediately after publication, the Oregon Medical Board suspended Dr Thomas’s license on an emergency basis, without a hearing. The journal received complaints. The publication was “irresponsible” because it would encourage vaccine hesitancy. The study was “misleading” in unspecified ways. A year later, the journal retracted the article without explanation to the authors.

And so we don’t know whether the extensive vaccine schedule now recommended (often mandated) for children is doing more good than harm. We don’t know because someone doesn’t want us to know.

Suppression of COVID treatments to clear the way for vaccines

I consider this story to be the most egregious scandal in the history of medical publishing. It unfolded almost two years before publication of Sickening, yet it was nowhere mentioned in the book.

Hydroxychloroquine (HCQ) is a drug with multiple uses and a well-established safety profile. It is taken daily by millions of people who have Lupus, and hundreds of millions more who live in areas where malaria is prevalent. HCQ was used successfully in China to treat the first SARS outbreak in 2003. It works by opening cell walls to allow zinc ions to enter; zinc strongly suppresses the replication of respiratory viruses, including SARS and SARS-CoV-2.

During the spring of 2020, many small studies were being conducted around the world to see if early treatment with HCQ and zinc could keep patients out of the hospital. Then, in May, a major study appeared in the British journal The Lancet. (A companion article appeared in New England Journal of Medicine.) The authors compiled hospital records from six continents, with 100,000 patients who received HCQ and those who did not. In this huge sample of COVID patients, those treated with HCQ were dying at twice the rate of those who did not. The results were so compelling that dozens of smaller studies around the world were discontinued. It would not be ethical to expose COVID patients to HCQ under the circumstances.

But this was the opposite of what had been found previously in smaller studies. Other medical researchers, reading the article, wanted to check the calculations. They asked for the database of patients and outcomes. Weeks passed, and the authors of the Lancet study could not produce the database. Quietly, without announcement or apology, the study was retracted, along with the companion in NEJM.

The story came out: the database had been presented to high-profile academic doctors at Harvard and Stanford by a small Chicago company called Surgisphere. The doctors were excited to have such an extensive database to work from, and they failed to ask even the most obvious questions. Surgisphere had no relationship with dozens of hospitals around the world. The patients in the database were not real people. The data had been fabricated from whole cloth.

But the damage had been done. HCQ studies had been shut down, and the drug had been tainted as dangerous and ineffective, a reputation which has survived to this day.

It gets worse. Subsequent studies of HCQ were designed to fail. They were limited to hospitalized patients, in late stages of the disease when the virus is already gone. Toxic dosages were given to test subjects, causing heart complications and deaths that were completely avoidable. The low dose of HCQ would have worked just fine in early stage COVID.

HCQ was deliberately discredited. In most of the 50 states, pharmacists are forbidden from dispensing it for COVID, or else they think they are forbidden, which has the same effect. The measure of this crime is that HCQ and zinc, used early, would likely have saved millions of COVID patients from hospitalization and death worldwide, extrapolating from some of the honest studies.

The reason for suppressing HCQ and Ivermectin was not just that they are cheap, out-of-patent alternatives. FDA’s rules for emergency authorization say that a vaccine can only be considered for emergency use if no available treatments exist. HCQ (and later IVM) threatened the vaccine strategy that had been determined in advance, with tens of billions of dollars invested.

Afterword

Abramson recounts the late-breaking story of FDA approval of the Alzheimer’s drug Aduhelm, despite the fact that its own advisors had found the drug had no clinical benefit and serious side effects. There is no longer any daylight between FDA and the industries that it was created to regulate. Exactly the same dynamic is underway with approval of the mRNA vaccines. The vaccines’ efficacy plummets after a few months, while the number of deaths reported after mRNA vaccination has been 90 times greater than the worst previous vaccine (Shingrix). These vaccines were based on an entirely new, speculative technology, and rushed to market with zero long-term testing, yet the FDA ignored all precedents, ignored the company’s own data, made no pretense of risk/benefit analysis, and approved the vaccines for every age group. What does Abramson have to say about this? The vaccines “saved countless lives and prevented enormous suffering.”

The bottom line

Dr Abramson does a good job describing the inflation of drug costs and the importance of data transparency. I think he seriously underestimates the harm that has been done to America’s health by a medical system centered on patented drugs.

I can end this review on an upbeat note by retelling my own experience with hospitals, doctors, and the medical establishment. I had almost no such experience until this time last year, partly because I distrusted what Western medicine had to offer, partly because I was both lucky and careful, and had no chronic health issues into my 70s. But last July, the front end of my bicycle had a date with a speeding truck, and I immediately had an opportunity to sample the best that Western medicine has to offer, namely trauma medicine.

My ambulance hit the ER mid-afternoon and I was given a 20% chance of living through the night. Not only did the surgeons save my life with intensive, simultaneous attention to a dozen places where I was bleeding (internally and externally) faster than they could transfuse blood into me; they also were preparing to rebuild my shattered and lacerated left leg, even as they gave me low odds of ever living to enjoy it.

They did a lot of things right, stopping the bleeding, putting rods and screws in both legs, repairing my shattered pelvis with a rod and a second titanium pubic bone, tying off a vein that was too badly damaged to repair.

I was flat on my back, unable to roll over in bed for three months. One year later, I am swimming and bicycling almost at the level of a year ago. My yoga practice is coming back, and I am hiking in the woods more comfortably each day, so far without the balance and dexterity that I used to have. I can’t jump or run, but I am building in that direction and I haven’t given up. Given my age and the severity of my injuries, I am an outlier in the rate and extent of my recovery. Given the kind of collision that sent me to the hospital, it is a miracle that I lived, let alone that my brain and spine were not injured.

Perhaps of interest, I refused all pain medication in the hospital, with the exception of ibuprofen on a handful of nights. I believe, but can’t prove, that pain medication slows recovery.

“How many people have to receive a given drug in order to save one life?” This number is called the “number needed to treat,” or NNT. For metformin and the best drugs we have that treat chronic disease, this number is in the range NNT=30. In other words, 29 people will have all the side effects of the drug and no benefit so that we can save 1 life. For preventive statins and the most questionable drugs in common use, NNT can be over 1,000.

For the treatment I received last July, NNT=1.

Harold Katcher’s patent was unveiled last week, and it’s not what I thought it would be.

I thought it would be a list of several molecular forms, together with recipes for how to make them and how to administer them intravenously for increased longevity. 

I hoped it would inspire laboratories around the world to replicate Harold’s results and to vary the formula with the intent of optimizing results and streamlining delivery. I imagined a quantum advance in parabiosis-derived experimentation. 

Instead, the patent seeks to cover a broad range of techniques for extracting proteins and entire exosomes from blood plasma. It may be designed to obfuscate. I am unfamiliar with patent law, and this may be entirely conventional; instead of giving explicit instructions that another researcher can follow, there are several alternatives at every step, with the claim that they are all variations on the basic technique, and the patent covers them all. I presume that Harold knows which of these options at each step are the ones used to create E5; but no one reading the patent could recreate Harold’s work without some inspired guesses.

