Open Letter on Research Priorities in Aging

Last week, I had the honor of speaking with Cynthia Kenyon, who has been recruited by Google to direct research activities at their new venture into aging medicine, called CALICO, for California Life Co.  She was kind enough to listen to my thoughts on research priorities seeking near-term breakthroughs in human life extension.  Here is what I said to her, paraphrased with some added background and comments.


It is my belief that the timing of development and aging is determined by chromatin* state.  The body knows how to be young, and it knows how to be old.  The difference is coded in chromosomes, especially in telomere length of stem cells and epigenetic markers in endocrine cells.

* Chromatin is the DNA in the cell nucleus, together with the histone spools around which it is wrapped and all the proteins and side-groups that are loosely and temporarily attached.  Spooled DNA is called “heterochromatin” and it is mostly silent.  Unspooled DNA is termed “euchromatin” and it is more likely to be active.  All the protein markers, the methyl groups and acetyl groups strategically placed, together determine when and where particular genes are expressed.  This phenomenon is called “epigenetics”.  How is epigenetic programming effected?  The cell’s epigenetic language if much more complex than the Genetic Code, and is yet poorly understood.

I am proposing that aging is, in large part, a matter of epigenetics.  A different set of genes is turned on when we are young compared to when we are old, and that makes all the difference.  Here are four references on the subject, including my own #4 [Ref1, Ref2, Ref3, Ref4].


Background assumptions

I believe that aging is controlled by several biological clocks.  This is a strong claim, but I think it has good support, outlined in the references above.  Biological clocks certainly control development, puberty and related schedules early in life.  How the body knows its own age is yet incompletely understood.  It’s a good bet that the same clocks that control development have been re-purposed to control aging.

There are three clocks we know something about.  These are the epigenetic clock, cellular senescence (telomere loss), and life-long shrinkage of the thymus, master gland of the immune system.

A common way to construct a clock is with a feedback loop.  A clock looks at itself to determine its next move.  The body has a feedback loop between epigenetic state (at a cell level) and circulating hormones and RNAs (at a systemic level).

  • The epigenetic state determines which hormones and RNAs are expressed.  Endocrine glands in particular are sending hormones out into the blood which are selected by their epigenetic state.
  • The circulating hormones feed back to cells and re-program the epigenetic state. All cells in the body are constantly receiving signals from the blood that guide them in continually reprogramming their DNA to express some genes and silence others.

There is evidence that telomere length in stem cells constitutes an independent aging clock.  Studies have shown that people (and other mammals and birds) with shorter telomeres have shorter life expectancies than people with longer telomeres.  Extending telomere length is simply a matter of signaling the body to express telomerase, which is always available in the genome but normally is expressed only in embryos.

The thymus is the organ where white blood cells are trained to attack foreign invaders and lay off the body’s own cells.  The thymus shrinks beginning in childhood, accelerating with age.  Late in life, the thymus becomes seriously deficient in its function, with the result that white blood cells make two kinds of mistakes.  Type I errors cause the T-cells to fail to attack invading parasites, with the result that we get sick more often as we age.  Type II errors cause the T-cells to attack healthy cells, leading to the auto-immune diseases of late life such as arthritis and exacerbating inflammatory damage.




1) There is intriguing data from parabiosis that circulating factors may be able to reprogram the body’s age state.  (This is the “back end” of the feedback loop described above.)  If we’re looking for quick progress against aging, the circulating hormones are more accessible and make a more convenient target than trying to get inside the cell nucleus to reprogram epigenetic state directly.

Some of the blood factors most important for aging have already been identified.  For example, as we get older, we have too much NFkB, too much TGF-ß.  We have too little GDF11, too little oxytocin.  Irina Conboy has led me to believe she knows a few more, and identifying these factors is at the center of her research.  It’s a good bet that Tom Rando, Amy Wagers and other parabiosis researchers are compiling their own lists.

If we’re lucky, then adding some factors to the blood while blocking others will have a long-lasting effect of re-programming epigenetics, and the body will take over by continuing to secrete a “young mix” into the blood stream.  If we’re not so lucky, it may be necessary to perform some epigenetic re-programming more invasively.  CRISPR technology holds promise in this regard.

