Fasting-Mimicking Diet: Can You Make it a Habit?

I was glad to see Valter Longo’s Fasting-Mimicking diet in the news again this week.  I have been enthusiastic about Longo’s work ever since he documented altruistic suicide of yeast cells for his PhD thesis in the 1990s. Programmed death in one-celled protists was considered an affront to evolutionary theory at the time, and he had a devil of a time getting his findings into print.

Longo discovered in 2002-2005 that fasting had a powerful benefit for cancer patients, and that in conjunction with either radiation or chemo, it greatly magnified the benefits while mitigating the side effects.  Intermittent fasting had benefits, too, for the general population, independent of cancer.  It seems to be a way to get the health benefits of caloric restriction and it is easier to stick to for many people than a consistently low calorie diet.

But Longo couldn’t get either doctors or patients interested in the fasting program.  Part of the problem was the toxic mix of capitalism with medicine: the US relies on testing and promotion by profit-making companies to push medical technology forward, and fasting isn’t a product that anyone can make money on.  There was also an emotional truth: cancer patients feel scared, beleaguered, emotionally drained.  So much is dragging them way outside their comfort zone that it takes extraordinary strength not to fall back on food as one of life’s most reliable comforts.

So many medical researchers see their job as finding treatments, and leave the problem of adoption and compliance to someone else.  But Longo set himself single-mindedly to the task of bringing the benefits of fasting to a wider swath of the population.  The question that led to the Fasting-Mimicking Diet (FMD):  What dietary regimen can provide the greater part of the benefits of a water fast while inducing less hunger and minimal disruption to concentration, vitality and the pace of life?

I have done about 9 cycles of the FMD over the past 1½  years, including this week.  In my personal experience, 5 days of the FMD is eminently tolerable once I begin, though I still face resistance when I think in advance about disrupting my comforting food routines.  (Yoga, swimming and meditation have the same barriers for me–difficult in the anticipation, enjoyable once I begin.)  For me, FMD is not a weight loss program.  I gain back all the weight I’ve lost within a week after the 5-day program is finished.  Others may have different experiences.  People have used the 3-meal version of FMD (3 meals at 360 calories) as a medium-term weight-loss program, but the protein content is probably too low for those concerned about maintaining lean mass long term.

In his new study, 100 participants were randomized into two groups.  The first group did three rounds of 5 days on FMD over three months.  The second group did nothing special for three months, but were given an opportunity to try the same three rounds during the following three months.  The average weight loss was 6 pounds for those who completed all three cycles; lean body mass was lost, in the same proportion as fat.  Blood pressure, blood sugar, triglycerides all improved on average, and C-reactive protein (an inflammatory marker) went down as well.  

The study included a range of healthy people as well as people who carried more weight and had higher risk factors.  It was those with the higher inflammation and blood sugar who realized big benefits from the program, and the already-healthy were averaged in.  There is a lot of evidence to indicate that intermittent fasting works, and that the FMD delivers similar benefits.  But if you’re already lean and healthy with low blood sugar, then it’s less clear whether there are substantial additional benefits from intermittent fasting.

Notable was a reduction in the hormone IGF-1, which I don’t necessarily regard as a good thing.  On the one hand, lower IGF-1 is characteristic of all caloric restriction models, in animals and humans, in which life span is increased.  So it is an indication that the FMD was effective.  But low IGF-1 has consistently been found to increase risk for all-cause mortality, and heart disease in particular [ref, ref, ref].  Benefits of higher IGF-1 include maintenance of muscle mass and growth of nerves that diminishes with age.  

An additional benefit documented in the past is a “reset” of the immune system.  The white cell population is pruned during fasting, and the most-needed naive T-cells regrow after eating resumes.

Antidote to Obesity

It’s the (large and increasing) population of unhealthy people that Longo is targeting.  There is every reason to expect substantial benefits, but the big issue remainss: how many people can be motivated to take up the practice and stick to it?  The question was touched on only peripherally in the current study, without discussion; of 48 subjects selected for the first round, 39 stuck it out for three FMD cycles over three months (81% compliance).  That’s encouraging, but what we really want to know is: how many people will actually modify their eating rhythms for years at a time?  Will they feel the benefits and will that motivate them to stick with it month after month, five days each month?

And will this translate into long-term weight loss?  Sustaining weight loss is notoriously difficult for about 95% of the population.  People can stick to a diet for a time, but the Siren song of food is with us everywhere, and sooner or later we succumb.  Fortunately, there’s good reason to hope that the FMD discipline offers benefits even if weight loss is not sustained.


How to do it

Longo’s own company, L-Nutra offers a packaged diet, called ProLon, availble through health care professionals.  It’s pricey and may be covered by insurance.  LifeBox offers a non-prescription alternative that is not as much cheaper as it might be.  For my own experimentation, I have preferred to use fresh, whole foods approximating the same macronutrient proportions as the ProLon package.  It requires some time and attention in food prep, but it costs less than you’re currently spending on the same meals, and you can fill yourself with satisfying portions of fresh vegetables for the same 360 calories.  Here is my page of instructions and advice, with recipes designed by Enid Kassner.

For many of us, our relationship to food is central to our psychology.  Shaking up food habits disrupts everything else as well.  It’s the main reason that food habits are so hard to change, but for me, it’s also a good thing.  I enjoy the challenge and the self-awareness that come from a new frame of reference; fasting changes my perspective, my emotional baseline, and my mental state.  For me, the first day is unfocused, low energy, but often a time of creative new ideas; the second day is distracted, obsessive, sometimes headache-y or otherwise uncomfortable, and beginning with the third day there is returning energy, along with a freedom that I didn’t know I missed.


Why is life expectancy in America lagging?

Part of the answer is certainly cultural.  Advertising, parties, lunch and dinner meetings often reinforce consumption of food that is designed to be addictive for the sake of corporate profits.  In America, we are surrounded by overweight people, but France and Italy have much lower obesity rates, and you can walk all day around the cities of Japan or China without encountering anyone who is seriously overweight.  Even in America, the problem has grown way out of proportion only in the last 40 years.  This and income disparity are the main reasons that life expectancy in America is at the bottom of the developed world.  Our unaffordable, dysfunctional healthcare system provides many additional reasons.  Meanwhile, life expectancy in Asia is climbing at an exemplary pace.

Longo’s FMD is designed to address this most accessible factor in the diseases of late life for a large swath of people who find they cannot lose weight.  His research is based not just on effectiveness but equally important on tolerability.  How many people will adopt it and reap the benefits?  This will be an important question for public health going forward.  But you are a unique individual, not a statistical median.  I encourage you to experiment with FMD, see what you learn about yourself, and decide if it can be a valuable part of your health program in the long term.