Background

Ever since the Stanford parabiosis experiments of 2005, there has been evidence that aging is centrally coordinated and that the blood transmits information telling the body how old it is. Young tissues quickly deteriorate when exposed to the blood plasma of an old animal, and old tissues are rejuvenated in the presence of young blood plasma.

So the pressing question is: what is it in the plasma that transmits these signals? Is it predominantly pro-aging signals that need to be removed, or predominantly anti-aging signals that need to be enhanced? How many such chemicals are there? Are they proteins or active RNAs or something else?

These are difficult questions because blood plasma contains thousands of molecular signals in trace amounts. The quantities vary with activity and time of day, and many of them vary with age. We would dearly love to have a recipe for a handful of transcription factors that need to be added or removed, with the result that they would trigger readjustments in the rest. 

I had assumed until last week that Harold has this information, and that he has held it back from the public while his business partner secures patent rights and builds a distribution network for humans. 

But now it seems that Harold has general knowledge of the class of chemicals signals that is most effective, but that he does not know specific molecular formulas. Indication is that it is a class of proteins. 

Harold has told us that he has been building facilities for synthesizing E5. The patent seems to say that he has some techniques for extracting from plasma a cocktail of many substances that remain incompletely characterized. Akshay has told me that they get plasma from pig’s blood, discarded by butchers.

There are large proteins and short peptides and everything in between. A “plasma fraction” may contain a specific range of molecular weights. But in the patent, several different ranges are listed, so we don’t have the crucial information, “which range is the effective one?” I presume that Harold knows.

Perhaps among readers of this blog there are people well-versed in biotech patent law and others who know more about the biochemistry of blood-derived proteins. If so, please contact me and respond to this patent from a more informed perspective than i can derive.

Imperative for the near future

We know that the active ingredients are proteins, and Harold knows the range of molecular weights. Several different ranges are listed in the patent, and several fractioning techniques are specified for specifying them. I presume that one of these leads to successful rejuvenation and the others are decoys. 

So, the next step will require Harold’s cooperation, because even after publication of the patent, no one else will be able to replicate his formula. If he and Akshay are willing to subject E5 to laboratory analysis, then the protein constituents can be individually characterized. I personally don’t know how this is done, but I do know it is possible because biochemists generate pictures like this one routinely.

The number of chemicals in a given range of molecular weights is probably small, perhaps a few dozen; and of these, the active ingredients necessary for the formula to work constitute a smaller set, perhaps less than a dozen. Once we have the chemical formulas for all the constituents of E5, we can test different combinations of them and within a year of trial and error, we should be able to identify the minimal effective set. Then these can be synthesized in a modern factory and we won’t need a river of pig’s blood to rejuvenate humanity.

Harold is not the only or even the first to conduct research with blood-derived proteins inspired by parabiosis experiments. There is ongoing research at Stanford, Berkeley, Harvard, Alkahest and now Altos Labs. 

The next steps are crucial, and they will require more investment than Harold and Akshay’s Yuvan Research has available. I hope Yuvan will partner with a laboratory that has resources to analyze E5 and then test constituent ingredients to optimize rejuvenation effects with a minimal set of injected proteins.

Preliminary results from lifespan studies with E5

Harold Katcher has developed a protocol for lab rats using intravenous injection with a blood plasma fraction he calls “E5”. Three years ago, he announced that treated rats evinced many features of rejuvenation, including improvements in grip strength, endurance, and learning capacity. Two years ago, he announced that treated rats also were epigenetically younger, according to a rodent methylation clock developed by Steve Horvath.

This year, with a grant from Heales Foundation, Harold and his partner Akshay Sanghavi have supervised a trial in which older rats were treated with E5 and then allowed to live out their full lifespans so we might know whether epigenetic and phenotypic rejuvenation translate into increased life expectancy. Just this week, I obtained from them birth and death data for the experimental rats. There were 8 control rats, untreated, all dead, and 8 treated rats, 5 dead and 3 still living.

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Executive summary of my findings: At any given age, treated rats are 4x less likely to die; but translated into life expectancy, this is less impressive. The rats are living a little longer, but not nearly so much as their methylation age would have predicted. There is good evidence for compressed morbidity — treated rats are healthier later in life, and their deaths are less spread out in time than control rats. Caveats: All rats in the epigenetic experiment were male, while all rats in the lifespan study were female. Also, the protocol was initiated at a later age in the lifespan study compared to the epigenetic study.

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Raw data: Time is the rats’ age in days. “Death” =0 indicates that 3 of the rats are still living. Group 1 is control, Group 2 is rats treated with E5.

How this data is analyzed

It is conventional and, IMO, also reasonable that the data on age at death are interpreted as a “probability of mortality”. Of course, deaths spread over a greater time period indicates a lower rate of mortality. Less intuitive, the rate of mortality is based on the number of rats that remain alive at any given time, and not on the total number of rats. Thus, when the first rat dies, its probability of mortality is just ⅛, but when the last rat dies, its probability of mortality is 1.0.

If a rat is still living it may contribute to the denominator only for rats who died earlier, and not for rats who died later.

Using these conventions, I produced the following plot for probability of mortality for the two groups. I have plotted probability of mortality on a log scale because it is an empirical fact that probability of death increases exponentially with age. This is called the “Gompertz rule”. If the Gompertz rule holds, then we expect the plot on a log scale to be a straight line. I have drawn the best straight line through the two sets of points.

The Gompertz distribution is characterized by two numbers. One is the base mortality rate, which is related to how early the animals start dying. The other is the mortality rate doubling time. The probability of death doubles again and again over the life of the animals. A short doubling time indicates that the deaths are all bunched together, and a long doubling time indicates that the deaths are spread out over a broader range of ages.

You can see that, compared to controls, the treated rats started dying later and that their mortality doubling time is shorter, with deaths bunched more closely in age.

There is substantial uncertainty in these conclusions because of the small number of rats, but there is enough data here to give us confidence in the basic conclusions:

• Treated rats are less likely to die young
• Once they begin dying, treated rats die faster than controls
• It is unclear from data so far whether maximum lifespan has been increased. We will have a better handle on this question when we see how long the remaining rats live.

One more concern about the experiment: Rats are social. Treated rats were housed separately from control rats, 2 or 3 to a cage. Just like people, rats are more likely to die after their cage mates die. I don’t have information about which rats were housed with which, but the death dates show some signs of being bunched together. This social effect could amplify the difference in mortality patterns between treated and control rats.

Cox proportional hazard

The most conventional way to analyze contingent survival data is called the “Cox proportional hazard model”, a relatively new statistical innovation introduced by David R. Cox in 1972. Many drug treatments and environmental hazards are reported on the basis of Cox models.

Result of the Cox model is reported as a “hazard ratio”, interpreted to mean that “if you do X you will be Y% more (or less) likely to die at any given time.”

The Cox model has the advantage that it is independent of the Gompertz rule or any other assumption about how mortality risk changes over time. It has the disadvantage that it can be misleading if the two different groups have qualitatively different mortality patterns.

The Cox model assumes that the difference between the two groups can be expressed as a simple ratio. If the Gompertz rule holds, a simple ratio translates (using the mortality rate doubling time) into an age change. For example, for humans in modern Western cultures, mortality doubles every 7 years. A Cox ratio of ½ is thus equivalent to rejuvenation by 7 years.