2) I believe that telomeres will also have to be extended in a fully-effective anti-aging program. Many herbs and supplements are known to have small activity in promoting telomerase (e.g., cycloastragenol, silymarin, carnosine).  Bill Andrews claims to have a synthetic telomerase promoter that is 50 times more potent than any of these.  Mike Fossel and others are also pursuing the search for telomerase activators.

3) Multiple treatments have been documented over the years to increase thymus size in humans and in animals.  These include growth hormone, zinc, melatonin, and thymic peptides.  A recent breakthrough from Univ of Edinburgh suggests a particularly effective treatment.



Telomerase activators are ready for safety tests and human trials now.

Various techniques for thymus regrowth are ready for clinical trials.

Based on encouraging results with mice just last spring, Tony Wyss-Coray of Stanford Med School has just begun human trials (for Alzheimer’s Disease).  This work should be rapidly expanded if his preliminary results are promising.

GDF11, oxytocin and other blood factors should be tested for rejuvenating potential in rodents.  Drugs can be developed that block NFkB and other pro-inflammatory signals.

Poking Fun at Longevity Science

“In science one tries to tell people, in such a way as to be understood by everyone, something that no one ever knew before. But in the case of poetry, it’s the exact opposite!”
                                — Paul Dirac

Gretchen Reynolds, in her chart on “Longer Living Through Science” does a good job of making science into poetry.  Full of qualifications and afterthoughts and 180o reversals, longevity research makes an easy target for satire.  Reynolds herself has established herself as a consistent advocate for some of the clear messages concerning exercise and diet that come from this research.  As we smile, let’s remember that our lives and our health hang in the balance, and through all the contradictions, there are some persistent truths.


This chart was published in the New York Times Magazine on Sunday, summarizing the last four years of scientific studies concerning longevity.

The point of the chart is to convince us that longevity science is a hodge-podge of contradictory results.  The things that consistently lead to better health and longer life are beyond our control (genes, pollution, wealth).  Among things that are under our control, mere mortals cannot know what is effective (diet, exercise, smoking and drinking).

There are many reasons that specific items in the chart are not as inscrutable as they appear.  Reynolds cites only studies of the last four years, and current research is always focused on the unresolved questions, not the well-established basics. Studies based on human longevity are the gold standard, but they must be interpreted with care since they cannot be properly controlled.  (You can’t put humans in cages and vary one factor at a time.  This makes it difficult to disentangle the many correlated variables and draw conclusions about root causes.)  Studies of mice and rats are generally the best indication of what will work in humans.  Studies of flies and worms cannot be directly extrapolated to humans.  They are valuable for biochemical understanding and suggestions for further study; but most treatments that work to extend life in flies fail in humans.

Every result cited in the chart is, in fact, a subtlety, a nuance at the edge of what we already knew about behaviors that affect longevity.  Absent from the chart was the one result that is new, and a reversal of what doctors had been recommending for decades.  Standard doctors’ advice has been to minimize salt intake, and last year it was found that higher salt intake is associated with lower mortality.

Perhaps the most contentious area involves weight loss.  It’s an issue frought with emotion for most of us.  On the one hand, caloric restriction has been the most robust technique for life extension in lab animals for the last 80 years.  On the other hand, using will power to eat less doesn’t work for most of us, and in fact willpower has been found to backfire and produce weight gain more often than not.  Further complication comes from social prejudices against heavy-set women.  For most women, appearance is a stronger motivater than health, and this has produced an epidemic of unhealthy dieting.

I believe this phenomenon has a lot to do with why studies of BMI have failed to show any advantage to being skinny.  In fact, these results always underestimate the damage that is done by overeating.  

People’s weight is determined by a combination of genetics with diet and exercise.  But being congenitally overweight is not a health risk, while overeating and under-exercising are clear health risks.  There are “lucky” people who can overeat without gaining weight, and “unlucky” folks who are disciplining themselves to eat less and exercise more, because they fear that extra weight will make them unattractive.  These two people may have the same BMI, so they are lumped together in the statistics, but the latter will have much better health prospects than the former.  It’s a kind of poetic justice—regardless of cosmetic appearance, nature has been even-handed in rewarding temperance with health.

BMI studies should be re-scaled to separate genetics from life style.  In support of this idea, results from genetically obese mice indicate that they have exceptionally long life spans when calorically restricted, even though their appearance is not at all lean.

