Anti-Aging Medicine: Two Paths Diverge

…and sorry I was I could not travel both.

  • Aging is an accumulation of damage.  If we want to return the body to a more youthful state, we’re going to have to repair that damage.
  • The body never forgets how to be young.  Given the appropriate signaling environment, the body will restore itself to a youthful state.

The future of medicine is the future of anti-aging medicine.  I don’t think anyone seriously disputes this.  Infectious diseases are a minuscule problem compared to a century ago, and with hygiene, good public health practices, and responsible restraint in applying antibiotics, we may hope to avoid a return to the days when tuberculosis and syphilis were pandemic.  We are fast learning to treat congenital disorders, and safe gene therapies are already being tested.

This leaves diseases of old age as the next frontier.  To slow the progress of aging, there is no doubt that signaling approaches work in animals, and will work (probably with less efficacy) in humans.  Caloric restriction (CR), exercise and other forms of hormesis are the best approaches we know at present.  Pills (e.g. metformin, berberine) may offer some of the benefits of CR without the hunger, and an “exercise pill” has been proposed.

The next step is to actually reverse aging, to restore the body to a more youthful state.  Among those of us who advocate research in the technology of age reversal, there are two prevailing paradigms.  I am with the school that says the same signaling approach can be extended to trick the body into thinking it is younger than it is, and the body will renew its cells and replace damaged biomolecules on cue.  The other school says that once the toothpaste is out of the tube, it’s not going back in.  We will have to engineer prosthetics, use bioengineering and regenerative medicine to replace body parts that have worn out.


“Everything degrades over time–it’s basic physics”

This is just wrong, but it’s so prevalent (among gerontologists and the great unwashed masses alike) that I’ll refute it yet again:  There is no physical necessity for aging.  Analogies to wearing out and to chemical corrosion are flawed and misguided.  The body may accumulate more damage than it repairs; but it may also repair more damage than it accumulates.  The choice is made by the metabolism (as programmed by evolution), not by physics.

  • The Second Law of Thermodynamics is specifically about closed systems, meaning systems that don’t interact with the outside world.  But living beings are evolved to take in order from food or sunlight and dump entropy back into the environment.  All of life is an end run around the Second Law.
  • Still, some people say the “end run” has to come to an end some time.  How can repair be “perfect”?  Well, it doesn’t have to be perfect. There is nothing perfect about a 20-year-old body, and it is the body’s metabolic choice whether to build itself ever stronger, more resilient and less vulnerable to disease, or allow it to decay, or (in between) to maintain a constant level of youthful robustness indefinitely.
  • …and indeed, some animals and many plants do go on getting stronger and larger, with lower and lower mortality risk, year after year after year.  This is called negative senescence, a fancy word for aging backwards.  Most trees do it, as well as lobsters, clams, some turtles, and possibly sharks and whales.
  • If physics demanded that living organisms always degrade then growth and development would be impossible.

Evolutionary biologists almost all appreciate this—aging is a problem for evolution, not for physics.  Though many of the symptoms of old age may look like accumulated damage, there is no necessity for the damage to accumulate; the body is making a choice to repair the damage only partially, as opposed to rebuilding better-than-new, which is perfectly possible, both physically and biologically.

More detail is in my blog post from 2014.  Here is an academic paper on the subject.

“If the body could rejuvenate itself, it would already have done so.”

This is also a common view, and harder to dispel.  I think it is just as wrong as the one above, but full disclosure compells me to admit that I’m still in a minority on this question.

Since the 1960s, Nature has become an object of reverence, especially among the secular quarter in Western culture, people who are skeptical of religious dogmas.  The myth is that evolution has worked for millions of years to perfect the individual, and that human intervention is more likely than not to trip over the law of unintended consequences.  Biochemistry is not only highly optimized, it is also highly intricate and every biochemical plays multiple roles.  

Like most myths, this one carries some truth.  A lot of Western medicine treats symptoms, not causes, and has questionable value in the long run.  Human attempts to “manage” nature have been fraught with rude surprises.  And a natural diet of vegetables and fruits is a much better starting place for healthy nutrition than is a diet of processed food.