Glycine and Mitochondria

A venerable theory of aging is the Mitochondrial Free Radical Theory (MFRTA).  Mitochondria are the energy factories of the cell, where sugar is burned to create electrochemical energy.  Of necessity, the mitochondria use high-energy chemistry, and this creates toxic waste in the form of ROS–pieces of molecules that are too eager to combine with delicate biomolecules, turning useful compounds to toxic waste.

The MFR theory says that these ROS cause mutations in the DNA of the mitochondria that build up over time and cause the mitochondria to perform less well with age.  Mitochondria are constantly turning over, that is, creating new mitochondria that inherit the mutations and accumulate new ones.

Over the years, this story has come apart.  The key finding goes back to 1980 : mutations (for whatever reason) are not more severe in older people than in younger people.  The mutations that appear in mitochondria with age are at a low level, and inconsistent with the assumed ROS mechanism [2013].

But it remains undeniable that we have fewer mitochondria as we get older, and those we have become less efficient.  Brain and muscle cells are the most energy intensive, and we have less energy for everything from running to thinking.  Mitochondria are not the source of age-related decline; nevertheless maintaining (or restoring) mitochondrial health should be a part of any strategy to resist the ravages of age.

I recently became aware of this Nature paper from Japan:  More important than genetic changes in old mitochondria are the epigenetic changes (changes in gene expression) that render them less efficient.  Is there a way to restore the gene regulation in aging mitochondria to look more like the gene expression in energetic, young mitochondria?

“When glycine was added to culture media containing cells from the 97-year-old, the mitochondria in these cells became like new.” [quote from summary by PD Mangan].  Glycine is the simplest of the 20 amino acids that are building blocks of proteins in all eukaryotes.  It is not classed as an “essential amino acid” because our bodies can manufacture glycine, but maybe we don’t make enough of it to maximize our lifespans.  



The theory in the Japanese paper is that glycine treats the downstream symptom of epigenetic reprogramming in the mitochondria.  In other words, glycine does not stop the detrimental epigenetic changes in mitochondria that come with age, however one of the most important of these changes results in a glycine shortage in the mitochondria.  Hence, glycine supplementation effectively attacks the problem at an intermediate stage.

Could a molecule as simple (non-specific) as glycine be an anti-aging compound?  Glycine comes to us with a sketchy but promising history.  In one rat study, a hefty dose of glycine increased lifespan by 27% longer than controls.  “Hefty” is the human equivalent of ~3 ounces per day.  I’m tentatively filing this study in the “too good to be true” drawer, because it appeared only as a conference abstract 5 years ago and has never been fleshed out with a peer-reviewed full text.

A shortage of protein has a powerful anti-aging effect across many species.  And a shortage of one critical amino acid–methionine–is sufficient to trigger this response.  This may be because methionine is the “start codon”; every gene begins with a methionine, and a severe shortage of methionine can slow down all protein synthesis.  

Directly engineering a shortage of methionine in the human body is just too difficult to manage, because too many protein foods have methionine, and we’re too fond of protein.  (Animal proteins are consistently loaded with methionine, whereas some vegetable sources have less.)  In studies of lab animals, a methionine shortage is engineered by using fully artificial protein sources, constituted from individual amino acids.  People would never want to live this way on synthetic food, even if we could afford it; but using glycine to create a methionine shortage sounds more palatable.  Glycine plays a role in breaking down methionine in the liver, and if the glycine level is jacked up super-high, it is (theoretically) possible to force this reaction so far as to create a methionine shortage.

For some of us, methionine restriction holds up the tantalizing prospect of gaining benefits of dietary restriction while allowing us to eat to satiety.  But the idea remains untested in humans.  Protein deficiency can lead to loss of strength and endurance and the ability to concentrate–even as it increases life expectancy.  Depression is another risk.  Rats that have tried methionine restriction are not recommending it for humans; in fact, they quickly come to crave methionine; they recognize methionine-deficient foods and shun them.

On the other hand, there are other diverse benefits documented for glycine supplementation, beginning with better sleep, insulin sensitivity and cancer resistance.  A minimum of 3 or 4 grams is required to have any effect.  You can buy it in powder form by the pound.  From Finland, here’s Valdu Heiskanen’s comprehensive page on glycine.


Mitochondria have their own DNA

Hundreds (sometimes thousands) of mitochondria dot every cell in our bodies.  They perform the task of burning sugar in a controlled process that captures most of the energy in electrochemical form (ATP) that is convenient for all the cell’s usage.  In the deep evolutionary past, mitochondria were an invading bacteria, which gradually lost their virulence, then became domesticated in a symbiotic relationship, then fell into line doing the bidding of the cell nucleus (like other parts of the cell).  But from that distant era they still retain a snippet of their own DNA–just 37 genes, all essential for the energy metabolism.   

In the old MFR theory, mitochondria were thought to lose genetic integrity through mutations.  In the new view, the genetic information isn’t lost, but the mitochondrial DNA is reprogrammed later in life, with the result that their performance suffers.  Nominally, this is a promising finding; random mutations in a hundred trillion mitochondria would not be a feasible target for anti-aging interventions; but epigenetic reprogramming is presumably something the cell already knows how to do.  The cell knows, but we don’t; our understanding of epigenetic markers and the way that they are programmed is still rudimentary (even in the nucleus, let alone the mitochondria).  Our best hope for the near term would be if we don’t have to understand the process, because the nucleus takes care of the details.  This brings us back to the general strategy of signaling to make each cell think it’s part of a young body.

How does PQQ work?

PGC-1a is a circulating hormone that says to the cell, “make more mitochondria.”  You can’t take PGC-1a orally because it is a large protein molecule, and does not survive digestion.  PQQ is a small molecule, more bioavailable when ingested, that increases circulating PGC-1a.  The two-step process has been documented in rodents; oral PQQ leads to more mitochondria [ref, ref].  


Does CoQ10 help?

CoQ10 (or ubiquinone) is essential to the metabolic function of mitochondria.  Supplementation with CoQ10 has been found to enhance athletic stamina in most human studies [ref, ref, ref, exception].  This benefit is not to be sneered at, though it is unrelated to aging.  Heart patients taking statin drugs have an induced deficiency in CoQ10, and need to take supplements.  Other studies of CoQ10 suggest benefits for cardiovascular risk [ref] and for maintaining insulin sensitivity [ref].  On the negative side, CoQ10 cannot stimulate growth of new mitochondria, and rodent studies with CoQ10 have never demonstrated increased life span [ref, ref].