Here are some uncontroversial recommendations from the community of scientists who study human longevity:

  • For most people, smoking is a health risk and shortens life expectancy.
  • Exercise contributes positively to every aspect of physical and psychological health, as well as longevity.
  • Conversely, overeating, especially carbohydrates, has a negative effect on health and longevity.
  • Community, engagement, love and relationships of caring have as great and robust a benefit for health and longevity as any physical factor.
  • Anti-inflammatory foods and supplements have shown consistent benefits.

There’s much more on my Aging Advice page, including my personal recommendations that are not yet standard medical advice.

We all need help laughing at ourselves, and I’m happy to accept a poke from Gretchen Reynolds. But let’s not forget that we live in a culture that seduces us into the obsessive earning of money, consuming of food and entertainment, all distracting us from the basics of our health.


Lithium for Life Extension?

Last month, Anna Fels wrote in the Sunday NYTimes suggesting that lithium be added to the drinking water because trace amounts of lithium are associated with lower rates of mental illness, violence and suicide in particular.  What she didn’t say was that communities with naturally-occurring lithium in their drinking water enjoy greater longevity as well.  Though the evidence is still thin, there is a credible mechanism, through inhibition of a chemical signal called GSK-3β.  The dosages we’re talking about are ½ to 2 mg per day, which is less than 1% of the dosage typically prescribed for bipolar disease.


Lithium is not a drug, but a chemical element.  It is right above sodium in the periodic table, and the theory is that the body can’t tell the two apart.  Sodium is an essential electrolyte, and the body uses it everywhere.  Nerve signals are propagated as waves of substitution of sodium for potassium.  The theory is that trace amounts of lithium in the body replace sodium, and move a little faster across membranes, because the ions are smaller and lighter.

The only study looking at all-cause mortality compared different regions of Japan.  Drinking water was analyzed and mortality rates were compared in 18 different towns, 1.2 million people in all.


Top graph: 18 Japanese towns Bottom graph: Survival curve of lab worms

The top graph shows about 10% decrease in mortality in regions of Japan that had naturally high concentrations of lithium.  Large dots correspond to counties with large populations. Note the log scale on the X axis; the high counties had about 30 times as much lithium in their drinking water compared to the low counties.  10% decrease in mortality corresponds to about an extra year of life, extrapolating boldly.

The bottom graph is a survival curve for lab worms with lithium added to their medium, compared to control worms without.

The most abundant and compelling data is about suicide and violent crime rates in towns with varying amounts of natural lithium in the water.   Twenty different studies in different parts of the world are summarized here.  This same review covers four studies in which lithium was used to treat Alzheimer’s Disease, and all four found benefits, measured by cognitve performance.


Lithium in the diet

There is general agreement that animal grazers don’t concentrate lithium, and the best dietary sources are plants.  Which plants are best?  The answer seems to depend on lithium in the soil at the site where the plants happen to be grown.  We can’t characterize some foods as “good sources of lithium” except according to the location in which they were grown.  So it is impractical to figure out how much lithium you’re getting in your diet.  A blood test might be helpful, with the qualification that lithium passes quickly through the body (swept through with sodium), so the test is sensitive to what you happen to have eaten in the last 24 hours.


How does it work?

Of course, we don’t know how lithium works, but speculation all centers around a powerful and ubiquitous (if little-known) chemical signal called GSK-3β.  Lithium suppresses the action of GSK-3β.  All that I know about GSK-3 (alpha and beta forms) I learned from this article by James P Watson (not to be confused with the Watson who got the Nobel for DNA).

The alpha and beta forms of GSK-3 are distinct proteins, derived from separate genes.  The nomenclature would lead you to believe that they are different forms of the same thing, but the nomenclature is deceptive.  I’m not going to tell you what GSK stands for, except that the last word is kinase, because the name reflects only the particular circumstances in which GSK happened to have been discovered (in 1980).

If “energy is the currency of the body,” then phosphate groups are the dollar bills.  Kinases are enzymes that activate other chemicals by attaching a phosphate group to them.  The GSK-3s are kinase amplifiers.  They specialize in finding placs where there is already a single phosphate, then adding more to fully activate the substrate.

GSK-3β has been implicated in the formation of amyloid plaques in the brain, which is one theory for the cause of Alzheimer’s Disease.  This was the motivation for trials of lithium against AD, which have shown early signs of success.