I’ve done the Cox analysis for Katcher’s rats because it is conventional, but my opinion is that its assumptions are not satisfied in this case. The mortality rate doubling time seems to change in the treated rats, indicated by the fact that the slopes of the two lines are different. So interpret the Cox results with this in mind.

Cox analysis indicates that the hazard ratio for treated rats is 0.24, meaning that treated rats are 4x less likely to die. The p value = 0.02, indicating confidence in the conclusion that treated rats are living longer than untreated. Increase in life expectancy is about 7%, which is 85 days for the treated rats. Again, these numbers can change when we see how the remaining 3 rats fare.

Conclusions

I have been committed to the idea that methylation clocks provide a real indication of biological age, and that reduction in methylation age will translate to a longer lifespan. My DataBETA study is premised on this hypothesis. There is good theoretical and indirect experimental support for the idea that epigenetics is a driving force behind aging (last week’s blog).

On their face, these new results suggest the possibility that methylation age might be decoupled from life expectancy. This is worrisome, but there are other possible interpretations of the situation.

We don’t have methylation results for the actual animals in the lifespan study. I’ve heard there was some mixup sending tissue samples to Horvath’s lab for analysis. There are various reasons these animals may not have responded to E5 treatment as well as the previous group.

Katcher’s rats are our best opportunity to answer this urgent question about a causal link between methylation status and lifespan. Fortunately, he is beginning another lifespan study with both male and female rats, which will follow more closely the protocol of the original study, but will extend in time to offer lifespan data. Unfortunately, the composition of E5 is still proprietary, so the minds of other scientists and the resources of other laboratories are not available to study the remarkable effects reported from E5. Wider collaboration is urgently needed to study lifespan and also to optimize dosage, timing, and delivery procedures. A collaboration with Johns Hopkins University has been announced by Katcher’s company (called Yuvan), but we have as yet no details.

Possible theoretical interpretation

I have written in the past about the Achilles heel of methylation clocks. Aging is like a civil war within the body. In youth, all metabolic systems are protective, but with age there are systems that attack and destroy the body. Examples are autoimmunity and inflammation.

Typically, methylation sites (CpG’s) chosen for inclusion in a clock algorithm are correlated with age. There are two possible reasons that an epigenetic change might be correlated with age, depending on which side of the civil war the system is fighting for. A given CpG might be associated with a self-destruction gene, or it might be a protective response to the body sensing higher levels of damage. The training algorithm, based on correlation with chronological age or even with mortality, is generally unable to distinguish between these two possibilities.

I have proposed on theoretical grounds that drivers of aging ought to be more common than responses to damage. Methylation clocks are only useful for evaluating anti-aging interventions to the extent that they are based on genes that drive aging. It’s only through experiments like Katcher’s that we can learn if our methylation clocks have been contaminated with genes that protect from damage.

These preliminary results are a signal of caution and a call for more research, but the evidence is indirect and the results are too thin to change theoretical perspectives now.

I have promoted the idea that aging is programmed and that the program is epigenetic. Hence epigenetic age is fundamental. But what is it that imprints epigenetic age on the chromosomes and keeps it updated? Is the “methylation clock” responding to a higher authority, a separate clock which coordinates epigenetic age throughout the body? Do epigenetic clocks in different tissues talk to each other? Such questions are important not just for theoretical understanding, but also because they have two practical consequences. (1) Can we rejuvenate the body with system-wide signaling, or do we have to de-age cell-by-cell?  (2) Can we be confident that if we set back the body’s methylation age the person will feel younger and live longer? 

I have been reading and thinking about these questions for several weeks, and I can report no clear answers.

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Is aging a cell-by-cell deterioration, or is it orchestrated at the level of the whole body and managed through signal molecules in the blood? If pressed, I think everyone would have to admit there is some of each, and differences within the community of aging biologists are about the relative importance of the former vs the latter.

One thing I think we ought to be able to agree on is that the system level, including signal molecules in the blood, makes a vastly more accessible target for anti-aging interventions. Repairing the body cell-by-cell is a daunting proposition; whereas modifying levels of signal molecules in the blood is a piece of cake, once we identify those molecules and determine their optimal youthful levels. The words “low-hanging fruit” come to mind, as well as “Pascal’s wager”.

If there are multiple, independent aging clocks, it is probable that the one that registers the oldest age is the one that can kill us, independent of the others. To make the big leaps in life extension that we are looking for, we probably will need to reset all the clocks. How much do the cell-level and system-level clocks talk to each other? How much progress can we expect to make by working at the (more accessible) system level without addressing the (more challenging) cell-level aging?

Why is the preponderance of research devoted to aging at the cellular level? A small part of the explanation comes from scientific inertia; aging was understood in terms of increased cellular entropy for many years, whereas the paradigm of central control remained in a Russian backwater until publication of the Stanford parabiosis experiments in 2005. A larger part of the explanation has been the infusion of venture capital into aging research in the last decade. You can’t patent hormones and you can’t make money from rebalancing blood levels of the body’s native signal molecules. I believe that the profit motive has deeply corrupted aging research, as it corrupted medical research through the previous century.

I am passionate about these issues, but I leave them aside to talk about questions of fundamental interest: Differential gene expression—epigenetics, and methylation in particular— seem able to change the body’s age state. It seems clear that gene expression is the primary way in which the age state of the body is transmitted and coordinated system-wide. But is gene expression the end of the line, the ultimate upstream aging clock? Or is there a “higher authority” that keeps track of time and programs the body’s methylation, etc accordingly? Does the epigenetic state of the body constitute an autonomous time-keeping mechanism, or is there a time-keeping reference clock, perhaps in the hypothalamus, which dictates the body’s age through secretions, and distant cells respond to these secretions by adjusting their methylation patterns?

And, if the answer is that methylation constitutes an independent clock, does that clock advance cell-by-cell independently, or does gene expression at the cell level export proteins that coordinate methylation age across the body?

I don’t have answers, but several experiments bear on these questions, and offer a nuanced outlook.

The practical question

We need measures of biological age in order to efficiently tell us when we are on the right track with an anti-aging intervention. Methylation clocks are presently the best technology we have for measuring biological age. So, can we be confident that if an intervention sets back the methylation clock that the intervention really is making a person (or animal) younger?

Reasons to think yes:

• Methylation clocks track chronological age better than any other biomarker
• Some of the difference between methylation age and chronological age is meaningful. It correlates with mortality. In other words, each of the major methylation clocks is a better predictor of life expectancy than chronological age. Remarkably, this is true even for the clock algorithms that were trained only on chronological age.
• There are theoretical reasons for believing that epigenetics is the primary driver of aging, so that methylation changes may actually be close to the causal nexus of biological age. (This conclusion is especially cogent for theorists like me who believe that aging is an evolutionary program; however, there are also prominent scientists in the field who reject programmed aging but embrace epigenetics as a primary driver of aging.)