Exercise is the best thing we know for promoting replication of mitochondria.  This has been substantiated in humans and in rodents.  Exercise is a powerful stimulant for producing PGC-1a, and there are additional channels by which exercise promotes mitochondrial biogenesis, apart from PGC-1a [ref].  There is evidence for endurance exercise and interval training, but maybe not for strength training [another ref].  I was unable to find any direct comparison of the three.


Fasting and Ketogenic Diets

Fasting promotes mitochondrial biogenesis by a different pathway: AMPK [ref].  AMPK is expressed in response to a tight energy budget, but the AMPK response also decreases with age [ref].  Ketogenic diets (very low carb) also promote increases in mitochondria [in humans, in mice].

Chronic caloric restriction (as opposed to intermittent fasting) contributes to the health of mitochondria, but not to their number [ref].


The Bottom Line

Loss of Mitochondrial energy is connected to many of the deficits of old age; but most of the things you can do to improve mitochondrial function are the same things we do for a generalized anti-aging program.  The new thing here is glycine.  It’s $10 a pound and helps you sleep better.

I’m grateful to P. D. Mangan at Rogue Health for providing the inspiration and seed references that got me started on this story [link].

First Fruits of Research with Young Blood Plasma

A recurrent theme on this page is the idea that human aging is driven by a combination of proteins circulating in the blood.  Blood is not just red cells and white cells; there is the blood plasma which contains thousands of dissolved proteins (and RNAs), signal molecules which regulate all aspects of metabolism, on time scales ranging from minutes to decades.  As we get older, the mix of these protein signals changes in ways that are relatively subtle, with less of some proteins and more of others.  It has been pretty well established that the mix of proteins is characteristic of your age.  My bet is that the mix of proteins actually determines your age, in the sense that changing the  blood plasma of an old person to that of a young person will, to a significant degree, transform the metabolism toward a younger state.

The promise of this work came to prominence in parabiosis experiments with mice, beginning about 2005 out of Stanford.  Old mice were surgically paired with young mice, so their circulation was tied together.  The old mice become younger and the young mice became older.  In the intervening years, we have learned that blood plasma (no cells) from young animals has a rejuvenating effect on old animals.

But giving old people frequent transfusions from young donors sounds like an experimental procedure for aging tycoons, not a practical plan for population-wide life extension.  Alternatively, to reproduce the full suite proteins in young blood artificially is a daunting task.  Are all the proteins necessary for rejuvenation, or, perhaps, might the same success can be achieved with just a small number of proteins?   Some would be added, others effectively subtracted from the blood by blocking their receptors with an inhibitor.

So the race is on to find candidates for proteins in the blood that could be part of this small subset, a handful of proteins that might, if we’re lucky, stand in for the thousands whose concentrations change with age.  The Stanford students from 2005 have graduated and now have labs of their own at Berkeley and Harvard  In the last few years, Mike and Irina Conboy of Berkeley identified oxytocin as a key protein, and Amy Wagers at Harvard identified GDF11, both proteins that we lose with age, and concentrations might be beefed up for rejuvenation.  Oxytocin is holding up; there is controversy about GDF11.

But more effective than adding “youth factors” to old blood may be removal of pro-aging factors.  This was the preliminary finding put out by the Conboys a few months ago.  Right around this time, from the lab of Tony Wyss-Coray at Stanford, came the first report of anti-aging benefits from blocking a circulating protein.  VCAM-1 is a protein that increases with age, but has not previously been identified as a bad actor of primary import.  The “CA” in the middle of VCAM stands for cell adhesion, an essential cell function which in itself is not good or bad.  Cells stick together for many reasons.  But VCAM-1 has been loosely linked in the past to cardiovascular disease and to arthritis.

Hanadie Yousef, a post-doc at Wyss-Coray’s Stanford lab, presented preliminary results at a Neuroscience meeting in November, indicating that

  • VCAM-1 increases by only about 30% in blood of the elderly, but this is enough to make a difference.
  • Higher levels of inflammation and lower nerve growth in brains of older mice were linked to VCAM-1
  • An antibody that binds to VCAM-1 and pulls it out of circulation was successfully used to prevent these effects.  Inflammation and nerve growth were both restored to levels typical of young mice.

Of course the findings are preliminary, and yet unpublished [Yousef abstract].  No anti-aging has been demonstrated in normal, living mice, but the benefit of intravenous antibody injections has been demonstrated in mice that are served up artificially with too much VCAM-1, and the molecular mechanism has been validated in cell cultures.

I find it promising that the research is being done on brain function.  The central timekeeper that coordinates change in blood chemistry through a lifetime has not yet been identified, but neuroendocrine regions of the brain are a promising place to look for it.  Human clocks are built on feedback loops, and if evolution’s engineering immitates human arts, then we might look for an epigenetic aging clock based on secretions from the brain that feed back to act indirectly on the brain.

Other blood proteins that increase with age, and which presumably could be targets for antibody therapies include the pro-inflammatory signals NFkB and TGF-ß, also the reproductive hormones LH and FSH.

I believe that the work of these three groups is the best prospect we have for powerful human anti-aging interventions in the medium term.  In the short term, I think that senolytic agents will be the Next Big Thing.  In the long term, we will learn how to reprogram our epigenetics.  For the next decade or two, keep an eye on ciculating blood signals

Three previous posts with background on this subject:

How does the body’s hormonal signaling change with age?
Signal molecules in the blood: what do we have too much as we age?
Signal molecules in the blood: what do we lose with age?

Epigenetics and the Direction of Anti-Aging Science

Dear Readers –

It’s been a deeply gratifying year for me.  Twenty years ago, I first started writing that aging is something the body does to itself, a body function, rather than deterioration or loss of function.  Journals would not even send my submission out for peer review.  Journal of Theoretical Biology sent me the considered opinion of their anonymous reviewer, “JTB shouldn’t touch this topic with a ten-foot pole.”  The conflict with prevailling evolutionary theory was just too deep.

But in the interim, the evidence has continued to pile up, and many medical researchers have taken the message to heart in a practical way, setting aside the evolutionary question and just pursuing approaches that seem to work.  The most promising developments in anti-aging medicine involve changing the signaling environment rather than trying to “fix what goes wrong” with the body.

My popular book exploring the evolutionary origins of aging (and implications for medical science) came out in June, and an academic version of the same content came out in October.  Gandhi taught me,

“First they ignore you…
then they laugh at you…
then they fight you…
then you win.”

