Imagine Horvath’s thought process last year, when the PhenoAge clock (described last week) was derived. In order to evaluate anti-aging interventions in humans, the most useful measure would be a clock that estimates not how many years since your birth but how many years until your death. The 2013 methylation clock and the (non-methylation) blood tests combined to create PhenoAge both did a good job, and there was little overlap between the two. So combining an epigenetic/methylation measure with non-methylation blood tests might be the basis for an even more accurate estimate of time-to-death. There are also life-style factors that could be factored in, e.g., smoking, diet, exercise, socio-economic status.
Last spring, Horvath set his insightful project scientist, Ake Lu, to work on their “GrimAge” clock (named after the grim reaper). But a funny thing happened on the way to the spreadsheet. They started with a large training set of 2400 blood samples from the Framingham Heart Study, which has been collecting data since 1948. They supplemented the methylation data with blood markers and the known smoking history of each patient to create a composite index. The next step was standard statistical procedure: quantifying the overlap between the methylation and non-methylation data to eliminate redundancy. For example, they asked: to what extent is smoking history already reflected in methylation status? The surprising result was that the methylome already knew all about the smoking history and the body’s response to it. In fact, the methylation sites associated with smoking history predicted how long the person would live more accurately than the smoking history itself.
Remember from last week that the PhenoAge methylation clock was derived from the PhenoAge blood markers, and that the methylation version did not do as good a job at predicting mortality as the blood markers from which it was derived. This is the expected situation.
But this time, Horvath and Lu were confronted with a case where the information they had hoped to use to supplement methylation data was actually reflected in (different) methylation data, and the reflection worked better than the original. The methylation changes–presumably a response to smoking–told more about each person’s health risk than did the smoking history itself. Even stranger, the methylation marks most closely associated with smoking were found to be a powerful indication of future health even when the sample was confined to non-smokers.
If they continued undeterred on their original plan to add smoking status as a health indicator alongside methylation status, then the coefficient for smoking would have to be positive; yes, the math was telling them that, after allowing for all the information in the methylation profile, the extra information that a person had been a heavy smoker would actually lengthen the estimate of life expectancy, after the methylation response to smoking had been taken fully into account.
What could this possibly mean? Lu and Horvath don’t speculate on this point, but here are the three possibilities I can think of:
Smokers are not reporting their history accurately, perhaps from shame or from censored memory. The methylation response is actually a better indication of the number of pack-years smoked than the person’s memory of the number of pack-years.
The lung damage by smoking is highly individual. Each person’s response to smoking depends both on the number of cigarettes smoked and also his susceptibility to damage, and these two factors are reflected in the methylation pattern, which is a response to smoking.
Most radical of all is the possibility that smoking kills not directly by damaging the lungs and arteries, but indirectly by inducing the body to alter gene expression toward an older, less healthy state. Radical, yes, but the only one of these three ideas that might explain why the methylation patterns predict mortality in non-smokers.
Rather than continue with this perverse conclusion, Lu and Horvath pursued their analysis with redoubled respect for the power of methylation indicators to predict age and age-related health. They looked for other markers–blood levels of certain proteins that might supplement methylation data in their Grim Age clock. And they found the same phenomenon as with the smoking. Yes, the blood markers held information about the individual’s future health prospects, but each marker also had its image in the DNA methylation pattern, and in several other cases (e.g. PAI-1 and TIMP-1) the methylation based surrogate marker was a better predictor of lifespan than was the original plasma protein level from which it was derived.
Some of these proteins will sound familiar to aging researchers: GDF15=Growth differentiation factor 15 (which should not be confused with GDF11). CRP=C-Reactive Protein, is a well-recognized marker of inflammation, which contributes to all diseases of old age. Others are more obscure. Cystatin-C is a blood marker of kidney function that more recently has been found to be a robust predictor of cardiovascular outcomes. TIMP1 is a protein that displays an impressively tight correlation with age, but I couldn’t begin to describe its biochemical function.
The article calls attention to the gene PAI-1, which I had never heard of. Plasma Activator-Inhibitor 1, aka, SERPIN-E1, regulates blood clotting, which is an important contributor to heart attacks and stroke. Later in life, de-methylation of suppressor regions in a chromosome causes more PAI-1 to appear in the blood, leading to increased heart risk. For no apparent reason, PAI-1 turns out to be a powerful predictor of heart disease, diabetes, fatty liver, and of age-related disease in general.
I would have liked to see correlation coefficients for all these measures because p values get better with more data, even if the correlation is weak. r tells you how much scatter you can expect if you try to extract information from the methylation profile of an individual or group of individuals in the future, but p only reassures you that yes, the correlation is not the result of chance. Horvath responded to me that there are technical reasons that r values cannot be inferred directly using the kinds of data on which his calculations were based.
Direct vs Indirect
Here’s another paradox. The DNAm GrimAge clock was developed in two stages, a correlation of a correlation. How does it compare to a direct, single stage computation of the methylation pattern that best predicts mortality (in technical language: a linear regression of time to death on the methylation profile)? In the Supplemental Materials published online with GrimAge, Horvath and Lu compare their GrimAge clock to Zhang’s clock (see last week) and to their own single-stage computation, developed for this purpose. Curiously, the indirect computation yields the better result. Why? In an email message, Horvath said he is just as surprised and puzzled by the result as I am.
An implication for Anti-Aging Lifestyle
Aside from the corroboration that we shouldn’t smoke cigarettes (duh), there is just one other direct implication for lifestyle in the GrimAge paper. They report longer life expectancies for people taking omega 3 supplements. The effect was on the edge of statistical significance, and more pronounced in men than in women. But it corroborates results from human epidemiology. A word to the wise.
Why the methylation clock is able to detect omega 3 supplements is again puzzling. We imagine that omega 3 in the diet acts directly on the lipids in the bloodstream, and that is where the health benefits come from. But it seems that dietary omega 3 affects the methylome as well. If this were just a response to the blood lipids, we would not expect it to correlate so well with the aging clock. Once again, the methylation clock is proving more robust than even its proponents would have guessed.
Methylation clocks to evaluate life extension technology
I have been enthusiastic about the potential of methylation clocks to screen life extension interventions and tell us what works. In fact, I’m organizing a trial in humans to test many common interventions and their interactions. If we think of the methylation clock as a faster, cheaper replacement for lifespan statistics, then the DNAm GrimAge clock is the latest and greatest tool we have. It is thus important to ask, what is the evidence for a close correspondence between interventions that slow the methylation clock and interventions that lengthen life expectancy? In short, there is evidence of a close but not perfect correspondence. I reviewed the evidence last year,
Eating red meat shortens life expectancy, and indeed it increases GrimAge. Conversely, vegetables, nuts, and fruits in the diet increase life expectancy and they lower GrimAge. HDL levels in the blood are good for longevity and lower GrimAge. Markers of inflammation are associated with faster aging, and also with higher GrimAge. Blood sugar control is important for longevity, and it appears to be reflected in GrimAge. Perhaps less expected, higher levels of education and income are associated with longer life expectancy, and both seem to be robustly mirrored in methylation, as measured by GrimAge. Age acceleration from smoking is well-reflected in GrimAge. Early menopause forbodes and early death, and this, too, has fingerprints in GrimAge.
On the other hand, we think rapamycin is the best candidate yet for an anti-aging drug, and no significant effect of rapamycin on methylation age has yet been detected. Obesity is associated with life shortening, but only weakly accelerates GrimAge. Aspirin, metformin, and vitamin D are supplements that are thought to have a small but significant benefit for lifespan. Do the methylation clocks pick up these effects? I have not seen data that they do. The fact that methylation clocks correlate in the wrong direction with telomere clocks is puzzling.
And this study provides grounds for caution. Blood stem cells from the bone marrow were transplanted for medical reasons, and years later, the blood cells derived from the donor stem cells were collected and analyzed for methylation age. The result was that the blood cells remembered the age of the donor. They were not re-programmed by the new environment to match the age of the recipient’s body. While this result can’t detract from the accuracy of aging clocks based on methylation, it raises a theoretical and a practical issue. The result weighs against a theory (which has been a favorite of mine) that aging is programmed centrally, and that information about the body’s age is transmitted throughout the body by signals in the blood plasma. And it also calls into question the assumption (at the root of my Data-BETA study) that methylation clocks based on the blood will respond with the body if an anti-aging intervention is effective.
Other applications—other clocks
GrimAge takes the prize as the best candidate to replace the lifespan study, which is our current gold standard for evaluating anti-aging interventions.But there remain other uses for methylation clocks, and there is every reason to develop other clocks which predict other aspects of aging:
Brain aging–perhaps a composite of reaction time and ability to form new memories
Fast twitch muscles for sprinting
Mitochondrial efficiency and aerobic capacity
Cardiovascular age, from loss of elasticity in artery walls and stiffening of the heart muscle with glycation
Aging of the immune system
The Bottom Line
Horvath and Lu have given us the most accurate epigenetic predictor yet of future mortality and morbidity, and, surprisingly, it is based in methylation alone, and not the other blood markers and lifestyle factors that they had originally thought would supplement methylation. Horvath’s finding that secondary methylation indicators are more accurate than the underlying primary indicator from which they were derived is provocative, and calls out for a new understanding. It suggests that methylation clocks might be even more robust than we thought. On the other hand, the recent finding that blood stem cells transplanted from one body into another retain a memory of the donor’s age suggests just the opposite.
As I wrote last spring, we can efficiently test treatments for aging once we have an objective measure for the rate of aging. Without it, we’re left with the standard epidemiological: treating thousands of people and waiting for a few of them to die. I have predicted that methylation-based aging clocks will turn a page in the history of epidemiology.