But “natural medicine” can never reverse aging.  The problem is that we are not just evolved to be strong and fertile individual competitors, but we are also evolved to be part of a stable ecosystem.  Aging was bequeathed to us by evolution, not for our sake as individuals, but as a way to stabilize ecosystems.  Individuals need to die on a schedule that is internally determined because if we left the matter of death to the world outside, then starvation would be the principal cause of death, and starvation tends to take everyone down at the same time.  This is called “extinction”.  The population can’t afford to eat whatever is available and die only when the food runs out, because then everyone would die at once.  The population would swing wildly up and down.  Evolution has taken pains to protect our species from extinction, just as surely as she has taken pains to make us individually tough and resilient and fertile.

When it comes to aging, we can’t assume that “we tinker with evolution’s product at our peril, because evolution has already done her best to make us live as long as possible.”  In fact, the body’s repair mechanisms slow down as we get older (just as we need them most).  The immune system goes haywire, failing to attack pathogens but turning on the self (arthritis, diabetes).  Healthy nerve and muscle cells commit suicide (Loss of nerve cells is part of Alzheimer’s Disease; loss of muscle is called sarcropenia, a universal wasting disease.)  

As we get older, the balance of signals in our blood changes in some ways that are random and some that are predetermined.  All the predetermined changes are detrimental; signals in the blood raise the level of inflammation, which is the most significant root cause of all the diseases of old age.

The idea that aging was programmed into us for the sake of the ecosystem isn’t just an abstract theory; the theory was devised to explain the reality that the aging body both shuts down repair mechanisms and turns on active self-destruction, in a way that looks quite deliberate.  All the principal mechanisms of aging have been preserved over the vast stretch of evolutionary time. 


Examples of the Rebuilding Approach

Prosthetic limbs, artificial knees and hips are nothing new, but they do keep getting better.  Computer technology promises artificial limbs that can interface with existing nerves so that amputees can learn to control them.  When lenses in the eyes become clouded by cataracts, surgery to replace the lens with plastic have become routine.  Artificial eyes are now conceivable, and there are crude working models.  Mechanical hearts would be most useful, but the technology has been the subject of an intensive bioengineering program since 1969, while mortality rates remain stubbornly high.

Tissue engineers are working on techniques to grow organs on scaffolds.  Tracheas and bladders have already been implanted successfully in humans.  

Despite impressive technological advances, the challenge facing this approach is formidable.  Things that go wrong as we age include clogged arteries, inelastic skin, and weak, degraded muscles.  These parts are not easily replaced.  Brain aging presents the ultimate challenge.  No one wants a prosthetic brain.  (Maybe I’m wrong about this.)

Aubrey de Grey and his SENS Foundation have prominently championed the repair-and-replace approach to geriatric medicine.  The current research program of the SENS Foundation (from their web site) includes

      • Engineering new mitochondrial genes
      • Fighting cancer by shutting down the cancer cell’s ability to maintain telomeres
      • Convincing the body’s immune system to attack amyloid plaques
      • De-fanging or eliminating senescent cells
      • Enhancing lipofuscin clearance
      • Engineering a new thymus
      • Epimutations in single aging cells
      • Finding amyloid in the heart
      • Quantifying extracellular crosslinks
      • Rejuvenating risk/benefit analysis
      • Rejuvenating the microenvironment
      • Repopulating the Gut
      • Scaling up glucosepane research

Four of the thirteen may be regarded as signaling approaches; the rest are conceived as building understanding and a technology of control at the molecular level that SENS hopes will ultimately be the basis for engineering aging out of the human metabolism.


Examples of the Signaling Approach


A growing number of anti-aging researchers are betting on the idea that we don’t need to repair everything that goes wrong with aging because the body can repair itself, if only we can rejuvenate the signaling environment.

FOXN1 rejuvenates the thymus

The slow disappearance (“involution”) of the thymus over a lifetime has been implicated in the age-related decline of the immune system.  The rebuilding approach seeks to replace the aged thymus with tissue engineering [ref, ref]; in contrast, the signaling approach seeks to stimulate the body to regrow the thymus on its own.  Of course, this is the easier approach, if it works.  Greg Fahy has reported success with growth hormone.  Several labs have recently reported hopeful signs that a signal protein called FOXN1 might be a specific trigger for regrowth of the thymus [ref, ref].



Last week, a press release from David Schubert’s group in the Salk Laboratories in La Jolla made headlines for J147, a compound they have focused on more intently.  The world was introduced to J147 with a 2011 article in the high-profile journal PLOS One, which didn’t receive as much attention as it deserved.  There is a new article in the subsidy journal Aging that is getting more attention that it deserves.