The paradigm of programmed aging passed this year from stage 2 to stage 3, with prominent articles arguing against the possibility of programmed aging [Kirkwood, de Grey, Vijg & Kennedy].  Current Aging Sciences devoted a full issue to the question.  I welcome the discussion.  This is a debate that colleagues and I have sought to initiate for many years.  There are powerful theoretical arguments on one side, and diverse empirical observations on the other.  The scientific community will eventually opt for empiricism, but not until theory digs in its heels and fights to the death.  A basic principle of evolution is at stake, and many theorists will rise to defend the basis of their life work; but a re-evaluation of basic evolutionary theory is long overdue.

The idea that fitness consists in reproducing as fast as possible is no longer tenable.  For plants, this may be approximately true.  But animal populations cannot afford to reproduce at a pace faster than the base of their food chain can support.  Animals that exploit their food supply unsustainably will starve their own children, and there is no evolutionary future in that.  This is a principle that links together entire ecologies, and the foundation of evolutionary theory will have to be rewritten to take it into account.


The Programmed Aging Paradigm: Is it a Cause for Optimism in the Quest for Extended Human Life?

For many years, I put forward the argument that programmed aging means there are genes that serve no other purpose than to hasten our death, and that medical research should be targeting the products of those genes.  (Once a pathway has been identified, pharmaceutical science knows well how to block it with engineered drugs, like beta blockers and MAO inhibitors and serotonin re-uptake inhibitors.)

But in recent years, epigenetics has eclipsed genetics as the major theme in molecular biology.  Everything that happens in the body is determined by which genes are expressed where and when.  The vast majority of our DNA is devoted not to coding of proteins but to promoter and repressor regions that control gene expression with exquisite subtlety.

There has been a growing recognition of aging as an epigenetic program.  As we get older, genes that protect us are dialed down, and genes for inflammation and apoptosis are dialed up so high that healthy tissue is being destroyed.  Many epigenetic scientists have discovered this, and they find it natural to see aging as a programmed phenomenon.  (Most have never been to graduate courses in evolutionary science, where they would have been indoctrinated into the perspective of the selfish gene.)

At first blush, it seems that an epigenetic program is just as amenable to pharmaceutical intervention as a genetic program.  A few years ago, I wrote about transcription factors as the key to aging.  Transcription factors bind to DNA and turn whole suites of genes on and off in a coordinated way.  If we can restore a youthful transcription environment in an older animal or human, the body knows how to repair damage and re-create a younger self.  The model I had in mind was based on a small number of powerful transcription factors controlling expression of a much larger number of genes, controlling a yet larger population of metabolites.

I no longer believe in this model.

This summer, I had a chance to work in a worm genetics lab and consult closely with people who know the experimental details.  I learned that there is no clear line between functional proteins and transcription factors, that many proteins have multiple functions, and that metabolites feed back to control gene expression.  Instead of a pyramid, I should think of a web of causes and effects.

The entire system is primed for homeostasis, meaning that it responds to any intervention, seeking to move the system back toward its previous state.  Of course, it is this capacity for recovery that makes life robust; but it also means that there is no “command central” which can be tweaked to move the whole system at once toward a desired state.

I still believe that there are one or more aging clocks that inform the body of an age-appropriate metabolic state, and synchronize the aging of different systems.  Telomere length is one such clock.  If we can reset an aging clock, the body will repair and clean itself up.  If we can reset several clocks, the body may be able to restore itself to a younger state.  But I recognize the possibility that the clock is diffused through the detailed epigenetic status of a trillion cells, and may be beyond the reach of foreseeable technology.

A few years ago, Steve Horvath of UCLA gave us the most explicit picture of an aging clock.  He found it in one particular epigenetic marker: the pattern of DNA methylation.  The Horvath clock is distributed over 353 sites.  This is a clock that can be read for any given cell, but can it be changed or adjusted in each of the body’s trillions of cells?  The prospect is daunting, and we do not yet know how to go about it.  2016 saw the first use of CRISPR technology for therapy in a living human.  CRISPR could, in principle, be used to alter gene expression, one gene at a time.  To re-regulate the expression of 353 genes in one treatment would probably require new concepts and new discoveries.

Short of resetting the aging clock, there are several technologies just over the horizon that should offer substantial life extension benefit.  I believe the best prospects are senolytics (ridding the body of senescent cells), telomerase activators (rejuvenating old stem cells), and adjusting blood levels of key hormones and cytokines that increase or decrease with age.


The Bottom Line

Programmed aging is the right model to keep in mind as we search for interventions that slow the aging process and lessen the incidence of heart disease, cancer and Alzheimer’s all at once.  Prospects are good for real breakthroughs, perhaps as soon as 2017, but I am no longer as optimistic as I was just a few years ago that complete rejuvenation is on the horizon.

Wishing you health and vitality for the coming year,




– Josh Mitteldorf

From Santa Diego, a Jolla Xmas Gift

From the Salk Institute in La Jolla, CA came an announcement last week that the four factors previously identified to turn ordinary cells into stem cells (in cell cultures) was successfully used as a rejuvenation procedure in live mice.  The results provide important new evidence for the hypothesis that aging is under epigenetic control, and a proof of principle that we might slow aging by modifying the chromosome markers and attachments that determine gene expression.  But the way in which this was done involved genetic engineering before birth, and there is no obvious way to translate the results quickly into an anti-aging teatment for living humans.

Ten years ago, Shinya Yamanaka’s Kyoto University laboratory announced that just four proteins could turn an ordinary, differentiated cell back into the stem cell from whence it came.  The four were transcription factors, high level switches that turn whole systems of genes on and off with one signal, and the “Yamanaka factors” became known by their initials, OSKM.

Last week, Izpisua Delmonte’s laboratory at the Salk Institute announced a success in rejuvenating whole animals, live mice, using the same OSKM.

Whether this is the germ of a potent new rejuvenation treatment remains to be seen; but the immediate message is a dramatic affirmation of the new paradigm in anti-aging medicine: aging can be reversed by signaling, without artificially-engineered repair of damage.  A bold form of this paradigm is the epigenetic hypothesis—now just 4 years old—which says that aging is controlled by gene expression.  It is the set of genes that are turned on and off, and the genes’ levels of expression that determine the state of the body’s age.  (This idea does not deny that tissues and biomolecules suffer damage with age; but the hypothesis says that the body knew how to repair this damage at one time, and is capable of repairing the damage again, when the signal molecules engage repair mechanisms appropriately for a young individual.)