Six years ago, UCLA biostatistician Steve Horvath realized the potential value of an aging clock and set out to measure human age using methylation markers in DNA from across the body. He used statistical pattern-recognition software to look for relationships between a person’s age and the methylation state of his DNA. Methylation is the best-studied of the epigenetic markers that control which genes are turned on and off, and different sets of genes are active at different stages of life.
thanks to the Horvath lab for this image
Age is an important predictor because the diseases that kill most of us all occur in a highly age-dependent way. In fact, the risks for cancer, heart disease, and Alzheimer’s disease all rise exponentially with age.
One statistical result from the original Horvath clock has a profound implication which aging researchers have been slow to take to heart: The Horvath clock was derived with statistical methods that looked only at chronological age. The algorithm was optimized to produce the best estimate of a person’s calendar age. Of course, age by the calendar is a good predictor of a person’s risk of death. In Americans over 40, the probability of death doubles every 8 years.
We should expect that since the Horvath clock is well-correlated to age and age is well-correlated to mortality, the Horvath clock should be correlated to mortality. (This isn’t guaranteed mathematically except when the two separate correlations are strong.) The interesting twist is this: The Horvath clock is more tightly correlated with mortality than age itself. The clock algorithm was derived from chronological age, so the math knows only about calendar years. But the clock algorithm predicts mortality better than age itself.
We can conclude that this extra accuracy of the methylation clock derives not from math but from biology. The message is that methylation is linked to the biological process of aging. Methylation changes don’t just happen over time; they are coupled to whatever it is that causes the risk of death to rise, linked, in other words, to aging itself.
With more recent developments in the clock, this conclusion gets stronger, and also stranger.
2017 The Zhang Clock
Yan Zhang of the German National Cancer Inst in Heidelberg has developed a methylation-based computation of mortality risk which is based on historic samples of blood from 406 people who died over a 15-year period and from 1,000 demographically-matched control.
They identify 58 sites that were tightly coupled to mortality. In 49 out of 58, less methylation was associated with a higher risk of death, and in the other 9, more methylation led to higher risk of death. (More methylation corresponds to less gene expression. The message is that increase in age-related mortality is due more to turning on genes that destroy us than to silencing genes that protect us.)
None (count ’em–zero!) of the 58 were incorporated in any of the previously published aging clocks (by Horvath and Hannum). What do we make of this? Age is associated with mortality more closely than any other biological indicator, and in fact mortality risk rises exponentially with age. And yet Zhang et al set out to look for methylation sites most closely associated with mortality risk, Horvath et al set out to look for methylation sites most closely associated with chronological age, and there was zero overlap between the sites they identified! In fact, less than half the sites they identified (23/58) had statistically significant correlations with age at all.
The recently established epigenetic clock (DNAm age) has received growing attention as an increasing number of studies have uncovered it to be a proxy of biological ageing and thus potentially providing a measure for assessing health and mortality. Intriguingly, we targeted mortality-related DNAm changes and did not find any overlap with previously established CpGs that are used to determine the DNAm age. [Zhang]
Part of the explanation may be that Zhang’s study was conducted in an older population (median age=62) at higher risk of death, and that the Horvath clock to which he compared it was designed to generally reflect age, from womb to tomb. Zhang says, “Methylation levels were measured on average 8.2 years before dying.”
Zhang’s mortality risk estimator is a count of how many of the 10 most telling methylation sites are in the “worst” quartile of his test population. (The “worst” quartile is the highest quartile for some and the lowest quartile for other sites.) A score of 5 corresponds to a 7-fold increase in mortality risk. This qualifies the Zhang score as one of the most powerful risk indicators that we have (don’t tell Aetna). For comparison, a BMI of 35 qualifies as “obese” and corresponds to a mortality risk ratio of only 1.36. Hemoglobin A1C, and HDL are common indicators of health status in older adults, and all of these have marginal associations with age-adjusted mortality. C-reactive protein and IL6 are blood markers of inflammation, and they were associated with risk ratios of 1.6 and 1.9, respectively [ref]. By this standard, the Zhang score is a big step forward.
Methylation is presumed to be under the body’s programmatic control. There are two reasons that methylation might be powerfully associated with mortality. First, some changes in methylation may be an indication of an acute response to some life-threatening stress; second, some changes in methylation may be part of an intrinsic death program associated with age. My guess is that there is some of each going on, but probably more of the former, since (as I said) only 23 of the 58 sites are significantly correlated with age.
Another curious fact: the methylation sites associated with smoking provided a better indicator mortality risk than was smoking itself. More about this below.
2018: The Levine Clock
Morgan Levine, working with Horvath at UCLA, developed a second-generation clock last year based on mortality and morbidity data as well as chronological age. The Levine clock was optimized with hindsight, factoring in age-related disease that occurred years after the blood was sampled.
Levine and her team worked in two stages. First, they developed a measure they call “phenotypic age” which includes age itself plus 9 modifiers that contribute to mortality risk.
Albumin: dissolved proteins in the plasma, including hormones and other signal molecules. Creatinine: this is a waste product cleared by the kidneys, thus a high value suggests kidney malfunction; but it can be confounded by exercise, which raises creatinine. Glucose: blood sugar rises with Type 2 diabetes and loss of insulin sensitivity. C-reactive protein: this is a measure of systemic inflammation. Lymphocyte %: the most common types of white blood cells. Mean red cell volume (MCV): the average size of red blood cells Red cell distribution width (RDW): standard deviation of the above Alkaline phosphatase (ALP): this is elevated in liver disease, including cancers and hepatitis. White blood cell count: total white blood cells of all types
The list surprised me. This was not a popularity contest; it was developed from statistical association with mortality, with no prejudices up front. I was not surprised to see glucose and CRP in the list (though I would have thought they would substitute A1C for glucose, because A1C is more stable, while glucose varies from hour to hour). I would have thought to find HDL and IL-6 in the list, and I was particularly surprised to see the strongest weighting was Red cell distribution width, which I had not heard of. RDW is measured as the standard deviation in volume of individual red blood cells (erythrocytes). It turns out that small red blood cells are a symptom of diabetes, while high RDW scores are associated with cancer and heart disease. There’s a modest association between RDW and Alzheimer’s Dementia.
Also curious: total white blood cell count is positively associated with aging diseases, while lymphocytes, a subset of white blood cells, has a negative association. So, what are the white blood cells that are not lymphocytes? These comprise neutrophils, eosinophils, monocytes, and basophils. Large quantities of these are a warning of bad health to come. Neutrophils are the largest category among these, and they are part of the body’s innate defense against cancer and infections. Lymphocytes, on the other hand, comprise natural killer (NK) cells and T- and B-cells. NK cells are part of the innate immune system, while T-and B-cells are part of the adaptive immune system, but all of these are indicative of good health and long life.
All these components were put together by Levine et al to form their measure of phenotypic age. The team then went on to stage two, looking for methylation sites that correlate best with their newly-defined measure of phenotypic age. 513 sites were incorporated in their computation (see below). This can be confusing: PhenoAge is the measure derived from the above 9 blood tests + chronological age. DNAm PhenoAge is the methylation clock derived from the PhenoAge blood test.
The resulting PhenoAge methylation clock (DNAm PhenoAge) correlates only about 75% with chronological age (compared to 94% for the original Horvath clock). But DNAm PhenoAge predicts mortality and morbidity far better than either chronological age or the original Horvath clock. As you might expect, the methylation clock which was derived from the newly-invented PhenoAge measure does not predict mortality rates as well as PhenoAge itself, from which it was derived. This is expected because the DNAm PhenoAge clock is targeted directly to predict PhenoAge, and only indirectly to predict mortality. I am only making a point of this because the story is different and surprising in the case of the new GrimAge methylation clock–described next week.
Fifty sites vs Five Hundred
The first step in producing a clock is to produce a list of individual methylation sites in order of how tightly they correlate with age. If you construct a clock out of the first few, you get the best correlation and the most accurate measure of age. But the measure is fragile, and the accuracy may be illusory. When selecting a few items out of a list of hundreds of thousands, there will usually be accidents and outliers, statistical flukes. By including more sites assures that the overall age measure is not unduly affected by any one site, so if a few of the correlations turn out to be statistical errors, the overall average is still quite good. Horvath has generally chosen to be conservative and sacrifice some accuracy for robustness.
Next week, the new GrimAge clock…
Methylation measurements have provided the most accurate measure of age and prediction of age-related disease, head and shoulders above other measures. But can we do even better if we supplement methylation data with other things we know about a person–not just other blood tests, but life style factors. When I visited Horvath last summer, he introduced me to his post-doc Ake Lu, who was working on a composite clock, based on this thinking: methylation plus. That was the origin of the GrimAge clock.
I say “rumors” because there is no publication and results from just 6 rats, all of which were sacrificed for the sake of tissue biopsies. Worse, we have no announcement of what the active agent(s) were that rejuvenated the rats, so discussion of mechanisms will have to wait. I’m writing this largely from personal and scientific trust, while recognizing that even the most careful and honest scientists can deceive themselves. “You are the easiest person to fool,” Feynman warned us.
Some of you may recognize the name of Dr Harold Katcher, who is one of the most prolific and best-informed among many well-informed readers commenting on this blog. I’ve known Harold for about 10 years. We came together because we have the same idea about what aging is. The difference is that I have only the evolutionary reasoning, the logical shell. Harold also has the background in biochemistry to fill in the details. Filling in the details is what he has been doing, and this week he convinced me that he has the most promising age-reversal intervention yet devised. His treatment protocol is in preliminary stages of testing, and because the ideas that he and I share are out of the mainstream, it has not been easy for him to get funding. Now that he has preliminary results, perhaps that is about to change. He is committed to bypassing the standard channel of Big Pharma, proceeding on his own with appropriate partners to assure that the the technology gets to a wide public at affordable prices–but it is early to think in these terms.