Two things that could go wrong:

• There could be a higher authority, a centralized clock that sets up the methylation state. If this is the case, then setting back the body’s methylation age may be temporary, and the methylation state will revert to the age programmed by a central clock. (Cavadas and Cai have adduced evidence that aging signals are transmitted from the hypothalamus.)
• In the worst case, methylation changes with age could be an adaptive response when the body senses the accumulation of damage. In other words, the body changes its gene expression when damaged because it is working overtime to repair that damage. In this case, resetting methylation state to a younger age just makes the body less able to cope with the consequences of aging and actually shortens lifespan.

Evidence from parabiosis

In parabiosis, a young mouse is surgically joined to an older mouse of the same genotype. Tissues of the old mouse respond by becoming functionally younger. Since this 19th-century finding was brought to the modern scientific community, the search has been on for chemical factors in the blood that either promote aging or promote youth. [read more].

The parabiosis phenomenon and related findings in rejuvenation through blood plasma transfusions has led to a paradigm that says aging is coordinated throughout the body by signals in the blood. To the extent that single cells age, this is happening under central control, and the process can even be reversed if the cell is exposed to the right signals.

BUT

Evidence from bone marrow transplants

Bone marrow transplants are the most powerful available treatment for leukemia, and are also applied for some rarer diseases. The bone marrow comes with the epigenetic age of the donor, and thus the (white) blood cells subsequently generated by the transplanted bone marrow also carry age information. Several different studies [ref, ref, ref, ref] have found consistently that the white blood cells (and presumably the bone marrow from whence they came) retain the age signature of the donor. The donor may be younger or older than the patient. In either case, the methylation age of the patient’s white blood cells—post-op and for years afterward—remains keyed to the donor and does not correlate significantly with the patient’s age.

The lesson of parabiosis experiments was supposed to be that cell aging is not cell-autonomous, but rather a response to signals in the blood that instruct the cells what age to be. Young somatic cells could be aged rapidly in an old blood plasma environment, and — more impressively — old somatic cells could be made younger in a young environment.

Now we have a series of bone marrow transplant studies where the methylation age of the donor is the determining factor, not the patient into which the marrow was transplanted. Bone marrow contains the stem cells from which blood cells grow. Blood cells turn over every few months and they represent an accessible tissue sample which reflects the age state of the bone marrow in approximately real time.

“We found that the DNAm age of the reconstituted blood was not influenced by the recipient’s age, even 17 years after HSCT, in individuals without relapse of their hematologic disorder.” Soraas et al (2019)

This seems on its face to contradict our paradigm from parabiosis that says cell age is not cell-autonomous, but is programmed by the environment. How can we interpret the two results together? Some possibilities…

• Maybe only differentiated somatic cells are susceptible to age programming by plasma proteins, and not stem cells.
• Maybe these stem cells are providing the biochemical environment in the plasma. Maybe the stem cells and the white blood cells that they generate are the agents that secrete the plasma proteins responsible for sending age signals.
• Please think creatively about other possibilities.

Another result from these bone marrow studies

Consistently, the blood cells get older after transplant, whether they are transplanted from young-to-old or from old-to-young. This says two things. First, the point of comparison is the donor age, i.e., the age of the cells pre-transplant, and not the age of the patient who is associated with the systemic environment. Second, the cells seem to age rapidly after transplant, as measured by the methylation age. From there, the age of the cells may (in some studies) revert slowly to their original age trajectory over a period of several years.

Why the rapid methylation aging? It seems like a good guess that the rapid aging initially comes from high rates of reproduction in these transplanted cells that are generating a whole new source of much-needed blood. Could this be a link between telomeres and methylation age (which previously were found to be inversely correlated? Or is there another mechanism by which stem cells keep track of the number of times they have divided asymmetrically?

Am I the only one asking these questions?

Already a decade ago I was thinking about the question How Does the Body Know How Old It Is? Questions about time-keeping mechanisms and coordination of age information through the body go hand-in-hand with conceptions of aging as a programmed phenomenon, and perhaps the prejudice against programmed aging helps to explain the fact that few aging researchers are thinking in this way. A welcome exception is this article by Argentine gerontologists, which I was delighted to discover just yesterday. Lehmann et al:  Hierarchical Model for the Control of Epigenetic Aging.

Although there is evidence suggesting that the cellular epigenetic clock possesses an intrinsic ticking rate [ref, ref, ref] multiple observations at organismal level in humans and other mammals lead to the inference that in vivo, the ticking rate of the clock in tissues is synchronized by a master pacemaker.

Lehmann cites as prima facie evidence for this

For a given chronological age, it was found that in DNA samples taken from whole blood, peripheral blood mononuclear cells, buccal epithelium, colon, adipose, liver, lung, saliva, and uterine cervix, Horvath’s algorithm read essentially the same epigenetic age, the only exceptions being some brain regions and very few other organs.

In addition, she cites Katcher’s success in rejuvenating rats (and their diverse organs) using only a set of intravenous signals. The article goes on to propose a model in which there are four time-keepers in the body, coordinated by signals in the circulatory systems. The four are:

1. Methylation
2. Light-sensing and neural processing
3. Neuroendocrine signaling (esp the suprachiasmatic Nucleus of the Hypothalamus)
4. The Immune system, including thymic involution

Curiously, she does not include the replication counter implicit in telomere shortening, which Fossel, Blasco and other luminaries have adduced as the primary source of aging. I also would add that the hypothalamus is the best candidate we have, not just for one aging clock among several, but as a central, coordinating organ.

Fig. 1. Proposed organismal regulatory network in mammals. The diagram includes the autonomic nervous system (ANS, acting via neurotransmitters), the neuroendocrine system (NES, acting via blood-borne hormones), the immune system (acting via blood-borne cytokines and thymic hormones), the circadian clocks (acting via blood-borne hormones and neurotransmitters) and a putative pathway connecting the neuroendocrine network to the DNAm clock in organs and cells. All networks act on peripheral organs. Inset- Bidirectional interactions among all networks including (in red) the hypothetical DNAm network.

 

In addition to Lehmann, there is a 2021 review by Raj and Horvath, speculation from the horse’s mouth. They note that all the Horvath clocks are based on small differences in % of cells methylated at a given site (conventionally notated as β).

Increase in epigenetic age is contributed by changes of methylation profiles in a very small percent of cells in a population.

One way to interpret this fact (my speculation, not R&H) is that immune sensitivity, (anti-) oxidation, and inflammation are all under tight homeostasis in the body, because these are sensitive functions, balanced on a knife edge between insufficient protection and self-destruction. It is easy to tip the balance over toward self-destruction with small changes in the set point for a few signal molecules in blood plasma.

Another way to interpret this (again, my speculation) is that it is only a handful of cells at the tail end of the distribution that go over an edge into a state where they cause all the damage of aging. This hypothesis is consonant with the story about short telomeres, cell senescence, SASP, and the powerful benefit of senolytics. However, a big hole in the narrative is that it requires a set of CpG’s that would be capable of precipitously tipping the cell over into a toxic state. We know that critically short telomeres can do this, but there is no study yet of methylation-induced cell senescence. R&H speculate about such a mechanism connected with PCR=Polychrome Repressive Complex.

Raj and Horvath also stress the continuity between epigenetic changes that begin in utero, associated with development, and the changes that lead to senescence late in life. Blagosklonny as well has emphasized this point.