The most notable thing about J147 is that it is a promising result from a new methodology for drug development.  Schubert’s lab began with curcumin, the active neuroprotective and anti-inflammatory component of turmeric.  Chemists synthesized and isolated hundreds of chemical cousins of curcumin, which were screened in cell cultures for neuroprotective activity at lower and lower doses.  

In the end, the molecule J147 doesn’t look much like curcumin.



Both molecules have two aromatic rings.  The curcumin molecule is mirror symmetric, which J147 is not.  And J147 contains fluorine, which no natural biomolecules do.  (Among popular drugs Prozac and Lipitor contain fluorine.)

The best ones were tested in rodents.  J147 improved memory in young mice and old.  In a mouse strain genetically engineered to be vulnerable something close to human Alzheimer’s disease, daily doses of J147 were able to delay onset of memory loss.  Even after the mice suffered memory loss, J147 was able to reverse it [ref from 2013]

The reason the new paper made more of a splash than the old was that it was framed in terms of general anti-aging benefits, rather than neuroprotection or memory improvement.  The new paper reports that mice on a lifelong regimen of J147 show generalized abatement of markers of aging as they grow older.  The work is promising, but it was all done with SAMP8 mice, genetically engineered to contract a version of Alzheimer’s disease, which usually kills them before they are a year old.  J147 has not yet been assayed for life extending potential in normal mice.  

J147 is presently available in tiny quantities for a prodigious price.


ALK5 Inhibitors

Mike and Irina Conboy working at UCBerkeley have identified ALK5 as a pro-aging signal, and report success in rejuvenating tissues and whole mice with a molecule engineered to block the ALK5 pathway.  Their recent paper may be viewed as a manifesto for the signaling approach to anti-aging medicine.  It begins:

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

This sentence is dense with meaning that is worth deconstructing.

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches,

The traditional view is that cells suffer damage with age.  Stem cells know they are old because of shorter telomeres.  They accumulate lipofuscin, and their DNA mutates over time.  Of course, aged stem cells cannot be as effective as young stem cells.  But the claim here is that the cells themselves are fine.  They are responding to signal molecules in the blood that tell them to lay down on the job.

elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus,

The bad actor is fingered and, what is more, its source is traced to the hippocampus—a region of the brain known for neuroendocrine signaling, and implicated in other time-cyclic processes.

analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

The Conboys had previously found that TGF-β signaling was responsible for inhibiting muscle growth in aged mice.

The article goes on to describe the receptor for TGF-β, one step downstream, that is responsible for the negative consequences of TGF-β signaling.  The receptor is called ALK5, and there are known molecules that can clog ALK5, blocking the signal pathway that has inhibited new growth in old bodies. “Very interestingly, both neurogenesis [new nerve cells] and myogenesis [new muscle tissue] were significantly enhanced in the aged mice treated with ALK5 inhibitor, compared to the animals receiving control buffer.”

ALK5 inhibitors are also available from lab supply houses, even more dear than J147.  But, to be fair, the molecule is more difficult to synthesize and the dosage is probably smaller.  (In fact, we have only theory to guide us for human dosages, since both these molecules have yet to be tested in humans.)


The Bottom Line

In the beginning, anti-aging medicine was thought to be fanciful, if not impossible.  How could human engineering improve on processes that Nature has been perfecting for a billion years?  Then a science of regenerative medicine began very slowly chipping away at that conventional wisdom, and a glimmer of hope pointed to promise of fixing the body directly with engineering, at least in the long run.  

But a funny thing happened along the way.  There are indications in many areas that the body knows perfectly well how to rejuvenate itself, and we need only learn to speak the body’s (biochemical) language in order to say, “Have at it!”  A few people like me are pointing out that this contradicts everything we thought we knew about evolutionary biology, and that the “selfish gene” is in need of an overhaul.   But bench scientists are choosing to sidestep this theoretical debate and simply to do the practical thing.  They are pursuing a signaling approach because  it works.


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Does donating blood extend your life expectancy?

Last week I came upon a 1998 study finding that the risk of heart attack was 18 times lower in people who donate blood, compared to a matched sample of people who don’t.  I ran out to my local Red Cross Blood Drive, and then came home for some follow-up reading.  The consensus from a handful of studies on blood donation seems to be far less dramatic, but still worth considering.

Hippocrates thought that women purged blood every month to release their toxic humors, and that men might benefit from an artificially-induced version of menstruation.  From ancient times until the 19th centuries, bloodletting was a common medical procedure.  Leeches were  prescribed for a wide range of ailments.  