The heretical idea that unites Harold’s thinking and mine is this: Aging is controlled through evolutionarily conserved mechanisms. Some of the same genes and proteins that control the rate of aging in yeast cells serve the same function in mammals, which may live a thousand times longer than yeast. This implies that aging isn’t just random damage to individual cells; rather it is tightly regulated at the systemic level. Maybe there is a central clock, or maybe there is a consensus that is reached body-wide. But in any case, there is communication, assuring that different parts of the body keep to a common schedule. The natural place to look for this communication of the age state of the body is through signal molecules in the blood.
Thus our hypothesis, Harold’s and mine, is that even an old body remembers how to be young, if only it gets the message in the appropriate biochemical language. If an old mouse were to have the blood of a young mouse coursing through its veins, the old mouse would become a young mouse. Parabiosis experiments, sewing together mice of different ages so that they share a common blood supply, originated in the 19th century, but they took a leap into the 21st century beginning in the Stanford laboratory of Irv Weissman. His students spread out to Berkeley and Harvard, and the successors to these programs are studying the rejuvenation potential of various blood plasma components. (It’s not the red blood cells or the white blood cells. It’s not any cells at all, but the proteins and RNAs and short peptides that are dissolved in the blood’s clear liquid background, called plasma.) Some of the best-known people working on this idea are Mike and Irina Conboy at Berkeley, Amy Wagers at Harvard, Tony Wyss-Coray at Stanford. Two companies (Ambrosia and Alkahest) have begun selling transfusions of young blood to wealthy old folks, brave or desperate enough to experiment on themselves with untried technology, and to pay for the privilege.
Harold doesn’t have the funding or the university infrastructure that these people have, but by his report he has leapfrogged their research. He claims to have isolated the crucial molecules in young blood plasma, and that it is feasible in the not-too-distant future to synthesize them, so we’re not all running like vampires after 20-something men and women, bidding up the price of their blood.
His experimental results are preliminary, but impressive. On the one hand, there are big questions that remain; on the other hand, I’ve never seen success like this from any other intervention. (The possible exception is the Mayo Clinic’s work with senolytics, extending the lives of older mice; but the two approaches are so very different and what we know about the two is so different that there is no basis for saying one is more successful or more promising than the other.)
So, what were the results that we find so impressive? I’ve linked to his own chart of results, and I’ve asked Harold to tell us in his own words.
To tell you the truth, when I first was invited by my partner, Akshay Sanghvi to conduct research at a laboratory in Mumbai (India, formerly ‘Bombay’) I had a very definite idea of what I wanted to do. I wanted to transfer the plasma of a young rat, to replace the plasma of an old rat, which I have called Heterochronic Plasma Exchange (HPE). This idea was originally based on heterochronic parabiosis, which apparently resulted in rejuvenation at the cellular level in mice, but without the bizarre and cruel aspects of sewing two animals together; and yet, it should have more profound effects as 100% of the old animal’s blood could be replaced–while in heterochronic parabiosis, a young rat is half the weight of an old rat, so that the combined plasma circulation in the parabiots is considerably less than 50% young plasma. If it is assumed that there are ‘pro-aging’ factors in the blood plasma of old animals, those factors would remain. By using HPE however, sufficient rounds of plasma replacement should leave the old animal with nearly pure ‘young’ plasma. The greater concentration of youthful factors and the absence aging factors should push the cells and, eventually, the body to youthfulness.
Although transfusion technologies for humans are mature and quite safe, transfusing small animals requires state-of-the-art lab techniques. Try as we might, we could not perform plasma exchange in rats. Time was growing short (I was on a two-month visa) so what to do? I made the decision to completely change my approach: yes I believed HPE would work, but I decided to leap ahead, to see if we could make the process of HPE into a marketable product.
Our first pass was to try a combination of known herbal supplements that are known to bind with the targets we’d identified. We gave them to rats, and at first nothing seemed to be happening. But after two months (about 4 years in human terms) the rats showed signs of rejuvenation. We were encouraged. Rather than continue with the herbs, though, we formulated the elixir that we report on here. This is our first iteration, with dosage and timing determined theoretically, yet to be optimized in the lab.
We have addressed several different problems:
Identification and purification of youth-inducing factors and a process for their large-scale production. Our processes are scalable from microliters to metric tonnes
Raw material supply: we have gone beyond the need to obtain blood from young people, our sources are virtually limitless
Removal of the effects of ‘pro-aging-factors’. We have discovered a way to do that, one hidden in plain sight.
Here are our results. Notice the striking and simultaneous occurrence of increases in mental speed and physical strength coupled with lower inflammatory markers and blood glucose levels. Also encouraging is that these changes began days after the IV treatment, and the markers that were improved but not quite down to youthful levels continued to improve right up until the day of their sacrifice. It would appear that the changes induced are permanent, but it will take additional experimentation to confirm this.
Clearly, our next steps are
repeating and extending our rat results to include molecular and epigenetic signs of aging (Steve Horvath is developing a methylation clock for rats).
extending results to dogs (in collaboration with Dr Greg Fahy)
Looking for other molecular changes, including telomere length and various mitochondrial parameters
and, of course trying the elixir in humans.
I am looking ahead to envision an elixir that brings you back to apparent youth in a week and a day with no side effects. Time will tell, but I feel that the results we have at this point justify optimism.
— Harold Katcher
I’m full of questions, but Harold tells me these will have to wait until intellectual property is secured.
For some interventions, the body is made stronger and levels of tissue growth repair are restored to youthful states, but there is a cost in elevated cancer risk. This is something that will take time to determine, and perhaps working with mice would be better, since they have higher cancer rates than rats.
I would guess that a fully youthful phenotype will require restoration of the thymus, which shrinks severely with age both in rats and humans. The current report doesn’t mention thymic regrowth.
What would rejuvenation look like in humans? Physical strength and mental acuity are a great start. Would my eye lenses soften to youthful levels? Would I grow new discs between my vertebrae (and regain the 2″ I’ve lost in the last decade)? How about teeth and hair?
I’ve read that many blood factors are transient, with a half-life of seconds to minutes. I can imagine long-term effects from epigenetic reprogramming through blood factors, but I’m surprised this could happen without a continuous IV feed.
And, of course, I’m curious about the content of the elixir. Thousands of different compounds have been isolated from blood plasma, and hundreds that differ between young and old. I think of the Conboys as leaders in this field, and when I spoke to them less than two years ago, they had been unable to identify a small subset of key factors that would induce changes in the rest. Harold has said, “these factors are ‘bio-similar’ to factors already present in the blood, they work by natural means…”
The bottom line
I respect Harold’s caution in protecting his discovery out of the reach of Big Pharma. On the other hand, so many questions are not being addressed because his resources are limited. This is indeed a very promising start, and let’s hope that the appropriate connections come along so that further experiments can proceed without delay.
At year end, I have a tradition of writing a column more speculative and personal than usual. In this post, I consider critically the standard physicalist belief that our consciousness depends on a physical brain, and hence death is the end of all awareness.
I was 46 years old when I first considered the question, what is aging and where does it come from? Before that, I had been a physicist with diverse scientific interests pretty much all my life. What was I thinking? Why had I never considered this topic before? I think the answer is: fear.
Ever since I can remember, I’ve been interested in preserving my health and extending my life. But it was several years into a committed study of aging science that I thought to ask, why? Do I love life especially well, or am I afraid of death?
I’ve gradually come to realize that fear of death has cast a shadow over my thinking about aging, and possibly about many other other things as well. I was a young child when I taught myself to avoid thinking about death because I couldn’t handle the abyss of terror into which my thoughts spun. As I developed the habit of tiptoeing around thoughts and discussions of death, what was I missing? I’ve come to think that whole areas of my humanity became occluded, and have only begun to re-emerge in recent years.
In 1972, Ernest Becker wrote a book called The Denial of Death, which I knew even then that I ought to read. I bought it, but years went by and it never made it remained unopened on my bookshelf. Becker proposed that all of human civilization—art and literature, architecture, music, settlements and empires, stories of heroism, religious teachings, projects great and small—all of it stems from a drive to compensate for our mortality by creating something more permanent than our physical selves. Even if this is only a little true, we have to wonder: Who would we be if we weren’t trying so hard to avoid death?
The Bhutanese people are reputed to be the happiest in the world. Their mountains are majestic, their lifestyle modest and close to the land; but in this they are no different from many nations whose people seem to be pitiable. So what is their secret? Eric Weiner tells us that their culture is steeped in death rituals, and that death is out in the open in Bhutan. Bhutanese Buddhists contemplate their own death five times a day. Weiner goes on to cite studies that suggest thinking about death makes us more joyous. These studies wouldn’t convince anyone, unless they wanted to be convinced. Maybe I want to be convinced
Of course, Buddhism is pervasive in Bhutan, with its belief that our souls cycle through birth and rebirth in karmic cycles. Death is not a final end. The abyss that terrified me is not part of their belief system. I used to try consoling myself with such possibilities, but I got nowhere. This is not science, it’s wishful thinking. Religions have manipulated people with promises about life after death since the dawn of human civilization. I’m too smart to be deceived with such fairy tales. Even if it makes me afraid, even if it paralyzes me with terror, I prefer the realism of science.
But there came a point when it occurred to me maybe that the immortal soul was the reality and the fear was the delusion. Did I believe in the Great Void just so I could feel smarter than people who believed in heaven? I peeked out from my fear just enough to question whether the abyss was a scientific deduction, or merely an artifact of scientific culture. Science or scientism?
But there came a point when I wondered whether the self-delusion was in the belief that it was all wishful thinking. I peeked out from my fear just enough to question whether the abyss was a scientific deduction, or merely an artifact of scientific culture. Science or scientism?
Let’s backtrack to a different scientific myth. We have been effective in reversing the scientific prejudice that says human lifespan is a fixed, unalterable fact of our biology. Given the intellectual bankruptcy of this thesis, why would so many people, scientists especially, have embraced it for so long? One reason is the experience with being disappointed by charlatans, fooled by mountebanks, alchemists and snake-oil salesmen who have profited from their customers’ willingness to believe. Perhaps a larger reason is the fear of death that they have walled off with a kind of despair masquerading as science. Hope is often more frightening than despair. As Milton wrote, “So farewell hope, and with hope farewell fear.”