The two forms of GSK-3 are involved in many different processes, turning on dozens of genes and turning off dozens more.  The actions are varied and complex, and GSK-3 cannot be characterized as helpful or harmful.  Watson refers to GSK-3α as the “mainly good guy” and GSK-3β as the “mainly bad guy”.  GSK-3β expression increases with age, and it may play a predominantly pro-aging role.  Suppressing it a bit seems to do some good.  GSK-3α does not modulate consistently with age, either up or down.  However, when the GSK-3α gene is knocked down in mice, the mice are not only viable but have lower fat mass and increased insulin sensitivity—harbingers of extended life.  Watson characterizes GSK-3α nevertheless as “mainly good” based on its effect dampening three aging targets: mTOR, Wnt and P53.  P53 controls apoptosis=cell suicide which, I have argued, is on a hair trigger as we age.  Dialing down apoptosis non-selectively has general benefits for preserving muscle and nerve cells, but it also increases cancer risk. TOR is “Target Of Rapamycin”.  Recall that rapamycin is a drug that made headlines three years ago when it was found to extend mouse life span, though fed to the mice late in life.  Rapamycin is a powerful immune suppressor, and may be too dangerous a drug for general human use, but other drugs that dampen TOR signaling may be promising.


Speculation on the future

I am convinced that both forms of GSK-3 are key players in aging and other metabolic functions.  However, they may not be good targets for anti-aging intervention because they play on both teams (promoting pro- and anti-aging pathways).  The fact that they need “priming”—a first phosphorylation by a more specific kinase—indicates that they are not an upstream source of aging.  We can find better targets.

Trace doses of lithium might prove to be useful for modestly extending life and protecting against Alzheimer’s.  I’d like to see studies in mice, and larger epidemiological studies, and then clinical trials if warranted.  There has been only one epidemiological study.  It should not be difficult to find some part of the world where people don’t tend to move very often and then correlate local concentrations of lithium in drinking water with local variations in age at death.


For early adopters

If you want to experiment with lithium, I think that doses up to 1mg/day are safe.  Just for context, this is a tiny quantity.  One ounce of lithium is a lifetime supply.  Larger doses are not better.  They are toxic.

Lithium is not a standard ingredient in multi-mineral pills. Nor is it a standard blood test.

Lithium carbonate is available as a prescription drug, in pills that cannot easily be divided into 100 doses.  If you felt comfortable with the procedure, I suppose you could dissolve a 500mg pill in a pint of water and take it by the teaspoon.  There are about 100 tsps in a pint.  Lithium carbonate is about ⅙ lithium.  You can also get lithium salts from chemical supply houses.

Google to find on-line sources of supplements with appropriate low doses of organic salts of lithium, like lithium arginate and lithium orotate.  They are not better or more bio-available than the simple carbonate, just more expensive.

Thanks for Michael Eaves for pointing me to sources for this article.

Anti-aging Oxymorons and         Anti-oxi-morons

The natural foods industry is deep into the anti-aging business, and it’s all based on two lies—one about pesticides and toxins, the other about anti-oxidants.  Neither toxins nor oxidation are the reason that we get old, and we can’t live longer by eating less toxins or more anti-oxidants.  In fact, toxins in small quantities stimulate the body’s longevity pathways, and anti-oxidants can nullify the very real anti-aging benefits of exercise.

People who are fanatical about clean air and organic food don’t live to extraordinary ages.  Animals raised in a super-clean, toxin- and pathogen-free environment actually die earlier than animals raised with bugs and dirt.

Anti-oxidants have been tried in animal experiments and human studies, and they don’t extend life.  In a definitive study, 29,000 Finnish men were given anti-oxidant vitamins in the 1990s, until the experiment was called off for ethical reasons.  It turned out people taking the vitamins were dying at a higher rate than the placebo group.

“Natural anti-aging” is a contradiction in terms, an oxymoron.  There are plenty of good reasons to eat organic.  Support more sustainable farming practices.  The vegetables taste better.  There’s more nutritional value and it might even be healthier, especially for young people.  But natural foods are not part of the recipe for a longer life.