“Collectively, these five features of DNA methylation allow one to summarize with some degree of certainty that epigenetic ageing is a measure of change of epigenetic heterogeneity, contributed by a relatively small percentage of cells, seemingly in line with developmental processes that are conserved across species and begins very soon after conception. This seemingly inescapable deduction provides us with a reference point against which models and hypotheses can be measured.”

If I may carry the logic of these two experts one step further, I would emphasize the role that methylation has in determining what hormones and enzymes are secreted into the blood. Therein lies the possibility that intracell methylation clocks are coordinating, both with other cells and with other clocks, via signal molecules in blood plasma.

Other provocative findings that we might hope to integrate into a theory of aging

The methylomes of naked mole rats age at a normal rate, but the phenotypes of the rats themselves show no signs of age [ref]. Males and females age epigenetically in somewhat different ways [ref].  Methyl donor molecules in the diet can lead to a younger methylome, with benefits both for hyper- and hyomethylated regions (validated for MTHFR snps only) [ref]. When human fibroblasts are reprogrammed (with RNA) to turn them into neurons, they remember their Horvath age even after forgetting their identity [ref]. BMI is associated with accelerated methylation aging [ref]. Mice challenged with a high-fat diet can be brought back to normal weight with a normal diet, but accelerated methylation aging persists [ref]. Cessation of smoking decreases Hannum and Horvath DNAmAge [href]. The methylation shadow cast by years of smoking is a better predictor of subsequent morbidity and mortality than the smoking history itself [ref]. Methylation image of telomere length is a better prediction of age and mortality than is telomere length itself [ref]. Pregnancy increases Hannum Age, DNAmAge, and PhenoAge [ref].
(Apologies to Rafil Kroll-Zaiti)

Bulletin Katcher has been conducting a longevity trial for rats treated with E5 (background story here). Partial results suggest that treated rats are living statistically longer than untreated, but not as much as you would expect if the greatly reduced methylation age indicated full rejuvenation. The results are preliminary, and I will publish a full analysis in this space as soon as I can get the detailed dataset. The finding, if validated, suggests that multiple clocks in the body are not completely synchronized, and the “fastest clock wins”, meaning that it kills the animal no matter what the other clocks may say.

Conclusions

I am disappointed as you are in not being able to provide fundamental answers, but I hope that (together with Lehmann, Goya, Raj, and Horvath) we have provided a framework and a set of questions that can guide fundamental research. Very few other researchers are addressing these questions, and the answers will be crucial both for devising effective interventions and also for measuring the effectiveness of interventions that we already have.

Surviving Death: a journalist investigates evidence for an afterlife
by Leslie Kean

 

Readers of this blog are interested in life extension. We relish the experience of being alive, and we struggle with dread of death, and there is diversity among us how much relish and how much dread we harbor.

We believe in the methodology of science, and we look to biological science for solutions that will preserve our bodies from the ravages of age. Most of us subscribe to the scientific consensus that our bodies support our experience, our brains engender our consciousness, and without our brains, we would be nothing.

How do we respond when we are presented with scientific evidence that the brain is not the source of consciousness; that experience can exist in the absence of neural activity; that death of the body will change but will not necessarily end the experience that we relish?

If we believe in Science with a capital S, if we have faith in the community of scientists and the conclusions in which a great majority of scientists concur, we say, “This is not worth my time. I know it must be wrong. I’m not going to think about it.”

If, on the other hand, we believe in science with a small s—the scientific method, the gathering of evidence and the testing of hypotheses against all the available evidence—then we read Leslie Kean’s book, and our mouths hang agape, and we wonder how we can ever reconcile what she reports with the picture of the world that has served us so well all our lives.

The material in this book is so radical that if we accept that even some portion of it is reliable, and if we are honest and courageous enough to explore the consequences, then we must rethink our relationship to life extension and then begin to overhaul our relationship to life.

Reincarnation

Kean begins with a story that is stunning enough in its own right, but previously well-established by other researchers. Carol Bowman first interviewed the Leininger family and documented the story of their son, who called himself “James the Third” because he had previously lived the life of James Houston, Jr, a World War II fighter pilot who was shot down over Japan in the Battle of Iwo Jima (1945). As a three-year-old (in 2001), James the Third recognized and name parts of the plane that Houston piloted and the aircraft carrier from which he was deployed. From a period photo, he was able to identify by name other members of Houston’s flight crew as well as his two sisters.

The Leininger case is particularly compelling because it is well-confirmed and includes dramatic detail. But in other respects, it is representative of thousands of stories that have been collected at Univ of Virginia. Most of them involve a sudden, violent death in a previous life, leaving a lingering sense of incompleteness. Frequently, children have knowledge of details from their past lives, and occasionally, children will speak in languages that they were not exposed to in their present reincarnation. It’s called xenoglossy

It is natural to take thees stories as support for a traditional (Buddhist or Hindu) account of reincarnation. In that narrative, each of us is an immortal soul, and we evolve through a series of excursions when we assume physical form for the purpose of education via broadened experience. For the most part, we forget our past during each incarnation, but sometimes memories leak through the veil. Leinginer’s story validates part of this, but is subject to other interpretations as well. Memories may be transferred without any continuity of personality across incarnations. Children may spontaneously experience remote viewing or clairvoyance. If reincarnation is a thing, it may be rare or common, and not necessary universal. The story cracks open our dogmatic commitment to a materialistic perspective, but it does not compel a particular alternative.

Can such stories be consistent with the “conservative” view that consciousness is generated by the brain, with all knowledge and experience completely dependent on the physical brain? Only if we postulate new physics that transmits information, not attenuated by time or space, and that our nerves are evolved to take advantage of this yet-to-be-discovered effect. In my mind, this is more of a stretch than simply to adopt William James’s view that the brain is a transducer, not a generator of consciousness.

Near death Experiences

For Kean’s book, reincarnation is just an opener, and as her accounts stretch the limits of our reality to the breaking point, her voice becomes increasingly familiar and convincing. In the last chapters, she relates accounts in the first person, and, fantastic though they are, we find it hard to dismiss her because she has used 300 pages to earn our trust.

Near death experiences are another well-plowed regime for anyone who is open to reading the literature. People in extremis have memories of experience that took place while their EEG plots (electrical activity in the brain) were flatlined and they were technically dead. These often include tunnels with a white light at the end, meetings with deceased relatives, and spirit guides. On the one hand, the cases are more specific in what they can tell us about what it’s like to be dead. On the other hand, they are easier to dismiss as illusions or false memories or hallucinations of an oxygen-starved brain. Kean reminds us of the occasional cases where people with brains that are technically dead remember details of their resuscitation, the doctors or nurses in their hospital room. More occasionally, people report visiting distant relatives during this time. And there is just one case where a woman on an operating table experienced floating up from her body and seeing a sneaker on the roof which could not be seen from any point inside the hospital or from the ground. Her description of the sneaker was later verified.

Disciplining herself to remain objective, Kean acknowledges that reports from people who have had NDEs (and actual deathbed experiences) cannot prove that consciousness outlives the body. But she notes a general similarity between what NDEers report and the accounts of children when they talk about the time between incarnations.