They leave their hope behind so they don’t have to face the discomfort of their fears. We have exposed their unreason.
Now, I wonder if we have been drawn into the same dynamic: that we have relinquished a hope that is too uncomfortable to carry. The hope we have relinquished is that the “self” persists in some form and awareness continues after physical death. For most of my life, I believed that physical reality is the only reality there is, that anything I feel as a “self” depends on 100 billion neurons and a blood supply.
And yet, my primary experience, the only thing of which I am truly certain, is that I exist as a point of consciousness, a primal self-awareness that all our science (as Chalmers has pounded home to us all) is powerless to explain. Many of us believe (with Dennett) that, since physical reality is the only reality, this primal self-awareness must be an epiphenomenon of neural activity in the physical brain—some would say an illusion created by computation. Maybe this is true, but there is no scientific support for this statement, nor does scientific evidence weigh against it. The statement that our feeling of self derives from computation is an article of faith, or of Scientism, rather than anything for which we can adduce evidence.
And for me, this idea is counter-intuitive. I have a meditation practice. I have studied astrophysics and quantum mechanics. I go for long walks in the woods and I allow my mind to run all over such topics, and the result until now has been for me to trust this feeling of selfhood more than I trust any reasoning about an alleged physical basis. The light of my awareness is a truth unto itself.
“Yeah, yeah,” says my scientific training, “where’s the evidence?” Evidence there is aplenty, but it is ignored by the scientific mainstream. Some of it is recognized as anomaly that we will understand someday, even though it seems strange now. The more direct kinds of evidence are actively suppressed, banned from mainstream scientific journals and exiled to the Journal of Scientific Exploration and other publications of mixed quality, where it takes some patience to separate the wheat from the chaff.
In the former category are some of the anomalies cited at the beginning of the Michael Levin video that I reported on last week. Caterpillars whose brains are literally dissolved in morphing into a butterfly, and yet memories survive. Monarch butterflies that pass memories about the route to return home over half a dozen generations. Ciliated protozoa that are capable of learning and memory, though they have no nerve cells. People who develop a musical ability or an interest in motorcycles or a vegetarian conviction when they receive a heart transplant.
In the latter category are a number of experiments for which the best source might be Dean Radin’s books, for example Entangled Minds and The Conscious Universe. There are near-death experiences, in which people have memories, often blissful and love-filled, from the time when there was no neural activity in their brains. Reflexively, the scientific rationalists dismiss these reports as fantasy creations of the oxygen-starved brain. But in many cases, the person recovering from an NDE reports things she would have no way of knowing if she had not been conscious during the time she was clinically dead. My introduction to NDE science was by Pim van Lommel. His latest book is Infinite Awareness. Similar stories have been collected by John Hagan, Chris Carter, Eben Alexander, and others. Finally, there is the scientific study of reincarnation, pioneered in the West by the late Ian Stevenson, professor of psychiatry at University of Virginia. His work has been continued by Jim Tucker at UVa and Raymond Moody (his book), Roy Stemman, and others elsewhere. Carol Bowman researched and documented one spectacular case of a Louisiana couple, non-religious skeptics, whose 2-year-old son had persistent nightmares, then displayed uncanny knowledge about the crash of a World War II fighter plane in Iwo Jima.
Why does the mainstream scientific community persist in dismissing all this research without evaluating it? Because it conflicts with a strictly-materialist, “scientific” world-view formed in the 19th Century, when the world of science was suffering under the delusion that every natural phenomenon might soon be explained by deterministic laws. A few decades later, quantum physics put that aspiration to rest, and offered a mechanics at the foundation of science that has room for mind, for intention, for Cartesian dualism, for those who see fit to interpret quantum mechanics in that light. Quantum mechanics may be 90 years old, but the scientific world has yet to absorb its message. In particular, it has been shown in independent experiments by Radin, Jahn, and others that the events that are treated as “random” in QM can be influenced by conscious intent, without any recognized physical connection between the brain and the quantum system. Furthermore, this connection is stronger when there is an emotional stake in the outcome, and its force increases non-linearly with the number of people whose attention is focused on a quantum target.
My tentative conclusion from this is that there is room within what quantum mechanics treats as “random” for (non-material) mind to influence material reality. And there is evidence from experiment and anecdotes that this actually occurs. Hence, the door remains open for a non-material locus of selfhood, or some aspect thereof.
“Despite the unrivaled empirical success of quantum theory, the very suggestion that it may be literally true as a description of nature is still greeted with cynicism, incomprehension, and even anger.” — David Deutsch
Aging is an extension of the developmental program into a phase of self-destruction. This much has become clear (if not yet uncontroversial) over the last decade. But this insight is of little use to us so long as developmental biology is so poorly understood. I have worked from a perspective in which development and aging are both driven by gene expression—an epigenetic program. Then, last week, I learned about an electrical dimension of developmental biology that is entirely new to me. I’m grateful to Johnny Adams for pointing me to a recent Stanford lecture by Michael Levin, summarizing two decades of research from his Tufts University lab.
Levin starts by contrasting the intelligence of an ovarian tumor (teratoma) with the intelligence of a tadpole under metamorphosis. The tumor has stem cells that can create organ tissue, teeth, bones, and hair—but their placement is haphazard, and therefore without function. The different tissues grow in every direction with no guiding logic or structure.
In contrast, the morphing tadpole knows exactly where it is going and what it wants to be when it grows up. Levin cites experiments from the 1960s in which a salamander tail grafted onto the side of the body turns into a functional leg, complete with foot and toes. In experiments in Levin’s lab, he moves an eye to the back of the tadpole head, and it migrates to its correct position as the tadpole becomes a frog.
Where is the information that tells the body how to form itself? In what form is the blueprint for the body’s shape and structure?
“Very much like the brain, Somatic tissues form electric networks that make decisions. The decisions are not about behavior, but anatomy.”
Nerve cells communicate by passing electric currents through ion channels and deploying neurotransmitters to pass electric charge from one cell to the next. Somatic cells use these same mechanisms to communicate with each other and decide where to go, forming into tissues and structures in a functional body. Using voltage-sensitive fluorescent dies, Levin and his colleagues have visualized the electrical structures that precede and determine corresponding anatomical structures.
This is radical. It is a new and unstudied mechanism of biology. Cells in a developing body are wired together electrically, and in their connectivity is encoded the structure of the body toward which they are aiming. The electrical connections work very much the way nerve cells in the brain do, but their purpose is entirely different. And Levin emphasizes that the time scale is very different. Electrical signals that make brains think and make muscles contract last for a few thousandths of a second. The circuits that code for bodily structure last for hours or days.
Extraordinary claims require extraordinary proof, and so Levin has been studying this system to manipulate it for almost 20 years now. Recently, his lab has cracked the code sufficiently to manipulate development and regeneration at a level higher than biochemistry. They have worked with planaria worms and developing amphibians, two experimental models that are capable of regeneration. They have experimented with rewiring the circuits, and now understand the system well enough to create two-headed worms and ectopic limbs on frogs.
The story of 21st Century biology has, thus far, been about gene expression. The body is controlled by chemical signals, and these are produced on demand by masking and unmasking different portions of the chromosome, exposing the code for the proteins that are needed in a given cell at a given time. Our activity and our homeostasis is maintained in this way from moment to moment, and I believe that our life histories, from development to aging and death, are also controlled via gene transcription.
Now comes Levin with a demonstration that, at least under some circumstances, there is a system upstream of gene transcription that is based on electric circuits. The system controls development at a level higher than gene transcription. For example, an entire eye can be ordered up by artificially creating an electric pattern in the right place, and the eye will have all its parts intact and be functional. They have placed eyes on a tadpole’s tail and demonstrated that the tadpole can see through them, and their brains can interpret the images.
Living fluids, within and between cells, contain dissolved salts in the form of positive (Na+, K+, Ca++, Mg++) and negative (Cl–, PO43-, SO42-) ions, Cell membranes have pumps that can pump ions out of the cell selectively and ion channels that allow some ions through, but not others. Typiclly, the cell has more negative than positive ions inside, so it has a negative membrane potential, ranging from a few mV for blood and skin to tens of mV for nerve and muscle cells. Rapid changes in membrane potential are the driving force behind muscle contraction and nerve firing.
There are drugs that can affect membrane potentials by blocking ion channels selectively. Membrane potentials have multiple signaling functions, most notably the potential has to drop close to zero before a cell can reproduce, and drugs that keep membrane potential high are able to inhibit cell replication. There are proposed applications for cancer treatment (inhibiting replication) and for regeneration (promoting replication). Within cells, different organelles also have membranes and there are associated intra-cellular potential differences. Mitochondria are the most negative parts of the cell, at about -140 mV.
DiBAC is a voltage-sensitive fluorescent dye that is used to visualize patterns of voltage variation in and around a cell. [ref] Patterns within a cell show locations and activities of the organelles. Patterns on larger, multi-cellular scales function like blueprints of development, and in animals that can regenerate, the patterns persist and guide later regeneration whenever limbs or organs become damaged.
How do they manipulate electric patterns experimentally, to demonstrate the effect on morphology?
This is not clear in Levin’s oral presentation, but an audience member asked the question. It is not done with external electric voltages. It is done with biochemical modification of the gateways that control ion channels. Levin drops a hint that there are photo-sensitive drugs that can control ion gates that can be used to translate a projected geometric image into a pattern of membrane potentials. He argues that the patterns encode “blueprints” rather than a “construction manual”, based on the fact that the program is adaptive in the face of physical barriers and disruptions, and organisms are capable of detecting damaged parts and growing new parts to the original specs. Levin’s group has tampered with membrane potentials in order to guide the growth of nerve axons in regeneratin tissue [ref]. This is just the beginning of the understanding that will ultimately be necessary to reprogram electric circuits to order for medical applications[ref].