In fact, there is plenty you can do to slow down aging and improve your odds for a long life, but the best practices aren’t particularly “natural”.  Weight loss, fasting and short bursts of vigorous, all-out exercise are high on the list.  There are also some hormones and two prescription drugs* (long out of patent) that seem to work.  The easiest thing you can do to improve your odds is to take tiny doses of aspirin and mega-doses of vitamin D. (Much more here.)


What aging really is

Aging is not about the body wearing out, and it’s not about accumulating  toxins.  Aging is something our bodies are doing to themselves.  All the stuff that goes wrong as we get older is no accident, and it’s not a failure of the body.  Aging is suicide on a schedule, programmed into our genes.

  • The stem cells in our body are tasked with renewing our skin and muscle and bones and blood, and even our nerve cells regrow over time.  But the stem cells have replication counters in the chromosomes.  Regular readers of this page are familiar with telomeres and “cellular senescence”.  Telomeres are the body’s primary aging clock; when the counter gets too high, the stem cells get the message to slow down growth and repair, to let the body go to pot.
  • Our immune system is brilliant at distinguishing invaders from self, attacking the former and protecting the latter.  This is done by the T-cells in our blood.  The T in T-cell stands for “thymus”, a little organ behind the breast bone where T-cells are trained to tell the good guys from the bad guys.  But your thymus has been shrinking ever since you were about 10 years old, and by the time you’re 40, it’s only ⅓ what it was when you were a child.  90-year-olds have almost no thymus left, and that has everything to do why 90-year-olds can’t defend against the flu, and why pneumonia is the Old Man’s Friend.
  • The T-cells don’t just fail to defend us against enemies, they make the opposite mistake as well, and attack perfectly good, healthy tissue.  Inflammation is your first line of defense against invading microbes when you’re injured, and it works great when we’re young.  But as we get old, inflammation turns inward.  Healthy cells are destroyed.  Stem cells are re-purposed as cancer cells.  Inflammation has been linked to the Big Four diseases of old age which, together, are responsible for more than 90% of all deaths:  cancer, heart attacks, Alzheimer’s dementia, and stroke.
  • There are more ways in which the body actively destroys itself in old age.  Read some of them here.

These aren’t failures of the body.  They’re mutiny.  We can’t fix these problems by supporting the body with a natural diet.  Instead, we have to trick the body into doing something it wasn’t designed to do.  That’s the very opposite of “natural”.

The reason that medical progress in the diseases of old age has been so slow is that the researchers are all working with the wrong model.  They are stuck in the paradigm of the 20th century, when “natural medicine” was so successful.  The idea was to work with the body, to enhance the body’s natural defenses,  to help the body heal itself rather than to engineer fixes from the outside.

This worked really well for trauma and for infectious disease and all the diseases that young people get.  But it won’t work for the diseases associated with aging, because the body itself is the enemy.  The body is programmed to self-destruct—that’s the very essence of aging.  We can’t fix it by coddling or helping or restoring the body, because the body is divided against itself.  We can’t oppose aging with “natural medicine” because aging itself is natural, designed into our life plan.


Why don’t anti-oxidants work?

Every cell in the body generates the energy it needs in hundreds of tiny factories called “mitochondria”.  And it’s true that they generate toxic waste, in the form of ROS, Reactive Oxygen Species aka Free Radicals.  The ROS can attack the body’s sensitive biomolecules and make them dysfunctional.  This much is true, and it has been the basis of one of the oldest and most popular theories, the Free Radical Theory of Aging.

The Free Radical Theory is more than fifty years old, and based on the theory, a substantial industry of anti-oxidant vitamins and supplements has grown up.  If damage from oxidation was the problem, then anti-oxidants should be the solution.  It was a plausible theory when it first came out, but we’ve known for twenty years now that anti-oxidants don’t work.  The only reason this news hasn’t reached the public is that it is bad for sales.  What is more, we now understand why they don’t work.  It turns out that the damage caused by free radicals is completely avoidable, and it occurs when the body dials down its own native anti-oxidant system.  The body has its own anti-oxidants, perfectly adequate to quench the free radicals and keep the damage to levels at which it doesn’t accumulate at all.  Some of these molecules are glutathione, ubiquinone (aka CoQ10), and SOD=superoxide dismutase.  But they are all held back, so we have less of them in old age.  Our defenses against oxidation are crippled by design, and that’s why oxidative damge tends to accumulate.