Gene expression  is controlled, in turn, by markers on the chromosome and on the histone spool around which the DNA is wrapped like thread on a spool.  These markers are known to change with age in a characteristic pattern.  Shifting epigenetic markers program all the stages of development, and (according to the hypothesis), the program continues, and causes the body to pass through the stages of aging.

But in nature this clock never goes backward.  The epigenetic clock is reset to zero as the genome is wiped clean and reprogrammed.  This happens twice: once in the creation of germ cells, the sperm and egg; and a second time after sperm and egg join to make a zygote.  (This is a simplification; some traits are epigenetically inherited, implying that some genome markers are retained and pass across generations.)

If we buy the epigenetic hypothesis, then the holy grail of anti-aging medicine would be to reset all the epigenetic markers, say from age 60 to age 20, but not all the way back to zero.  This must be “possible” in some sense of the word; but if it depends on us to read (for example) the methylation of a 20-year-old’s chromosomes and write the results onto the chromosomes of a 60-year-old, in every cell of the body, without otherwise disrupting the living organism, then the task is daunting.  And methylation is just one of about 100 known epigenetic modifications of the chromatin.

Nature knows how to reset the epigenetic clock all the way to age 0, but there is no precedent for a partial reset.  All tissue differentiation is lost, and the growth rate is pedal-to-the-metal high.  It should be no surprise that previous attempts to rejuvenate the living mouse by resetting the clock with OSKM have led to cancer disasters [ref, ref].  In this new report, the Salk researchers used short, intermittent exposure to OSKM to “partially reset” the epigenome.  If this really works, and if the epigenetic hypothesis continues to pan out, then this is indeed a week to celebrate.


The experiment

The procedure was first tested in human cell cultures, demonstrating “partial de-differentiation”, where functional cells were rejuvenated without returning them completely to stem cell status.  This was an important proof of concept.  The authors cite previous experiments suggesting that OSKM re-setting is a multi-step process, so it is possible in principle to halt the process after partial re-programming, and hope for a somewhat younger state.

Next, the procedure was tested on mice with genetically short life spans, living an average of  just 18 weeks.  Mice with the OSKM treatment lived 24 weeks.  Impressively, the treatment was tuned so that it did not increase cancer rates.  The particular life-shortening gene was defective LMNA (Lamin A).  Lamin A is important for structure and function in the cell nucleus (details hazy), and there is no way to distinguish from this experiment whether the OSKM treatment merely counteracts the deficiency of Lamin A or whether it slows aging generally. Finally, the procedure was tested in normal, aged mice.  They showed signs of improved healing, nerve regrowth, and mitochondrial chemistry typical of younger mice.  But the mice were sacrificed to determine these things, so there was no demonstration of increased lifespan for genetically normal mice.  Sometimes “publish or perish” pressure leads researchers to kill the goose that lays the golden egg…

But the big asterisk on this new result is that the delivery system was through a gene added to the mice at the egg stage.  It is easy to modify genes at the egg stage, when there is just one cell, and then the modification is copied in every cell of the adult; but to do gene therapy for adult humans is still at an early experimental stage.  Every cell in their bodies had an extra copy of each of the 4 genes for the OSKM factors, and these genes were so configured that they could be turned on and off with a drug (doxycycline).  Administration of the drug was arranged to be just right to reprogram the cells, but not all the way.  Optimum was found to be a low dose, just two days a week.


Theoretical hedging

Bench scientists have learned to adopt the epigenetic hypothesis in practice, but some are still bound to the obsolete theoretical ideas, inherited from sclerotic thinking about “selfish genes”.  Belmonte was quoted as saying the epigenome becomes “damaged” late in life “At the end of life there are many marks and it is difficult for the cell to read them.”

But studies of aging epigenomics show that in addition to random changes in the epigenetic state, there are definite, programmed changes—enough to make an accurate epigenetic clock—and that some of these changes turn down cell repair functions and turn up inflammation.  Aging involves a loss of order (“damage”), but it also entails a set of programmed changes.  It is the latter that we may hope to address through a streamlined, signaling approach to anti-aging medicine, and, if we are lucky, the body may take up the ball from here and undo part or all of the damage.


The bottom line

This is an important new confirmation of the epigenetic hypothesis.  Previous confirmations were

  • in parabiosis experiments, but the experiment could not be continued long enough to be sure that lifespan was extended
  • in “methylation clock” measurements, but there has been no way to distinguish whether epigenetic changes were a cause or a result of aging.

This new experiment shows that epigenetic changes can extend lifespan.  But the experiment offers no clear extrapolation to life extension for humans.  The treatment depends on four large molecules that need to be delivered to every cell nucleus in the body.  These molecules cannot be taken orally because they will not survive digestion, and even intravenous delivery will not get the molecules to cell nuclei where they are needed.

In cell cultures with the OSKM factors applied externally, stem cell yields are still just a few percent, even after ten years of experience.

The Salk researchers got around this by inserting the OSKM genes into the cell, but for already-living humans this is not a possibility.  The best we know how to do is to modify some of the body’s cells with gene therapy; CRISPR in living humans is itself a new technique in its experimental phase.

So for the foreseeable future, I see a two-pronged approach to cell-level rejuvenation.  One is to remove senescent cells (senolytics); and the other is stem cell removal, rejuvenation, multiplication in vitro, and return to the body.  OSKM may be useful in this second step, rejuvenation of stem cells in vivo.

Telomeres—too much of a good thing?

One of the major themes in aging science of the last 15 years has been that there is natural variation in telomere length, and individuals with longer telomeres have lower disease risk and longer life expectancy than those with shorter telomeres.  A paper last week in Nature Structural and Molecular Biology found that stem cell telomeres are actively maintained at a target length, not just by elongation (with telomerase or ALT) when they get too short but by active trimming when they get “too long”.  We know what “too short” means: short telomeres lead to cellular senescence.  Cells with short telomeres are not just falling down on the job; they are toxic.  But what does it mean for telomeres to be “too long”?

The headline in MedicalXpress says “Scientists find that for stem cells to be healthy, telomere length has to be just right”.  The story underneath includes the claim that “really long telomeres caused telomeric fragility, which can lead to initiation of cancer”.  But now that I’ve read the research article on which it is based and some of the references in that article, I see that the part about cancer was tacked onto a (new and interesting) research finding.  I’m convinced that the meme “long telomeres lead to cancer” has been resounding in an academic echo chamber for 25 years; that it never has had an experimental foundation, and its theoretical foundation is just wrong.