In the Levin Lab publication list, there are 28 academic publications in 2018 alone. There’s a lot here to absorb, and it’s all new to me.
Levin was a computer scientist before he was a biologist, and he continues to be fascinated by the ways in which cells in tissues outside the brain can act as logic circuits. Gap junctions are bridges connecting adjacent cells, through which ions can flow, transferring charge. This is the basis of electric circuitry that supports complex logic. A post-doc in Levin’s lab designed a computer simulation that can model the activities of gap junction circuits. This paper from 2018 ALife Conference proceedings is a good introduction, with context and lots of references.
What does this have to do with aging?
I’m writing about this work more because I think it is potentially a paradigm shift, not because I think it has immediate implications for aging. Still, because I am who I am and you are who you are, I include possible implications for aging science.
Body parts become damaged with age. Regeneration will probably be a necessary part of any long-term anti-aging program. We’ve learned that robust regeneration is available in many invertebrates and amphibians, but it is switched off actively in mammals. The mechanisms remain latent, untapped, and there are examples of turning them back on. Bioelectric programming is a new avenue to explore for regaining control of mammalian regeneration.
I believe that the developmental clock continues seamlessly into an aging clock. The same timing mechanism controls both development and aging. If development is under electrical control, then we might find that there are electrical signal networks that trigger aging. I’ve written to Levin to ask if he is looking into this.
Some people in the anti-aging community are also interested in simulating the brain in a computer program, and they imagine that if my brain’s connectivity can be simulated in enough detail, the computer simulation will start to “feel like me”. For people who believe that consciousness is a function of the brain, and that computer modeling of the brain provides a path to a sort of eternal life, Levin’s work may be sobering. Knowledge and information processing take place not just in the brain but throughout the body, and not at the level of neural circuits but at the level of molecules.
The spirit of modern biology is the reductionist spirit of 19th century physics. Levin argues that we have been remiss in not exploring ways in which living systems are organized from the top down. I agree.
It is widely assumed in developmental biology and bioengineering that optimal understanding and control of complex living systems follows from models of molecular events. The success of reductionism has overshadowed attempts at top-down models and control policies in biological systems. However, other fields, including physics, engineering and neuroscience, have successfully used the explanations and models at higher levels of organization, including least-action principles in physics and controltheoretic models in computational neuroscience. Exploiting the dynamic regulation of pattern formation in embryogenesis and regeneration requires new approaches to understand how cells cooperate towards large-scale anatomical goal states. Here, we argue that top-down models of pattern homeostasis serve as proof of principle for extending the current paradigm beyond emergence and molecule-level rules. [ref]
This is a letter I wrote to a dear friend from the 1970s who has been diagnosed recently with colon cancer. She had surgery last summer to remove the primary tumor, and is in the midst of a 12-week course of chemotherapy. She has, in my opinion, a well-balanced view of the relative merits of traditional vs alternative treatments. One unusual thing about her situation is that she has an extraordinary social support system, having led a community of peer counselors within the disability community for many years, and now benefitting personally from the community of people she has helped.
We would like to be able to derive from the research on controlled clinical trials a “best bet” treatment option, but the data to support this inference don’t exist. One reason is that only chemotherapy has been tested with controlled clinical trials, and for your particular brand of cancer, the odds that chemo offers don’t look attractive. For alternative treatment modalities, we have only anecdotes and not controlled trials. Another reason is that cancer is an individual disease, more so than heart disease or infectious diseases. Different people respond very differently, and the medical community has not yet figured out how to tell in advance which treatments will work for which patients.
Western medicine profoundly misunderstands the nature of cancer. The classical understanding is that cancer results from a series of random mutations as the body’s stem cells divide, culminating in some combination of genetic abnormalities that enable a single cell to evade apoptosis and all the body’s defenses against cancer. In this paradigm, the root of the problem is in the DNA of the cell nucleus. But we know from experiment this is not true. When the DNA-nucleus of a cancer cell is transplanted into a normal cell, the normal cell remains normal, and when the DNA-nucleus of a normal cell is transplanted into a cancer cell, the cell remains cancerous [ref, ref]. I don’t pretend to understand the true cause of cancer, but I suspect it is related to the mitochondria at the cellular level, and to immune and other deficiencies at the system level that make the metabolism as a whole hospitable to cancer.
When our bodies are healthy, cancer is nipped in the bud, probably as a frequent and routine occurrence. Cancerous cells are induced to commit suicide (apoptosis) or they are marked out by the immune system and destroyed by white blood cells. Cancer arises as a clinical reality only when the body fails to do this. Western medicine makes the mistake of focusing exclusively on killing the cancer, without attention to re-balancing the body or strengthening the immune system so cancer cannot recur. In fact, chemo and radiation both damage the immune system, which you depend on to guard against a recurrence.
I’ve heard some doctors say, and I believe it’s true, that all cancer treatment modalities rely in the end on your immune system to kill the last few cancer cells and to prevent recurrence. When cancer recurs, is it because just one cancer cell managed to survive the onslaught of chemo, or is it because the immune system is so weak that the body is highly vulnerable to new instances? It is an academic question, because in any case we need a healthy immune system to survive.
At some point, our plan will be to switch over from killing the cancer to healing your body and restoring your immune system. Maybe we’re already at that point, after surgery + four chemo infusions. Maybe you’re ready now to make the transition. Cancer-killing treatments make you feel bad, accelerate aging, and damage your body. In contrast, healing and immune support will feel good in the present and will have beneficial side-effects for other aspects of your health.
There are many credible alternative cancer treatments out there. None of them is a universal cure, but all of them have worked for some significant percentage of people who tried them. The plan will be to choose an alternative clinic or a medication or a diet plan and try it for about 6 weeks. The proposal depends critically on having a sensitive and non-harmful test that you can do every 6 weeks for feedback on whether the treatment is working.
Don’t worry about weight loss. Most doctors will tell you to keep your weight up, even when you don’t feel like eating. They minimize the impact of fatigue from chemo on your commitment to exercise, even though we know that exercise is a significant anti-cancer strategy. I like to quote this 2014 study of women with ovarian cancer. The lower the weight, the longer the survival. After 6 years, all of the women with BMI>30 were dead, while ¾ of those with BMI<18.5 were still alive.
My proposal will take time. I believe you have time. You’re not going to die this year or next year, and we have time to try at least a dozen treatments. We don’t expect the first one or the second to work, but there’s a good chance one of them will. There are many, many stories of people who have banished cancer from their bodies. You’re the next success story, waiting to be told.
I propose that you tell your oncologist that you want to find out if the 4 doses of chemo have killed the great majority of the cancer, so that you can now strengthen your own system to handle the last few (chemo-resistant) cells. Tell her that you are open to returning to chemo in the future should it be necessary, but that for the next phase, you want to try a series of alternative treatments that are non-toxic and have only beneficial side-effects. Each of these has worked for some fraction of patients, and your expectation is that one of them will work for you. Tell her that you would like to ask her to work with you as an expert diagnostician, using blood tests and subjective state of health to tell when a treatment is not working, so you can move to the next option, and to tell you when a treatment is working, so you can stick with it.
(I believe PET scans are the most informative test for cancer, but your oncologist will know much more than I. PET scans are expensive, and I imagine that insurers discourage their overuse. More concerning is that the radiation dose is about 100 times a chest x-ray [ref], so we’ll be counting on your oncologist to come up with a less damaging battery of tests that you can do, perhaps as often as every 6 weeks.)
We have lots of candidate treatments to try, from the Moss Report, from the Polizzi video or a long list of herbal medicines, from your sources and mine. There are approaches that involve killing cancer cells with medicines that are much less toxic to your non-cancerous cells, for example, intravenous vitamin C, curcumin, cannabis, dichloracetate, and many others. A complementary approach strengthens the body’s resistance to cancer, especially the immune system. In the end, it must be your own healthy immune system that protects you from cancer. Reishi and other mushroom extracts, Cimetidine=Tagamet, Nigella sativa (kalonji seed), spirulina, and green tea extract are among many nutraceuticals that strengthen the body’s resistance to cancer. I want to remind you especially of the research of Valter Longo, a USC professor who has worked with fasting and diets that discourage cancer. There are alternative cancer clinics in Canada and Mexico and around the world that have cured some fraction of the people who have sought their help.
Almost all of these interventions have been attacked or dismissed as frauds. Sometimes this is because they really are frauds, and sometimes it is the medical community circling its wagons to avoid infiltration by researchers outside the mainstream. Until we look in detail at the accusations and the results, it is difficult to tell the difference, and even then we’re often left guessing. Much of the debunking is based on theory–“there is no credible biochemical mechanism by which xyz can cure cancer.” I take these pronouncements with a grain of salt, and look only at the empirical results. We don’t understand cancer well enough to dismiss anything on theoretical grounds
Any one of these options has a low probability of providing deliverance from your cancer, but you have time to try 10 or 20 of them, and there is a very good chance that you will respond to one of them. You are destined to become the next “miracle cure” cancer anecdote — we just don’t know yet which one you will be.
I’ve mentioned to you a fallback option, in the unlikely event we should find ourselves two or three years from now with a persistent, active threat of cancer. The last resort would be to replace your immune system with a bone marrow transplant from your niece (or another related donor, preferably younger). The upside is that the transplanted immune system absolutely will not tolerate your cancer, and will eliminate it promptly. The downside is that you expose yourself to “graft-vs-host disease”, in which your immune system also treats healthy cells as “foreign” and attacks them. This is a potentially fatal complication, and would probably consign you to immune suppressants for the rest of your life.
I’m in this with you for as long as it takes. So are your dear friends and family and the deep community of people who are full of gratitude for the years of love and attention you have offered them.