Communicating with the dead

To appreciate mediumship, Kean opines, you have to be there. She incorporates a chapter by a credentialed researcher about rigorously controlled studies, but only after she relates in detail the experiences she had contacting her departed brother and another lost friend through three separate mediums. Some 80% to 90% of the details they report are accurate, including names and recall of specific conversations. But (says Kean), this can’t begin to convey the emotional intimacy of feeling a departed person’s personality coming through in the style and language of the communication. For each of the two deceased persons, Kean reports personal details known only to the deceased and herself, which the medium accurately references.

Is this evidence that the medium is in touch with a still-existing spirit of the deceased? Kean and her academic expert both admit that this is a difficult question. If the information is known to the sitter, then the medium could have obtained it through telepathy with the living (and if it is not known to the sitter, how can it be verified?) But mediums themselves report that the way information comes to them feels very different from telepathy, and EEGs of the same person doing psychic readings and mediumship seem to corroborate this.

Finally, Kean reports details of the compelling story of a man whose great uncle died on a battlefield of the Great War contacted him through a medium forty years later and related the exact coordinates of the unmarked grave site in which he was buried.

Physical appearance of the dead in seances

For some reason, it is easier for me personally to accept non-physical transfer of information than to believe in the physical incarnation of ghosts or specters. But by this point in the book, Kean has established herself as such a credible witness that these fantastical tales of her personal experience leave me baffled and perplexed.

The science that we understand gives us the technology for transportation and communication, for comfort and convenience. But the science that we don’t understand imparts to us a sense of awe and wonder, and motivation to continue our investigations in new and creative ways.

I am less concerned than Kean and her experts with distinguishing between explanations from telepathy and from post-mortem survival for the phenomena they describe. The big message for me is one of non-local mind. Once it has been established that mind has an existence that cannot be explained by functions of the brain—that, indeed, a part of the mind’s awareness appears to be untethered to any spatial location—for me, there is no longer any reason to suppose that the mind dies with the brain.

I carry with me from early childhood the memory of repeating the phrase, “I am Josh” and savoring an intuitive conviction of its absurdity. A part of me that was deeper than experience seemed to know that “I” am an abstract observer of this physical universe, and not a piece of matter within it. Today, this is just an intellectual curiosity, as I have long ago lost the cosmic expansiveness of the child’s experience.

I plan to continue pursuing life extension as a celebration of life rather than the hopeful forestalling of a dread event. And the sense of mystery and wonder that these anomalous phenomena provide continues to enhance the time I have on earth.

Antioxidants proved a bust for life extension almost 25 years ago, but glutathione stands out as an exception. We lose glutathione as we age, and supplementing to increase glutathione levels has multiple benefits, possibly on lifespan.

Glutathione is manufactured in the body via an ancient mechanism taking as input cysteine, glutamic acid, and glycine. Supplementing N-Acetyl Cysteine (NAC) and glycine are independently associated with health benefits, and possibly increased lifespan. Glutamine seems to be in adequate supply for most of us.

Each cell manufactures its own glutathione. (GSH is an abbreviation for the reduced form of glutathione.) Concentrations of GSH within a cell a typically 1,000-fold higher than in blood plasma. When we look for glutathione deficiency, we measure the blood level, because that is convenient. It is much harder to measure intracellular levels of GSH. These two studies [2011, 2013] demonstrated that intracellular levels decline with age more consistently and more severely than blood levels. People in their 70s have less than ¼ the glutathione (in red blood cells) that they had when they were in their 20s. The same study also found that intracellular levels of cysteine and glycine but not glutamate decline with age.

Supplementing with NAC is already known to boost glutathione levels. But here is a motivation to try a combination of glycine and NAC, dubbed “GlyNAC” to see if we can do even better. This work has been spearheaded by Rajagopal Sekhar.

In humans, “Supplementing GlyNAC for a short duration of 2 wk corrected the intracellular deficiency of glycine and cysteine, restored intracellular GSH synthesis, corrected intracellular GSH deficiency, lowered OxS, improved MFO, and lowered insulin resistance.” [Sekhar] Most of these benefits are theoretical. Lowering oxidation levels is a double-edged sword. MFO=mitochondrial fatty acid oxidation, and this benefit is on firmer footing. Membranes are made of fatty acids, and mitochondrial efficiency, like most everything in the body, depends on highly selective membranes. The crowning benefit is improved insulin sensitivity, and we can be fairly confident this leads to longer healthspan.

The two recent studies, in humans and mice, are indeed impressive.

The small human study found that “GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference.” Though they didn’t measure methylation age, this constellation of improvements gives us confidence that people were looking and acting younger.

In older (71-80 yo) subjects 24 weeks of GlyNAC supplementation raised intracellular GSH levels from 0.4 mmol to 1.2, compared to 1.8 in young adults. (Levels were measured in red blood cells.)

Two central players in aging are inflammation and insulin resistance; both showed excellent response.

Inflammation decreased markedly: Average C-reactive protein (CRP) dropped from 4.9 to 3.2 (compared to 2.4 for young people). IL-6 dropped from 4.8 to 1.1 (ref 0.5 for young). TNFα dropped from 98 to 59 (ref 45).

Insulin resistance fell just as dramatically, along with fasting glucose and plasma insulin.

Cognitive performance improved markedly! as did grip strength, endurance, and gait speed.

GlyNAC subjects lost a lot of weight — 9% of body weight in 24 weeks. This is both very good news and a hint that some of the benefits of GlyNAC may be caloric restriction mimetic effects, indirectly due to suppression of appetite or of food absorption.

Is all this evidence of a decrease in biological age?

But the effects faded weeks after the treatment stopped. This, I believe, is different from resetting methylation age. There is not a lot of data yet to test this, but I believe that methylation is close to the source of aging; in other words, the body senses its age by its epigenetic state, and adjusts repair and protection levels accordingly. Thus changing epigenetics to a younger state, IMO, effectively induces an age change in the body.

If this is correct, then my guess is that GlyNAC does not set back methylation age, based on the fact that the effects must be continually renewed by daily doses of glycine and NAC. On the other hand, mitochondria are such a central player in expressing multiple symptoms of aging that it may well be that continuous treatment with GlyNAC leads to longer lifespan.

…and indeed that is what was just reported in a mouse study. 16 mice lived 24% longer with GlyNAC supplementation, compared to 16 controls. 24% is impressive (see table below). For example, rapamycin made headlines a decade ago with an average lifespan increase of 14%. (In other studies, rapamycin was associated with even greater life extension.) The winner in this table is a Russian pineal peptide, which claims 31% increase in lifespan. I have previously bemoaned the fact that this eye-popping work from the St Petersburg laboratories of Anisimov and Khavinson has not been replicated in the West (though Russian peptides are now commercialized in he West). 

Table source: https://genomics.senescence.info/drugs/browse.php#details-549
(This is a sample — not a complete list.)