What is new and interesting is this:  researchers at Salk Institute have discovered a mechanism for trimming telomeres.  In our previous understanding, telomeres lose length every time a chromosome is copied (every time a new cell is created).  Telomeres are partially rebuilt by the enzyme telomerase, or by a less direct mechanism called ALT.  Telomeres are fully rebuilt only when new life is created, in a germ cell or a fertilized egg.  In the previous understanding, shortening of telomeres is passive, while lengthening is active.  The new study documents an active mechanism for shortening telomeres.

Part of each telomere is unpaired, a single strand of DNA extending past the end of the chromosome, and folded back over the main (double-stranded) part.  Single-stranded DNA normally means a problem, and the cell nucleus has multiple means to repair or degrade it.  To protect the telomere from being attacked (to prevent fixing of what ain’t broke) the telomere is chaperoned by various protective proteins, most famously shelterin.

We have known that stem cells can express telomerase to counteract telomere shortening, though (in humans) there is not enough to keep telomeres from shortening progressively through a lifetime.  The new finding is that when a stem cell detects that telomeres are “too long”, there is a way to trim them back.  A strand of DNA is manufactured that is complementary to the telomere’s repeated sequence TTAGGG.  The complementary strand (that would be AATCCC, repeated)  has an affinity for the telomere repeats, and it finds and binds to a segment of telomere, then circles, “bites its tail”, and breaks off a ringlet of double-stranded telomere-stuff (called a T-circle), effectively shortening the telomere.

What’s wrong with extra-long telomeres?

The obvious question: why is the cell doing this?  What is the danger of telomeres that are too long?  One natural place to look is in the telomere position effect (TPE).  Telomeres fold back over the chromosome in such a way as to silence genes near the ends.  We might expect that the right genes must be silenced at the right times, and that silencing too many genes with an extra-long telomere would cause problems.  My own best guess is that this is the right answer.

Another hypothesis is that extra-long telomeres are inherently unstable and unmanageable.  But the present studies were done with human cell cultures, where telomeres are ~10,000 BP in length; mice commonly have telomeres ten times that long without causing problems.

The conventional hypothesis is that telomeres are trimmed to prevent cancer, and that is the spin put on the findings by the authors of the paper in their press release.  “We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer.”  In the paper itself, they were more circumspect about this explanation, as is academically appropriate.  These people are masters at what they do (Since spending time at NIBS in Beijing, I have an expanded awe for the experimental virtuosi who are able to infer reliable data about the inner workings of cells.)  But they are not theorists and they trust the community of biological theorists to supply the theoretical framework for interpreting their result.

In this case, the trust is misplaced.  The idea that telomeres are kept short to prevent cancer was originally proposed by (Nobel laureate) Carol Greider (1990), and has been promoted most explicitly by Judith Campisi (1999) before she became convinced by experimental data that the situation is more complicated, that short telomeres are more likely to cause than to prevent cancer (2013).  Through strength in numbers the cancer/telomere hypothesis has achieved “echo chamber” status–many researchers cite each other’s secondary statements on the subject, until tracing the empirical support for the hypothesis becomes unnecessary.  It is common knowledge.

One of the authorities cited in the original paper is this article which is actually about deletion of a gene for a shelterin-related protein that binds to telomeres.  When this gene is deleted, telomeres become unstable and cancer rates rise.  But the article is not about telomeres that are “too long”.  Another authority for the hypothesis that is cited in the original paper is this book chapter.  The chapter is not about cancer, but it does peripherally cite this study from NCI, which finds that cancer is associated with short telomeres, but not long telomeres.

Contrary evidence: health benefits from extra-long telomeres

Just last spring, Maria Blasco’s group at the Spanish National Cancer Research Centre gave us this study, in which stem cells with hyper-long telomeres (up to 300,000 BP) were introduced into mice (in which telomeres normally are already 10 times as long as humans’).  “Mice with hyper-long telomeres…accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53….We further show that wound-healing rates in the skin are increased in chimaeric mice.”  No life span data is reported, but cancer risk was lower in the mice with hyper-long telomeres.

This study from another research group at the same institution linked the extraordinary healing and regeneration capacity of very young mice to their extra-long telomeres.

In this study from UCSF, published just this fall, heart patients whose telomeres were lengthening over the four-year span of the study had 1/3 the mortality rate of matched patients whose telomeres were shortening over the same time span.

Are short telomeres a symptom or a cause of age-related disease?

This is a controversial question only because the causal hypothesis is in direct opposition to standard evolutionary theory.  So much the worse for standard evolutionary theory.

One causal mechanism which is incontrovertible is that cells become senescent when their telomeres shorten beyond a critical length.  Senescent cells are not just non-functional, they are toxic.  Removing senescent cells from the body has been shown to lengthen life span in mice, and senolytic agents are being developed for human use.  Many of us in the life extension movement regard senolytics as the #1 most promising strategy for major life extension in the near term.

The question of causality can be answered definitively by intervening to make telomeres longer or shorter “by hand”.  If short telomeres are a mere marker of past stress, then this should make little difference in the trajectory of aging; but if short telomeres are a cause of aging, then we expect that lengthening telomeres should lengthen life expectancy and lower the (age-adjusted) risk of disease.  In fact, this experimental model has been realized several times in mouse studies, two of which are referenced just a few paragraphs above [#1, #2].  The most dramatic success was in dePinho’s Harvard lab, but there are also impressive results from Blasco’s group in Madrid.

If lengthening telomeres is an effective life extension strategy for mice, it should be all the more so for humans, who have shorter telomeres, longer life spans, and less telomerase than mice.

In the face of this evidence, there are still some influential researchers and advocates in the anti-aging community who opine that “On the whole telomere length looks a lot like a marker of aging rather than the cause of problems: the groups that primarily seek to engineer longer telomeres in search of a way to slow aging are probably putting the cart before the horse.” [quoted today at]  Meanwhile, Michael Fossel has initiated a clinical trial of telomerase gene therapy to treat dementia.  Cancer scares from the echo chamber are spooking the venture capital that would be so welcome for startups that are seeking to bring telomerase therapy to the public.

Can Traditional Chinese Medicine Help You Live Longer?

I have just returned from three months in Beijing as a visiting scholar at the National Institute for Biological Sciences.  My host was Meng-Qiu Dong, who heads a lab studying aging in worms.  At the end of my stay, I took a look at longevity from the perspective of Traditional Chinese Medicine.  There is no doubt that TCM has some gems to offer longevity science, but the overall effectiveness of TCM resists quantification by the usual scientific standards meaning not that it is ineffective, but that it is extraordinarily difficult to define suitable tests.  But the contrast between TCM and modern Western approaches offers us a valuable perspective on our own practices.