The deeper reason why anti-oxidants do more harm than good is that the body uses free radicals as a signal that switches on active repair and rebuilding.  Every time you exercise, you generate copious free radicals, and they signal the body to repair damage, and rebuild muscle and bone better-than-new.  Free radicals also signal the body to keep insulin sensitivity high, steering away from diabetes.  When we take anti-oxidants, we interfere with this system, and that’s why anti-oxidants do more harm than good.  Anti-oxidants shut off the signal that tells the body to rebuild tissues and upgrade defenses.



It’s an idea with enduring appeal, that the reason we age and die has to do with accumulating  toxins.  And modern life is toxin city—pesticides, fertilizers, plastics, GMOs, and heavy metals.  But, once again, the idea has not panned out.  It is based on a faulty foundation,  a mistaken concept of aging and where it comes from.

Tiny doses of toxins may, in fact, be good for us.  Homeopaths have been telling us this for 200 years, but only in the last decade has hormesis gained acceptance as a medical concept.  Confronted with a challenge, the body jumps to respond, and unexpectedly, the body over-reacts.  We are stronger and live longer in the face of hardships than if we live a protected life.  Dogs exposed to tiny doses of chloroform live longer than dogs that are fed a pure, toxin-free diet.  Rats raised in a germ-free environment don’t live as long as rats who get an average dose of dirt and disease.  And so on…there is a whole literature of hormesis.


Paleo diet

This is an idea based on a completely muddled understanding of aging.  But despite this, it happens that it’s not a bad diet.  The Paleo Diet is one of those ideas that works much better in practice than in theory.

Grains are mostly starch, and avoiding starch offers a substantial benefit.  Starch is turned instantly to sugar in the mouth, before it even reaches the stomach.  Less starch and sugar means less insulin, which slows the decline into insulin resistant “type II” diabetes, which is one deep cause of aging.  Raw foods are a good idea precisely because they are difficult to digest.  Raw foods are absorbed slowly and incompletely.  For those of us who enjoy eating or who are addicted to food, raw foods may allow us to eat to satiety, because more of the food goes through us, and less is absorbed.  Raw foods are also less prone to cause a spike in blood sugar, triggering insulin release.

Just try getting fat on a raw food diet, and you’ll see what I mean.

Less starch and more raw foods are the best things about the Paleo Diet.  The theory behind the Paleo Diet is something else again.  It’s based on the idea that our body is evolved to work with the foods that were available while we were evolving, which was, for the most part, before agriculture, in hunter-gatherer societies.  You might be suspicious from the get-go when you realize that life expectancy in hunter-gatherer societies is under 40 years, even when the high rates of infant mortality are factored out.  If the paleo diet worked so well, we would expect to find some extraordinarily old people among native peoples in parts of South America and Borneo where they still live the lives of our ancestors 20,000 years ago.


What works?

There is a lot you can do here and now to slow aging and improve your odds for continued good health.  I’ve summarized what I know on the page (a non-commercial web page with no advertising).  If you adopt all these measures, it should buy you an extra decade of health.  Much of it is standard medical advice:

  • weight loss
  • vigorous exercise
  • daily baby aspirin
  • a low-carb, anti-inflammatory diet
  • regular sleep habits

But there may be more effective and easier remedies available soon.  The future of anti-aging medicine is fast upon us.

The good news is that researchers are beginning to realize that aging is an inside job.  There are hormones and biochemical signals that tell the body to self-destruct.  Jamming a chemical signal is something that pharmaceutical companies know well how to do and it’s much, much easier than repairing a body full of random damage.  Some of the hormonal signals have been identified just in the last year or three:  Pro-aging (inflammatory) signals have names like NFκB and TGF-β.   Anti-aging signals include GDF11, melatonin, and the “love hormone” oxytocin.  Researchers at Stanford are beginning this month to test transfusions of blood plasma containing a hormone mix from young donors as a treatment for Alzheimer’s Disease in the elderly.

Telomere regrowth is another area that has the potential to extend life dramatically, and even to roll back the years.  There are several companies now selling herbal supplements that can turn on telomerase modestly.  Researchers are hot on the heels of powerful telomerase activators that might actually turn back the body’s primary aging clock.

Look for tangible progress in anti-aging technologies in the near term.

* One is glucophage=metformin; the other is deprenyl=selegiline=eldapryl=emsam.