An asterisk must be placed next to the new 24% life extension from GlyNAC. Eleven years ago, Flurkey, found the same 24% life extension with NAC alone. NAC supplementation without glycine is known to increase glutathione production. Do we need glycine in addition, or is cysteine the bottleneck? Levels of both free glycine and cysteine decline with age. This would suggest that supplementation of both should be more effective than supplementing NAC alone. But I was unable to find any study that asked whether GSH levels are raised to a greater extent by GlyNAC than by NAC alone.

Glycine supplementation in large amounts mimics methionine restriction, which is a known but impractical life extension strategy.

If you decide to take glycine, it should be at bedtime, and in large amounts, a teaspoon or two. (I did this for awhile using glycine as a sweetener in hot chocolate soymilk, until I decided it ruined the taste of the chocolate drink. Whether this is a sound reason for tailoring an anti-aging agenda I’ll leave you to decide.)

All this work comes out of the laboratory of Rajagopal V. Sekhar at Baylor College of Medicine in Texas. It’s time that a broader life extension community joined in the action. I’m grateful to Dr Sekhar for commenting on earlier drafts of this article.

A methylation clock is an empirical construct. There is no understanding of physiology or metabolism built into the process. The clock is engineered to do the best job predicting (in the case of the GRIM-Age clock, for example) future mortality and morbidity based on methylation patterns. The whole process is agnostic about biological mechanism.

It is a legitimate question whether a drug or diet that sets back the methylation clock has actually increased life expectancy. Maybe methylation is a downstream consequence of aging, like grey hair or wrinkled skin. We would hardly expect a skin cream or hair dye to increase life expectancy.

For me, personally, this is an easy question. I have devoted much of my professional career since 1996 to opposing the “selfish gene” version of evolution and promoting multilevel selection. I have collected evidence that aging is a systemic phenomenon, centrally controlled, and that epigenetics (including methylation) is the primary way in which aging is enforced on the body. I was poised to believe that methylation clocks measure something real and important even before the first clocks appeared [2013].

Many other scientists looking at anti-aging interventions have been happy to take a practical approach, not invoking theory at all, but accepting the impressive correlations of aging clocks with other measures of biological age as good enough reason to trust that any intervention able to sett back the methylation clocks is probably setting back biological age.

Morgan Levine is a biostatistician par excellence. As a post-doc working with Steve Horvath, she developed what I consider to be the best, most usefull methylation clock..With her own research group at Yale, she has continued to innovate, with a promising approach based on the mathematics of principal component analysis [my write-up last September]

In a recent preprint, Morgan Levine has deeply questioned whether methylation clocks can be trusted in the way that so many of us have trusted them. Although young and just at the beginning of her career, she has done more than anyone except Horvath himself to advance methylation clock technology. For her to question the foundational value of her own work is a gesture of courage and deep intellectual honesty.

Before the post-doctoral work with Horvath that created the PhenoAge clock, Levine studied evolutionary biology of aging with the incomparable authority, Caleb Finch. She has her own ideas about the evolutionary origins of aging, and they are rooted in classical evolutionary theory. She sees the cause of aging as somatic evolution and accumulation of damage. She is deeply influenced by Peter Medawar’s [1952] hypothesis that what happens late in life is outside the influence of natural selection.

And so she raises the deep question: how much of epigenetic change associated with age is a driver of aging, and how much is a response to the body’s increasingly damaged state?

“Though the connection between risk and time may appear probabilistic on the surface, the emerging pathology is rooted in the molecular and cellular remodeling of the organismal system over its lifetime. Such changes likely result from accumulated damage, selection pressures at the level of cells, compensatory mechanisms, and/or the unintended consequences of a biological program. However, alterations to a complex system must abide by a hierarchical structure2, initiating at lower levels of biological organization (e.g. molecules) prior to manifesting at the higher levels in which they are typically observed (e.g. tissue and organ dysregulation and failure, and eventually death)3. Thus, to delay, prevent, or even reverse the maladies currently awaiting us in late life, we must discover how to decipher and remodel the molecular fingerprint of aging.”

Here, Levine is raising the most basic questions about the origin and meaning of methylation changes with age. Levine proceeds from her strongest skill—She is master of a wide array of sophisticated statistical tools.

Part of the classification has to do with Yamanaka programming, which is about stem cell vs differentiated cell. Another part comes from Framingham Heart study patients, and which CpGs change with age in FHS subjects. She distinguishes sites that increase methylation with age from others that decrease methylation with age. She associates some CpGs with cancer.

She maps Shores, Islands, and Open Seas. CpG islands are promoter regions of the genome that have lots of CpGs in close proximity. Shores are regions on the boundary of CpG islands, and Open Seas are regions in which CpGs exist as isolated, disconnected units.

Having divided 4779 CpGs into 12 groups, she can ask, How much of each group is represented in each of the most commonly used methylation clocks?

And which modules are performing best and most consistently across clocks?

Conclusions

Levine entertains the idea of “epigenetic drift” as part of the story, however she recognizes that the changes that underpin the most reliable clocks are not “drift” but clearly directional. She asks, to what extent do methylation changes cause aging and to what extent are they responses to various, incidental results of the aging process?

“If DNAm changes were purely reflecting entropic alterations or epigenetic drift, we would expect to see a bias against changes in CpGs that start around 0.5 (corresponding to random chance of methylation at a given site) . However, what we observe is actually a regression away from the mean, in which these heterogeneous populations of cells are systematically losing DNAm with time. This suggests that the green-yellow module’s notable pattern of epigenetic aging is unlikely to stem from noise or aberrant DNAm changes with age. Instead, DNAm changes may reflect cellular selection pressure or clonal expansion in which the cells without DNAm at these CpGs are able to outcompete (proliferate more than) the ones with DNAm . Alternatively, it could reflect a regulated compensatory mechanism that gets initiated with aging, or a continuation of a developmental program that is not turned-off . These scenarios have different implications for our understanding of epigenetic changes. The first would suggest that individual cells are not changing DNAm patterns with age, but rather the changes that are observed in bulk data are happening at the level of cell populations, shifting prevalence of cells with heterogenous states. The second and third scenarios, on the other hand, would suggest within cell DNAm changes, perhaps as a response to extracellular environment or signaling changes with aging (e.g. integrated stress response (ISR) ), or as an extended developmental program that fails to be extinguished—somewhat aligned with the hyper-function theory of aging . In moving forward, single-cell DNAm data may help distinguish individual vs. population changes.”

Here she references “Integrated Stress Response” as a theory of the aging metabolism. She also refers to Mikhail Blagosklonny’s idea that developmental programs have a momentum that spills over into aging phenotypes.

Morgan Levine is a brilliant scientist, facing the harshest possible self-criticism of her work. Her conclusions are tentative and open-ended.

A more definitive, empirical approach

The big, interesting question may not require theoretical analysis. What we want to know is whether we have been justified in using methylation clocks to indicate whether aging has been slowed or reversed. The most direct answer to that question comes from Harold Katcher’s rats, — the most successful example of setting back methylation age in a whole animal. Currently, Katcher has two sets of 8 rats that are the same chronological age; one group has been treated with E5 and has a much lower methylation age. He is waiting to see how long each group lives. So far, 3 of the untreated rats have died, and 1 of the 8 treated rats. Of course, the treated rats look and act much younger, and have physiological characteristics of younger rats. Over the coming months, the survival test will produce an answer to the important question whether a younger methylation age implies a younger biological age, in a form that is independent of theory.