Senolytic drugs have been the most promising near-term anti-aging therapy since the ground-breaking paper by van Deursen of Mayo Clinic published in 2011. The body accumulates senescent cells as we age, damaged cells that send out signal molecules that in turn modify our biochemistry in a toxic, pro-inflammatory direction. Though the number of such cells is small, the damage they do is great. Van Deursen showed that just getting rid of these cells could increase lifespan of mice by ~25%. But he did it with a trick, using genetically engineered mice in which the senescent cells had a built-in self-destruct switch.
After that, the race was on to find chemical agents that would do the same thing without the genetically engineered self-destruct. They must selectively kill senescent cells, while leaving all other cells unharmed. It’s a tall order, because even a little residual toxicity to normal cells can be quite damaging. Before last week, the two best candidates were FOXO4-DRI and a combination of quercetin with dasatinib.
I’ve written in the past (here and here) that senolytic drugs are our best prospect for a near-term lift on the road to anti-aging medicine.
Last week, a large research group affiliated with the original May Clinic team published findings about fisetin, the latest and greatest candidate for a senolitic pill, another flavenoid, very close in structure to quercetin.
They grew senescent and normal cells in a test tube, then tested 11 different plant-derived chemicals for power to kill the one while leaving the other unharmed. The winner was fisetin.
(MEF stands for Mouse Embryonic Fybroblast, the cells that were cultured in the screening experiment.)
Fisetin is especially interesting because it is cheap, easily available, widely-regarded as safe, but not nearly as well studied as quercetin.
They took the winner, fisetin, and subjected it to a series of tests. They began with in vitro (cell culture) tests and proceeded to in vivo tests with live animals, culminating with an impressive life span assay in mice.
(The runner-up was curcumin, less interesting perhaps only because it has already been extensively studied. The curcumin molecule is unrelated to quercetin or fisetin, and is not a flavenoid. I can’t help but wonder if they had subjected curcumin to the same thorough testing that they reserved for fisetin, how would curcumin have fared?)
The paper’s principal findings were:
Fisetin has lower liver toxicity (at equivalent doses for senolytic benefit) than any of the other senolytics tested so far.
Fisetin reduces pro-inflammatory signaling in a short course given to mice and in long-term experiments where fisetin was added to the mouse chow.
Fisetin reduces number of senescent fat cells in a short course given to mice.
Mice fed fisetin for long periods had much more glutathione than control mice. (Glutathione is one of very few marker molecules that seems to be wholly beneficial.)
Most impressively, mice fed fisetin late in life lived 10-15% longer than control mice. This represents a 50% increase in the remaining lifespan after the intervention.
What we know and what we’d really like to know
We’d like to know, do humans who take large doses of fisetin live longer? Do they have toxic side-effects? These questions require decades to answer.
Does fisetin reduce age markers in humans, especially methylation age? This is a feasible study, since the test is mature and safety of fisetin is fairly well established for short courses. Perhaps this experiment is being considered; I’ve written to the corresponding authors of the most recent study, in case they haven’t already thought of it. This test would not be definitive because we know that methylation age is not perfectly correlated with biological age; but if positive it would confirm both that fisetin is accomplishing epigenetic rejuvenation and that methylation tests were correctly informing us of this; a negative result would be ambiguous.
It makes sense that senolytics should be taken periodically, not continuously. A high dose can be toxic to existing senescent cells, and then getting out of the way, it can allow normal cells to recover from any damage. This sounds like good theory, but different dosing regimens have not been tested experimentally. In fact, the new paper reports positive results from both high episodic dosing and lower everyday dosing.
The Mayo group had previously tested fisetin, and found it effective in killing some kinds of human senescent cells but not others. In previous tests, fisetin was found to be effective in senescent fat cells (pre-adipocyte, white adipose tissue), and that is where it was primarily tested in the new studies.
They note that the episodic treatment and short half-life suggest that the benefits of fisetin come from its senolytic action, rather than other actions as an antioxidant and signal molecule. They emphasize that clearing senescent white blood cells and making room for new, active white blood cells are activities that enhance the benefits of fisetin, since white blood cells contribute to clearing the remaining senescent cells.
If we choose to take fisetin at this stage in the science, we are early adopters, and our main concern ought to be safety. There is little doubt that killing senescent cells will be beneficial. But what is the toxic burden of fisetin, and what dosage can we safely take without risk of damage to normal cells? The current study covers a lot of ground but doesn’t answer this question, apparently because they are convinced that fisetin is quite safe.
Strawberries, apples, grapes, and onions all contain fisetin, but at low levels compared to a senolytic dose. For example, the highest food concentration, 160 ppm, is found in strawberries. A half pound of strawberries yields 36 mg of fisetin. We’re still guessing at the therapeutic dose, based on mouse studies, and the experimental dosage in human trials is about 1,000 to 1,500 mg (based on this clinical trial), the content to 30-40 pounds of strawberries on each of two consecutive days.
In the best cases, fisetin was shown to reduce senescent cell burden by 50% and up to 75% in cell cultures. This is a good start, and encourages us to think we can do better by combining fisetin with other agents, or perhaps with fasting.
It sounds impressive, but I’m not impressed. First, mouse models of Alzheimer’s have been discredited repeatedly. Mice don’t naturally get AD, so they have to be genetically engineered to do so, and the genetically modified mice don’t share the deep causes of human AD. Time and again, treatments have been found effective in the mouse model that fail to translate to humans. Second, the treatment used in the study to kill senescent brain cells also relied on another genetic modification, and would not be applicable to humans.
My guess is that effective senolytic agents for humans will be available within a few years, and that they will decrease risk of all age-related disease, including Alzheimer’s. But this study does little to advance us toward that goal.
This is the most important column I’ve ever written. The message is quite complex–dozens of new health parameters to test for and to optimize, all of them interacting in ways that will require new training for MDs. The message is also as simple as it can be: There is a cure for Alzheimer’s disease. You can stop reading right here, and buy two copies of Dale Bredesen’s book, one for you and one for your doctor: The End of Alzheimer’s.
Dr Bredesen’s spectacular success is easily lost in a flood of overly-optimistic, early hype about any number of diseases. This is an excuse for the New York Times, the Nobel Prize committee, and the mainstream of medical research, but it’s no excuse for me. I’ve known Bredesen for 14 years, and I’ve written about his work in the past. His book has been out for a year, and I should have written this column earlier.
I suspect you’re waiting for the punch line: what is Bredesen’s cure? That’s exactly what I felt when I read about his work three years ago. But there isn’t a short answer. That’s part of the frustration, but it’s also a reason that Bredesen’s paradigm may be a template for novel research approaches cancer, heart disease, and aging itself.
The Bredesen protocol consists of a battery of dozens of lab tests, combined with interviews, consideration of life style, home environment, social factors, dentistry, leaky gut, mineral imbalances, hormone imbalances, sleep and more. This leads to an individual diagnosis: Which of 36 factors known to affect APP cleavage are most important in this particular case? How can they be addressed for this individual patient?
Brain cells have on their surface a protein called APP, which is a dependence receptor. It is like a self-destruct switch whose default is in the ON position. The protein that binds to the receptor is a neurotrophin ligand, and in the absence of the neurotrophin ligand, the receptor signals the cell to die.
APP cleavage is the core process that led Bredesen down a path to his understanding of the etiology of AD 16 years ago. APP is Amyloid Precursor Protein, and it is sensitive to dozens of kinds of signals, adding up the pros and the cons to make a decision, to go down one of two paths. It can be cleaved in two, creating signal molecules that cause formation of new synapses and formation of new brain cells; or it can be cleaved in four, creating signal molecules that lead to trimming back of existing synapses, and eventually, to apoptosis, cell suicide of neurons.
In a healthy brain, these two processes are balanced so we can learn new things and we can forget what is unimportant. But in the Alzheimer’s brain, destruction (synaptoclastic) dominates creation (synaptoblastic), and the brain withers away.
On the right, one of the fragments is beta amyloid. Beta amyloid blocks the dependence receptor, so the receptor cannot receive the neurotrophin ligand that gives it permission to go on living. Beta amyloid is one of the 4 pieces, when the APP molecule goes down the branch where it is split in 4.
One of the signals that determines whether APP splits in 2 or in 4 is beta amyloid itself. This implies a positive feedback loop; beta amyloid leads to even more beta amyloid, and in the Alzhyeimer’s patient, this is a runaway process. But positive feedback loops work in both directions–a boon to Bredesen’s clinical approach. If the balance in signaling can be tipped from the right to the left pathway in the diagram above, this can lead to self-reinforcing progress in the healing direction. In the cases where Bredesen’s approach has led to stunning reversals of cognitive loss, this is the underlying mechanism that explains the success.
Amyloid has been identified with AD for decades, and for most of that time the mainstream hypothesis was that beta-amyloid plaques cause the disease. (Adherents to this view have been referred to jokingly as BAPtists.) But success in dissolving the plaques has not led to restored cognitive function. In Bredesen’s narrative, generation of large quantities of beta amyloid are a symptom of the body’s attempts to triage a dying brain.
To tip the balance back toward growing new synapses
Having identified the focal point that leads to AD, Bredesen went to work first in the lab, then in the clinic, to identify processes that tend to tip the balance one way or the other. He has compiled quite a list.
Reduce caspase-6 cleavage
Reduce caspase-3 cleavage
(All the above are cleavage in 4)
Reduce NF-κB (nuclear factor kappa-ligllt-chain-enhancer of activated B cells)
Increase telomere length
Reduce glial scarring
Enhance stein-cell-mediated brain repair
This explains why no single drug can have much effect on AD; it’s because the primary decision point depends on a balance among so many pro-AD (synaptoclastic) and anti-AD (synaptoblastic) signals. Addressing them all may be impractical in any given patient, so the Bredesen protocol is built around a detailed diagnostic process that identifies the factors that are most important in each individual case.