[Disclaimer: No one in my institute thinks much about Traditional Chinese Medicine.  They are all trained in Western scientific methodology, many with PhDs from American universities, and they tend to be more conservative, more Western than Western scientists, because they are seeking recognition from American and European bio-medical journals.  They can’t afford to have their reputations tainted by anything that might be labeled as unscientific.]

Personal note

I first became interested in China in the 1970s.  I was a Berkeley grad student, auditing Chinese I every morning at 8 before my physics classes.  I knew that I was viewing the world through lenses shaped by my own education and the culture around me; and I wondered what that world might look like from a very different perspective.

The same idea applies to Chinese medicine.  Its approach and its basis of validity, its range of effects and benefits are different from Western medical science in ways that help me question assumptions that I didn’t know I was making.  I am tempted to scour the English language literature for credible clinical trials of single ingredients isolated from traditional Chinese herbs.  I am more than “tempted” – this is all I really know how to do.  And yet I know that this is an unfair and very limited snapshot of Chinese medicine – see below.  US NIH has a page devoted to TCM, and concludes “For most conditions, there is not enough rigorous scientific evidence to know whether TCM methods work for the conditions for which they are used.”


Berberine is derived from goldenseal=小檗碱 and is a promising anti-diabetic drug, comparing favorably to metformin, though, of course there is much less data available.  Berberine increased lifespan in one fruitfly experiment, but has not been tested in rodents.

I wrote two years ago about Ginseng (人参), the Chinese longevity tonic with the longest pedigree.  Multiple benefits have been documented, including modest effect on lifespan.

The best-documented benefits of royal jelly (蜂王浆), harvested from beehives, are for retaining insulin sensitivity.  There are credible reports of anti-inflammatory activity and promotion of wound healing.  Benefits are claimed for blood lipid profile.  There is one mouse longevity study which showed a promising 25% increase in mean LS without increase in max LS, but the control LS was suspiciously short.  Dosage was 0.05% of dry diet, equivalent to ~2 g/day for humans.

LEF’s “AMPK Activator” =Gynostemma pentaphyllum= jiaogulan= 绞股蓝 is another traditional longevity herb, found in one trial to lower blood sugar.  AMPK is a sigal molecule in the insulin metabolism.  Jiaogulan promotes AMPK, which can reasonably be expected to preserve insulin sensitivity.  To my knowledge, there have been no trials of jiaogulan for rodent life span, and just one 30-year-old study in which it was found to prolong lifespan in flies.

Huperzine-A is derived from club moss=Huperzia serrata= 石杉, and is used for cognitive enhancement and neuroprotection.

Wolfberry (Goji berry= Lycium barbarum = 宁夏枸杞 = ning xia gou qi) has been studied in connection with glycation of proteins in the skin, which contributes to skin aging.


Acupuncture is effective for relieving pain and inflammation of arthritis [review].  Surgery patients anesthetized with acupuncture have shorter recovery times and better outcomes than patients under chemical anesthesia.  (Western science doesn’t have a clue how acupuncture works.)  Chinese herbs are effective in treating irritable bowel syndrome, and even more effective when the treatment is individualized by a TCM practitioner [ref].  Ginger in the diet is linked to lower levels of inflammation [ref]. Tree ear fungus (木耳=Aricularia) reduces risk of stroke and heart attacks from blood clots [ref], and oyster mushroom (蚝蘑) has anti-inflammatory effect and benefit for blood lipid profile [ref, ref].  Elders who practice Tai chi (slowest and gentlest of the Chinese martial arts) are less likely to fall and less likely to suffer fractures if they do fall (ref).  Meditation lowers morbidity and mortality, improves measures of mental and physical health, lengthens telomeres [my review].

Chinese and Western Medicine A general comparison

Traditional Chinese Medicine Western Biomedical Science
Legtimacy comes from thousands of years of collective experience, in oral and written traditions. Legitimacy based on statistical analysis of objectively measurable responses, averaged over large populations in the last decade or two.
Individualized treatment different for each patient. Standardized treatment; same for everyone diagnosed with a given condition.
Qualitative, multi-dimensional diagnosis. Binary diagnosis the patient has the condition or he doesn’t.
Treatment aimed at restoring long-term health. Treatment aimed at relieving acute condition.
Combination of many herbs with dietary recommendations, acupuncture, and some prescribed behaviors that seem to us random and irrelevant. One drug for one condition.
Integrated diagnosis and treatment of body and mind. Treatment of each body part or system as a separate entity.
Doctor-patient relationship is integrated into the treatment plan. Doctor-patient relationship is treated as an artifact, the “placebo effect”, noise that interferes with evaluation of the core treatment.

Those few Western scientists who pay attention to ancient medical traditions treat them as a trove of ideas for suggesting single chemicals that can be isolated and tested for efficacy, in animals and people the same way we might test any new drug.  It is hard to find funding for these tests, promising as they are, because the chemicals are not patentable.  

And when such studies are funded, they don’t do justice to the Gestalt of TCM.  If we find that individual molecules isolated from TCM herbs are potent healers, how much more benefit should we expect from synergy of the traditional combinations of herbs and the personalized diagnoses by healer with training and experience?

For all the reasons above, TCM doesn’t fit with the standard mode of scientific evaluation.  If each patient is treated differently, how can you make statistical inference?  If the doctor-patient relationship is part of the treatment plan, how can you subject the plan to a double-blind comparison?  If we test one chemical at a time, we may miss important synergies.  And if we look just at short-term outcomes, we are blind to what is most important to the patient over the course of his life.

Fictions of Western Medical Science

What can we learn about our habits of thought by immersing ourselves in another culture and looking back?  Our first reflex may be to subject TCM to standard evaluations from evidence-based medicine.  But equally important is the perspective we gain from criticizing  Western medicine fromt he vantage of TCM.  

We (Western, scientific types) know that different people’s reactions to disease and responses to treatments are highly idiosyncratic; yet we treat all differences as though they were random scatter in the data, and look for one-size-fits-all treatments.

We know that drugs interact with one another, including both synergies antagonisms, and that these .   All of life depends on homeostatic balance among thousands of active chemical agents, catalytic enzymes, and signal molecules.  Yet our research is based on testing one drug at a time. Building knowledge from the ground up is the only way we know how to do science.   Less than one experiment in 100 looks for pair-wise interactions, and almost none explore the effects of a dozen or more treatments in combination.  