One reason I love this topic is that I have centered my academic career around the thesis that aging is a socially-evolved phenomenon. Another is that it’s even more fun than intermittent fasting.

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There has been a great deal of prejudice against this topic since the most popular evolutionary theory of aging [1957] hypothesized (with scant evidence) a tradeoff between reproduction and longevity. Religious taboos probably have played a role as well. In insects, there is some evidence that sexual activity is associated with shorter lifespan. But we’re not insects, and the data for humans and other mammals supports a robust role for sexual activity as a promoter of longevity. (I last wrote about this topic in 2018.)

This is the classic longitudinal study by Davey Smith [1997] which, to my knowledge, has not been replicated since.  In males age 45 to 70+,“mortality risk was 50% lower in the group with high orgasmic frequency than in the group with low orgasmic frequency,” Twenty-five years on, there is no excuse for a corresponding study not having been performed for women, but there is indirect evidence that women, too, live longer if they have more intimacy and sex in their lives.

Enjoyment of intercourse was in the three top predictors of longevity in women [1982]. Women have been found to be more sensitive to the quality of loving attention and the depth of their connections in love, while men tend to respond to the cruder quantitative variable of sexual activity [ref]. Women (>57yo) who reported sexual relations that were highly satisfying had higher risk of cardiovascular disease, but women who reported most intense pleasure from sex had lower risk. “These findings challenge the assumption that sex brings uniform health benefits to everyone.”

Frequency of sexual activity is associated with later menopause in women, and later menopause is associated with longer life.

I’ve been an advocate of the theory that aging is programmed by signal molecules in the blood. Only a few of these have been positively identified, and among these, the hormone oxytocin is probably best established as a longevity factor [thanks to the Conboy lab]. Oxytocin is expressed in experiences of intimacy, and also in childbirth. It’s not much of a stretch to guess that oxytocin is responsible for some of the health benefits of sex and intimacy.

Hugging and cuddling decrease levels of cortisol. Cortisol levels increase with age, and higher cortisol levels are associated with poor health in the elderly.

It’s no surprise that competent erectile function is associated with less depression and higher quality of life in elderly men, but someone had to do the study. As you can imagine, it is difficult to establish a direction of causality. “For the time being, it cannot yet be proved that “good sex promotes good health” since good health also favors good sex.” [Gianotten 2021]

Sexual activity contributes to better sleep in both men and women, and good sleep is an important longevity factor. Frequent sex stimulates the innate immune system, our first line of defense.

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Long before modern methods and modern taboos

…there was an ancient literature associating sex with longevity.

In 1973, a Chinese tomb was excavated that had not been opened since 168 BC. Among other gems there in was the MaWangDui scroll. Harper translated and wrote about this scroll a few years later.

“The Mawangdui medical manuscripts bear the distinctive tendency of combining Daoist beliefs with medical knowledge. Some texts stress sexual intercourse as resembling the union of yin and yang. Others discuss sex’s benefits for physical well-being.” Although this, like all scholarly works of the era, was written from a male perspective, “the manuscripts emphasize the importance of women’s pleasure”. [ref]

The ms includes a poem which has been interpreted as a coded instruction manual for mystical sexual union.

There is a long Daoist tradition of sex ritual practiced to enhance health and longevity. There is also a prudish Confucian tradition which is scandalized, and seeks to suppress Daoist sexual practices. Consider this passage, already a thousand years into Daoism:

A man must not engage in sexual intercourse merely to satisfy his lust. He must strive to control his sexual desire so as to be able to nurture his vital essence. He must not force his body to sexual extravagance in order to enjoy carnal pleasure, giving free rein to his passion. On the contrary, a man must think of how the act will benefit his health and thus keep himself free from disease. This is a subtle secret of the art of the bed-chamber.

— Sun Si-miao, 7th Century Chinese scholar and medical researcher

Is it a pure rendering of the Daoist tradition, or is it tainted by defensiveness in the face of withering Confucian pressure?

“In the I Ching, the hexagram that symbolizes sexual union is the 63rd, called ‘Completion.’ It consists of the trigram for ‘water/woman/clouds’ placed over the trigram for ‘fire/man/light.’ This not only places Yin above Yang, it also suggests the image of water slowly coming to a boil over a fire. This is the quintessential Daoist image for human sexual intercourse, concisely symbolizing the essential differences between man and women in the sexual act. In order to last long enough to bring that cauldron of water to a rolling boil, the man must ration his fuel and carefully control his fire. If he burns his fuel too fast, his fire expires prematurely, leaving the water only lukewarm. But if he conserves his fire long enough to bring the water to a boil, then even the smallest flame suffices to keep it hot for a long time. — Daniel Reid

The yarrow tells of great good fortune now
(If not apparent yet, then very soon).
You’ve brashly prayed to God for Sun and Moon;
They’re granted! for your wish conforms with Dao.
You did not take the blame when things went wrong;
You must not gloat now that your luck has turned
No matter what you do, you won’t be burned,
But gains will be much greater if you’re “strong”—
Which just means “humble”—both connote the same.
To recognize that all depends on you,
Yet curb your will, avoid the urge to do,
Dissolve the Self, let intuition through,
Release control and laugh, forget your name—
No pride, no virtue, no judgment, no shame.

— poem by JJM, from the I Ching Sonnet Project

Denis Noble, a medical professor at Oxford University, has a recent article describing an ancient Oriental literature of sex and health, and placing them in a modern, scientific context. (Noble has been an articulate advocate for expanding the Darwinian tradition beyond the Selfish Gene.)  He cites studies of telomerase activity related to physical intimacy and touts the powerful rejuvenation effects of spermidine on mitochondria, autophagy, and other aspects of aging.

Leslie Kenny is an Oxford medical researcher who is familiar with the ancient Daois traditions around sex and longevity. She

“wondered aloud whether the reason for arousal but non-ejaculation was so that the man would resorb his own spermidine and thereby benefit from a boost in cellular autophagy and the resulting beneficial biological effects. I too had wondered about the possible benefits of resorbing sperm to male health.”

Noble speculates about the traditional exchange of saliva in some of these ancient Chinese texts. Saliva contains exosomes, virus-like packets of DNA and proteins that transmit information both within the body and between individuals. The Chinese scrolls emphasize

slow and gentle movements, beginning with caressing of what seem to be the mysterious energy meridians within the body…Breath, gaze and heartrate between lovers become synchronised during foreplay until actual coitus occurs, but it would be harmful for the man to consummate the love act at this point. The text of Su Nu suggests that consummation should occur only 3 times out of 10, and only with a woman when wishing to conceive a child. All other uses of a man’s precious bodily fluids – in this case, semen – would be viewed as exhausting the man’s body, ageing it prematurely. Whereas a woman and her yin energy were greatly strengthened by reaching climax, this was to be avoided at all costs by the man, whose yang energy would be robbed.

Noble closes:

“As the 20th-century French sinologist Marcel Granet put it, sex for the ancient Chinese was ‘far more sacred than for us’. It can be so once again for us too.”