Three primary types of AD
Bredesen’s diagnosis begins with classifying each case of AD into one of three broad constellations of symptoms, with associated causes.
Type I is inflammatory. It is found more often in people with carry one or two ApoE4 alleles (a gene long associated with Alzheimer’s) and runs in families. Laboratory testing will often demonstrate an increase in C- reactive protein, in interleukin-2, tumor necrosis factor, insulin resistance and a decrease in the albumin:globulin ratio.
Type II is atrophic. It also occurs more often those who carry one or two copies of Apoε4, but occurs about a decade later. Here we do not see evidence of inflammatory markers (they may be decreased), but rather deficiencies of support for our brain synapses. These include decreased hormonal levels of thyroid, adrenal, testosterone, progesterone and/or estrogen, low levels of vitamin D and elevated homocysteine.
Type III is toxic. This occurs more often in those who carry the Apoε3 allele rather than Apoε4 so it does not tend to run in families. This type tends to affect more brain areas, which may show neuroinflammation and vascular leaks on a type of MRI called FLAIR, and associated with low zinc levels, high copper, low cortisol, high Reverse T3, elevated levels of mercury or mycotoxins or infections such as Lyme disease with its associated coinfections.
There’s also a Type 1.5, associated with diabetes and sugar toxicity, a Type IV, which is vascular dementia, and a Type V which is traumatic damage to the brain.
These categories are just a start. The patient will work closely with an expert physician to determine, first, where are the most important imbalances to address, and, second, which of the changes that cna address them are most accessible for the life style of this particular patient.
Bredesen wrote a paper in 2014 about successes in reversing cognitive decline with his first ten patients. As of this writing, he has treated over 3,000 patients with the protocol called RECODE (for REversal of COgnitive DEcline), and he claims success with all of them, in the sense of measurable improvement in cognitive performance. This contrasts with the utter failure of all previous methods, which claim, at best, to slow cognitive decline.
Translation to the millions of Alzheimer’s patients will require training of local practitioners all across the country. A few doctors have already learned parts of the Bredesen protocol, and Bredesen’s website can help you find someone to guide your program, but you will probably have to travel. The first training for doctors is being organized now through the Institute for Functional Medicine.
This is a new paradigm for how to study chronic, debilitating diseases. Type 2 diabetes comes to mind as the next obvious candidate for reversal through an individualized, comprehensive program. Terry Wahls has pioneered a similar approach with MS. Cancer and heart disease may be in the future.
I’ll go out on a limb and say I think Bredesen’s protocol is the most credible generalized anti-aging program we have. (Blame me for the hyperbole, not Dr Bredesen — he has never made any such claim.) Could we adopt Bredesen’s research method to accelerate research in anti-aging medicine? Perhaps biomarkers for aging (especially methylation age) are approaching a point where they could be used as feedback for an individualized program, but Horvath’s PhenoAge clock will probably have to be 10 times more accurate to be used for individuals. Averaging over ~100 individuals can give this factor of 10 in a clinical trial. Still, we don’t have the kind of mechanistic understanding of aging that Bredesen himself developed for AD before bringing his findings to the clinic; and this is probably because causes of aging are more complex and varied than AD.
Disclaimers: I’m pre-disposed to think highly of Dale Bredesen and his ideas for 3 reasons. He was a friend to me, and gave me a platform when I was new to the field of aging. He believes that aging is programmed. And his multi-factorial approach parallels the research I have advocated for researching other aspects of aging.
I’ve been in the field of aging research from the late 1990s, just the time when Aubrey de Grey was getting his start. Before others, Aubrey had the vision to realize that cancer, heart disease, and Alzheimer’s would never be conquered without addressing their biggest risk factor: aging.
From the beginning, I admired Aubrey’s successes in communicating with scholars and the public, and I reached out to him. He has always been gracious and supportive of me personally, appreciating the large common ground that we share. There is, however, one foundational issue on which we disagreed from the start.
Aubrey regards aging as an accumulation of damage. Evolution has permitted the damage to accumulate at late ages because (as Medawar theorized in 1952) there is little or no selection against it, since almost no animals live long enough in the wild to die of old age. Aubrey’s program is called SENS, where the E stands for “engineering.” The idea is to engineer fixes to the 7 major areas where things fall apart with age.
I regard aging as a programmed process, rooted in gene expression. Just as we express growth genes when we are in the womb and ramp up the sex hormones when we reach puberty, so the process continues to a phase of self-destruction. In later life, we over-express genes for inflammation and cell suicide; we under-express genes for antioxidants, autophagy (recycling), and repair of biomolecules. I believe in an approach to anti-aging that works through the body’s signaling environment. If we can shift the molecular signals in an old person to look like the profile of a young person, then the person will become young. The body is perfectly capable of doing its own repair, and needs no engineering from us.
Over the years, research findings have accumulated, and both Aubrey and I have learned a thing or two. I’m happy to say that our favored strategies are converging, even as our philosophical underpinnings continue to differ.
A unifying idea in my research has been that aging is an evolved adaptation. This is a statement about evolutionary biology, but I came to it before I studied evolution, by looking at the phenomenology and genetics of aging.
The body does not appear to be doing its best to stay young. We can see this because when the body is under stress, it has less available resources, but manages to a better job of protecting us from aging damage. This phenomenon is called hormesis.
There are single genes that can be disabled, greatly extending lifespan in worms. Some of these have no known detrimental side-effects (pleiotropy). These could only have persisted in the genome if natural selection is favoring aging for its own sake. Similar genes exist in higher organisms, though their effects on lifespan are not as dramatic as the 10-fold increase in worms’ life expectancy in worms that comes from eliminating both copies of AGE-1.
Most genes that affect the rate of aging have been around for a long time, and do the same job. This means they are evolutionarily conserved. For example, insulin is the most effective modulator of aging in mammals (including humans). In higher animals, insulin is secreted by the pancreas, from whence it regulates blood sugar and fat storage. But yeast cells existed half a billion years before the first mammals, and have no pancreas; and yet insulin was already a primary modulator of aging in yeast.
Programmed aging and optimism
There was a time when I spoke of “aging genes” and looked for drugs that could jam their targets and turn the genes off. Meanwhile, the science of epigenetics, or gene expression, was coming of age, so to speak. We learned that genes are turned on and off, not just in different tissues, but at different times of life. I came to think less in terms of “aging genes”, more about multipurpose genes that are deployed in appropriate combinations when we are young, keeping us strong and healthy. But as we get older, the proportions change. Aging is not accomplished via new mechanisms of self-destruction, which evolution invented for that purpose. Rather, the proportions are re-shuffled and change gradually, with effects that are more and more detrimental over time.
For example, the immune system is vital for protecting the body, but it becomes indiscriminate with age. In older people, the immune system fails to protect us from microbial infections, and simultaneously, immunity turns against the self. Autoimmunity contributes to arthritis and to Type 2 Diabetes (metabolic syndrome), as well as playing a role in AD.
For example, p53 is a gene that promotes apoptosis, or cell suicide. We need for cells to be smart enough to destroy themselves when they are infected with a virus or if they are cancerous. But later in life, apoptosis is on a hair trigger, and we lose muscle and nerve cells that are still healthy and functional.
For example, inflammation is used as a primary defense against microbes, and a way to eliminate tissue around a wound so that it can be replaced; but as we get older, signals that promote inflammation are dialed up higher and higher. Chronic inflammation contributes importantly to all the diseases of old age.
Twenty years ago, I imagined one or a few medications that would block the effects of aging genes. I wrote that the thesis of programmed aging implied great optimism about the ease with which aging might be combatted. I thought that merely lengthening telomeres might add many years to our lifespan.
Ten years ago, I saw that what was needed was re-balancing of signaling molecules to create a more youthful environment. My hope was that a few transcription factors (master regulator genes) might control a large number of signal molecules and we might set the clock by controlling just a handful of master signals.
More recently, I have come to realize that shortening telomeres are only a small part of the aging program. Worse, there is no clear line between transcription factors and hormones. Most hormones affect transcription, and most transcription factors have direct metabolic effects. There are thousands of transcription factors in the human genome. As a result, my robust optimism has been tempered, and I have come to think that we need to look for ways to re-balance a great number of genes to effect rejuvenation. I still believe in a signaling approach, but I see signals as a tangled web of cause and effect, in which every cause is also an effect, and every effect has a side-effect. Modulation of the signaling system toward a more youthful state is possible, but not easy.
Aubrey’s program, too, has changed over time
Aubrey has never believed that aging evolved as a program, but rather that aging is a manifestation of damage that is permitted to accumulate because of evolutionary neglect. Recently, he has argued explicitly against the idea of programmed aging, not for the reasons that traditional evolutionists offer, but by an argument that is uniquely his own. In his words, “it is impossible for a species to maintain two sets of genetic pathways whose selected actions diametrically oppose each other. Specifically, since we clearly have a great deal of anti-aging machinery…we cannot also have pro-aging machinery.” (My response is that we have pro-aging and anti-aging machinery that are activated at different times of life.)
Over two decades, Aubrey, too has paid attention to research results, and his thinking about what is necessary to achieve rejuvenation is changing. I see changes in the combinations of signal molecules and call it an evolved program. Aubrey sees the same thing and calls it “dysregulation”, which is a kind of damage. Aubrey and I agree that re-balancing of hormones and other signal molecules is going to be essential.
Aubrey now finds optimism in the existence of what he calls “cross-talk”. If we engineer a fix for one kind of damage, the body may sometimes regain the ability to repair other, seemingly unrelated kinds of damage. Hence, we may not have to engineer solutions to everything—some will come for free. A dramatic example is in the benefit of senolytics. Cells become senescent over time. I see this as a programmed consequence of short telomeres; Aubrey sees it as a response to damage in the cells. But both of us were surprised and delighted to learn, a few years ago, that elimination of senescent cells in mice had 20-30% benefits for lifespan. Even though only a tiny fraction of all cells become senescent, they are a major source of cytokines (signal molecules) that promote inflammation and can cause nearby cells to become senescent in a vicious circle; this apparently accounts for the great benefit that comes from eliminating them. If we find appropriately selective senolytic agents that can eliminate senescent cells without collateral damage, then the signals that up-regulate inflammation will be cut way back, and a great deal of the work needed to repair inflammatory damage is obviated.