We value predictability and reproducibility, sometimes to the neglect of miraculous effectiveness.  We imagine that the world is a predictable clockwork, of which our task is to learn the mechanism, and we are suspicious of any intervention that works only some of the time.  We disdain anecdotal evidence.  Thousands of credible stories of one-off cancer cures are discarded in the dustbin of quackery; we refuse to learn from them because other people given the same treatment were not cured.

We have moved toward standardization of medical practice.  American caselaw in medical malpractice sets a disastrous incentive structure, defining malpractice as doing anything different from what the majority of other doctors are doing.  A good doctor’s experience and subjective intuitions can potentially provide a treasurechest of treatment options, but in America there is a powerful legal and cultural discouragement from trying anything that is not “the standard of care”.

As medical knowledge has multiplied, Western medicine has moved toward specialization.  We rely on experts who know one field, even a single disease, or even a single treatment for a single disease in great depth.  With specialization, we have lost the generalist’s knowledge of interacting body systems and organs, and the art of gathering diverse symptoms and observations to infer a diagnosis has been replaced with algorithmic medicine.

Background Western and Eastern Thought

Western science doesn’t have life completely figured out yet this is no surprise.  “Too complex” is the common refrain, but I think the problem may be deeper.  Since the 19th Century, biology has been committed to a reductionist approach.  Modern biologists are committed to a program of building an understanding of life from the bottom up, beginning with molecules.

It’s commonplace to say that Eastern thought is more holistic, Western more reductionist.  Many of the principles of Chinese medicine are conceived in terms that make a Western scientist snicker, and many are tempted to dismiss the whole field based on its theory.  But the other side of Chinese medicine is that it incorporates thousands of years of experience, and the treatments that have survived the centuries are the ones that work.  For example, the whole field of acupuncture was once dismissed as superstition, but now is accepted as a set of techniques that work for pain relief and sometimes for healing, but Western medicine has no way to think about its mechanism.

There are MDs here who practice both TCM and Western medicine, and they have the experience and the wisdom to know which patients will respond best to one or the other approach.  There are drug stores here that carry Traditional Chinese Medicine alongside their prescription drugs, in a separate department.  

A typical Chinese prescription consists of a bag full of a dozen or so herbs and roots that are boiled, and the broth imbibed once or more per day.  It’s safe to assume that tradition has combined these herbs in these combinations for a reason, but the Western analytic approach is yet quite far from a predictive science of how they interact.  The moral is that when we encounter evidence for the effectiveness of TCM, we should resist the temptation to look for the Active Ingredient, lest we risk killing the goose that lays the golden egg.  

I would like to see a study of people who have used TCM over several decades, not just to treat a particular malady but as a tonic for general health.  Compare specific health outcomes as well as morbidity and mortality for a cohort of such people with a matched cohort that has comparable diet, income and lifestyle, but does not use TCM.

Optimizing the Placebo Effect

Don’t look down on what Western medicine calls the placebo effect.  While its power is universally acknowledged, Western institutions do nothing to try to get the most out of the doctor/patient relationship, and in fact the Balkanization of medicine and the economic pressures that have progressively curtailed doctor/patient interactions speak loudly of disdain for the power of “bedside manner” in the healing process.  The mind/body connection may not be understood, but it is of paramount import, probably as powerful as all of Western medicine combined.  It is only common sense that some practitioners will be much more effective than others, and that time to foster a human relationship has potential both to restore meaning and satisfaction to the work-life of physicians, and also to turn them into more effective healers.  In contrast to Western medicine, a personal connection with the doctor is well-integrated into the culture of TCM.

Random observations on Chinese health and longevity

China is westernizing at a pace and TCM is declining in popularity, especially with the younger generation.  At the same time, TCM and acupuncture in particular are gaining adherents and practictioners in the US and Europe.

Life expectancy in China is 75 years, compared to 79 years in Taiwan (tied with USA), 85 years in Japan.  The amount that Americans spend per capita on health care is about $9,000, compared to $1,800 in Taiwan and $500 in China.  In fact, Chinese expenditure on everything put together (per capita GDP) is only $8,000.

Two thirds of Chinese men smoke (compared to <20% in the USA), but the smoking rate for women is actually lower than the US.  Only recently, the Chinese government has begun measures to reduce smoking, beginning with a ban in public buildings in 2010.

I have seen people in China eat liberal quantities of rice with each meal, and yet the obesity rate among Chinese men is 0.6% compared to >30% in America.  The weight difference is something you might readily notice while walking around any Chinese city.  The traditional Chinese diet includes small bites of meat as a condiment, but with recent prosperity has come increasing meat consumption.  The “sweet tooth” as an addictive affliction is less prevalent in China than the West.  “Gym rats” can be found in China, but much more rarely than in the US.  People have more exercise built into their day, less time set aside for exercise as a Thing To Do.  Chinese cities have undergone explosive growth in recent decades.  Pollution in Chinese cities (Beijing is worst) is bad enough to be a major factor in mortality statistics.  

…and a glimpse of the modern side of Chinese medicine

This week, oncologists at Sichuan University Hospital in Chengdu announced that they had used CRISPR technology for the first time in a human medical application.  Immune cells were harvested from a lung cancer patient, and the cells were treated with CRISPR-Cas9 to remove the gene for a protein called PD-1.  The function of PD-1 is to help killer T-cells identify the body’s own healthy cells and make sure that the immune system does not attack them; but some cancers have learned to evade immune attack by displaying a PD-1 target.  The Sichuan team cultured the modified T-cells and returned them to the patient, on the theory that they might renew the body’s failed immune response to the cancer.  Results of the trial are not yet reported.  Principal Investigator Lu You emphasized that this is a small trial focused on safety, and ten patients will be closely monitored to look for indications that the modified immune cells have attacked the patient himself.

The Bottom Line

The Western, scientific approach to medicine is my paradigm and (I presume) yours; but it is not the perfect paradigm or the only paradigm.  People who dismiss the 2500-year-old wisdom of TCM as superstitious nonsense are missing a potential influx of new ideas and an opportunity for self-reflection.  It is only by getting outside our paradigm that we can see its limitations, realize that our thinking has been within a box.  

Research scientists in America and Europe have to compete for grants and have to get their work accepted into one or another elite journal.  This creates incentives to stick to the kinds of biological questions that can be addressed through standard methodology, that will yield definitive answers within a few years at a cost the lab can afford.  We can hardly expect  researchers to behave otherwise.  But we might, at least, recognize that the system steers researchers to ignore approaches that involve multiple coordinated interventions, that rely on experience or expert judgment to be tailored to individuals, or that work via pathways that we do not understand.  We ought to recognize that some promising treatments for life extension and health have been excluded from investigation “in the name of Science”.