The SENS 7
The SENS web site still lists the same 7 categories of damage that Aubrey has used for many years. But the program to address these 7 has shifted a bit from bioengineering of exogenous solutions to signaling approaches that support the body’s innate mechanisms (which we know are sufficient to keep the body in good repair through several decades of early life). For eliminating the plaques associated with AD, SENS at one time favored the engineering of artificial antibodies that would attack them, but more recently they see promise in the discovery of Dr. Sudhir Paul that our bodies already have catalytic antibodies, each capable of destroying many antibodies and re-cycling itself for the next one. Where once Aubrey saw the need for tissue engineering to replace worn-out body parts, he now sees promise in reprogramming somatic cells to become stem cells, so that our bodies can regenerate damaged tissues endogenously. Aubrey’s 1999 dissertation in biochemistry was about the theory that aging was caused by the damage inflicted by free radicals generated in our mitochondria, but he has long since embraced the fact that free radicals have an important role as signal molecules, so that anti-oxidants are not helpful for anti-aging.
Aging is not the only threat to human life
One respect in which my thinking has always departed from Aubrey’s is that I see humans as part of a continuous web of life on earth, integrated into a global ecosystem. Aubrey doesn’t worry about the Sixth Extinction that human activity has initiated because he anticipates that future humans will invent ways to support future human life as necessary. I value nature for its own sake, and I also believe that human life depends on ecoystem support in ways for which we have seen hints, but that we have not yet begun to study. Aubrey draws a sharp line between the value of human life and the value of other life, and he is highly optimistic about the ability of our species to find new ways to sustain ourselves in a post-ecologic world.
The Bottom Line
In my youthful enthusiasm, I was entirely too optimistic about the prospects for near-term anti-aging fixes. Aubrey was probably too conservative about the scope of what needed to be done to generate man-made solutions for problems the body can’t solve itself. I have come to understand the complexity of the body’s signaling network, and the fact that it is inseparable from cellular metabolism. Aubrey has come to realize that the body has endogenous solutions that can be activated more easily than we can engineer substitutes for them. I’ve been moving the timeline out, as he has been moving the timeline in, and there is much that we agree about.
I’m grateful to Aubrey — we all are — for the energy, the expertise, and the humor that he has brought to his chosen role, as a public advocate for bringing anti-aging strategies into the mainstream of medical research.
Fo-ti is a root herb from traditional Chinese medicine that has been used for centuries as an anti-aging tonic, and has shown promise in limited Western-style analyses. Interest has been held back by reports of liver toxicity, but there is some indication that the benefits can be separated from the toxic effects. In my readings, I found anecdotal evidence for rejuvenation plus one older study of impressive life extension in quails. I also found many more recent studies documenting beneficial biochemical effects which may be counted indirect evidence that makes life extension more credible. There were two clinical trials, both with promising results.
I’ve been looking into the effects of a root herb called Fo-ti or He shou wu (何首乌) or Polygonum multiflorum Thunbergia, since a friend emailed me about rejuvenating effects when he fed it to his ancient German shepherd. I’ll call it PMT for the remainder of this page. I’ve consulted the usual PubMed sources, in addition to books on Traditional Chinese Medicine (TCM), and some scientific articles in Chinese, which I ran through Google Translate, with fair results.
TCM is based on herbal combinations and formulas. Each ingredient has many active compounds, and the art of TCM is to combine the combinations. Western medicine likes to study one compound at a time, based on a scientific tradition (reductionism) that tries to understand each separate piece, then study interactions from that understanding as a foundation. The reductionist approach was responsible for the explosive success of 19th Century physics, and has been popular ever since, but it is not obviously the best way to make progress in 21st Century biology [Carl Woese philosophy piece]. Another reason for the Western preference for single-compound treatments comes from patent law, which encourages the testing of purified compounds and disallows patents for whole plants. But our bodies are complex, homeostatic systems, and it is rarely true that the combined effect of two drugs is just the sum of the effects of each separately. Strong interactions are the rule, rather than the exception. I believe that we are not going to find a single Fountain of Youth molecule, so I have been an advocate for high-throughput screening of many combinations of treatments, looking for combinations that stand out as especially effective. If we continue to study purified molecules in isolation, it may be a long time before we get to the point where we understand the biochemistry well enough to identify magic combinations on theoretical grounds.
A curious side-note: It is reasonable to expect some combinations of biochemicals to synergize in the human body. But why should we expect these combinations to be found regularly in a single plant? Herbal medicines are unreasonably effective in this regard.
Here  is the one lifespan trial that I was able to find, which reports 50% life extension in Japanese quails. I looked on Cochrane and Examine.com, and found nothing. However, Joe Cohen over at Self-Hacked has an extensive article. “More than 100 chemical compounds have been isolated from Fo-ti, and the most biologically relevant components have been determined to be from the families of stilbenes, quinones, flavonoids, and phospholipids…Fo-ti exhibits a wide spectrum of pharmacological effects, including anti-aging, immunologic, neuroprotective, anticancer and anti-inflammatory effects.” Stilbenes are molecules in the resveratrol family; quinones are like CoQ10, and flavonoids are polycyclic molecules in the quercetin family.
Most of the rest of what I report here comes from this Chinese review [王伽伯, 2016] and this English language review [Bounda & Feng, 2015].
Laboratory studies and clinical practice have demonstrated that PMT possesses various biological and therapeutic actions, including anti-tumor,[16,17] antibacterial, anti-inflammatory, anti-oxidant,[19,20,21] anti-HIV, liver protection,[23,24] nephroprotection, antidiabetic,[15,26] anti-alopecia,[27,28] and anti-atherosclerotic activities.[29,30] It has been also reported to exert preventive activity against neurodegenerative diseases,[31,32,33,34,35] cardiovascular diseases and to reduce hyperlipidemia as well.[36,37] — Bounda & Feng
Anti-inflammatory:  is a Korean study that found inhibition of inflammatory cytokines in white blood cells of mice. Other studies  show suppression of NFκB.
Liver protection:  A Taiwanese study that demonstrated reduced toxicity from CCl4 after mice were treated with PMT extract.  PMT reversed liver cirrhosis in mice.
Antidiabetic:  inhibits enzymes that digest starch  is an impressive study, that demonstrates inhibition of TGF-β1 and COX-2, and simultaneous enhancement of SOD and glutathione from a chemical extract of PMT called 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG). TSG is chemically similar to resveratrol, and in a worm study was more effective than resveratrol at increasing lifespan (22%).
Anti-atherosclerotic:  Mice don’t get heart disease so they work with rabbits. Large reductions in measures of arterial blockage in rabbits fed a water-extract of PMT.  This is really about anti-inflammatory benefits of TSG fed to mice and rats.
Neurodegeneration:  This was about adaptogenic benefit in mice. Mice were protected from nerve damage by paraquat if they had been prepared with extract of PMT.  worked with a mice that had been genetically modified to give them Alzheimer’s disease. TSG was found to ameliorate the loss of memory.  Older rats lose their memory, as tested in their ability to remember from day to day the location of a hidden platform in a tank of water. TSG protected memory in older rats.  This is a study for people who believe in the Amyloid-β theory of Alzheimer’s disease. A large number of herbal substances were screened in cell lines that generate Amyloid-β, and the only effective inhibitor was found to be PMT extract.  Suppresses lipid peroxidation in response to Amyloid-β in a mouse model and increases glutathione.  Another successful trial, this time of TSG in a mouse model of AD. [119, 120 is in Chinese] Two clinical studies found substantial improvement in cognitive performance of AD patients with PMT.
Liver injury from PMT is linked to a certain genetic difference, labeled CYP1A2 * 1C. I didn’t find anything more about this genetic variant. Curiously, I found several studies that claimed that PMT protects the liver, for example this.
My inclination is to look for empirical evidence and downplay theory (both Western and Chinese theory). I believe that the emphasis on single compounds is a serious limitation of Western medical research, because the interactions are more important than the individual effects. For me, it is an attractive feature of TCM that there is so much accumulated wisdom, not just about herbs that contain many active ingredients, but about potions that combine typically a dozen or so herbs that have been found to work well together. So the maddening thing I’ve found is that the Chinese scientists who have studied PMT and other promising Chinese herbs fall into the Western trap and isolate one compound at a time to study their effects. What is missing is the lifespan studies based on whole herbs, or combinations of herbs, as they would be prescribed by a traditional Chinese herbalist.
I went to a local herbalist this week and asked for advice about He Shou Wu. She explained to me that in TCM, herbs are always given in combinations. There are classic formulas with 6 or 10 or 20 herbs, and these are adjusted for individual prescription. The main ingredients are large quantities of the herbs that move the metabolism in some direction, and the lesser ingredients counterbalance the main ingredients by pushing in the opposite direction. Some of the directions they talk about correspond to observables we might recognize (high or low energy, sexual stimulant), and some of them are more esoteric (wet or dry, hot or cold, yin or yang). She gave me a formula with He Shou Wu as the main ingredient, and I’m going to do some more reading before I decide whether to take it.
In the meantime, I’m taking a gram of He Shou Wu extract processed with black beans each morning before breakfast and I think I detect an increase in aerobic stamina which has not listed anywhere as one of the benefits.
Acknowledgement: The idea for this research came from Jeff Bowles, who is a frequent commenter on this blog. The Chinese research was kindly supplied by Wen-jun Li, a post-doc in the Beijing lab where I have worked the last 3 summers.