Bloodletting was thought to be beneficial in healing nearly every disease, from acne and asthma, to cancer and smallpox. Even the loss of blood from a wound was treated by…removing more blood! Bloodletting the already-wounded was thought to reduce inflammation (which is why it was employed prior to surgery as well). Bloodletting wasn’t limited to curing disease either, but was also used as a preventive measure to avoid getting sick. [source]

Modern medical wisdom dismisses these ancient, barbaric practices as fraud, mountebankery and snake oil.  But like most medical practices that stood the test of time (if not epemiology), this one held a core of truth.

Don’t let your barber do this.

For centuries, the local barber not only offered close shaves and sharp haircuts, but also provided medical services including bloodletting. In fact, the iconic barbershop pole with its two brass balls and red and white stripes is a vestige of the days when barbers would slit customers’ arms to relieve their ailments.


Epidemiology of Blood Donation

The raw statistics are quite promising.  Here is a study that found occasionally donating blood (every three years) is associated with a 50% drop in cardiovascular disease in men.  This study finds a 40% reduction in cardiovascular risk, after adjusting for other differences between donor and non-donor groups. These [ref1, ref2] looked at short-term benefits for blood lipid profiles studies following blood donation.  These two studies [ref1, ref2] found a slightly lower risk of cancer in blood donors.  In a large study of US blood donors, this study found a 30% lower rate for all-cause mortality.  This large Italian study found a modest decrease in overall mortality among blood donors.

These were balanced with other studies that found slightly higher cardiovascular risk among frequent blood donors, and several [review] that uncovered no benefit.  


The Healthy Donor Effect

It is an obvious point that unhealthy people don’t respond to blood drives.  How much of the statistical association with lower health risks is merely self-selection, and how much is causal?  Here is a current study claiming that the unadjusted benefit is 18%, and the residual benefit after accounting for the “healthy donor effect” amounts to 7%.  These percentages represent reduction in mortality rate for each additional annual blood donation.  Based on this unimpeachable source, I have decided to give blood exactly 14.3 times each year, thereby reducing my risk of dying to zero.



I’m old enough to remember Jack Barry on the B&W TV, the merits of Geritol for “tired blood” — a description of anemia that was intended to suggest that low iron was the primary culprit in an epidemic of chronic fatigue.

Jack Barry on the quiz show, “Twenty-One”

Geritol was advertised as an iron supplement.  Today’s epidemiology recognizes that anemia is far less common that the opposite, and that too much iron is a risk factor for heart disease, cancer, and Alzheimer’s.  (Geritol is still sold today, but its formula has less iron  

Modern thinking is that, yes, anemia might limit stamina or even cause fatigue, but people who eat meat and who don’t carry a gene for hemochromatosis are unlikely to be iron-deficient.  When iron is in short supply, the body can readily increase its absorption.  But the body cannot easily remove excess iron, thus excess iron accumulates in the liver.  In fact, too much iron is about four times more common than too little iron in a sample of people over 50 [ref].  The consequences of too little iron are short-term, but the too much iron is a risk factor for chronic disease.

The best-established health risk from too much iron is elevated incidence of diabetes [ref1,  ref2, ref3, ref4].  Insulin resistance, in turn, is associated with higher risk of all the diseases of old age.  But several studies have found only a weak relationship between excess iron and cancer or mortality risk [ref1, ref2].



Instinct tells me that lower iron is not the only benefit, or even the main benefit from blood donation.  First, the body can quickly recover iron lost to blood donation by dialing up the absorption from dietary sources.  The effect on the body’s iron stores is likely to be short-term.  Second, the evidence for association between high iron and high disease risk is actually weaker than the evidence for benefit from blood donation.  So my guess is that this is a hormetic effect.  Blood donation is like exercise or a low-calorie diet or low-dose toxins or radiation: it signals to the body that there is danger, which turns on protective mechanisms that go into high gear and overcompensate.  (There is an evolutionary explanation for the overcompensation.)

Social and emotional factors have a dominant influence on longevity.  It is often overlooked, but connectedness with others, sense of satisfaction and fulfillment, healthy loving relationships are all powerfully correlated with health and life expectancy.  Giving blood may be an indicator of pro-social attitudes that prefigure longevity, or it may be an active pursuit of a pro-social behavior that promotes longevity through psychological pathways.

My experience

For several years, Valter Longo has been expounding a theory that an extended fast can reset the immune system.  The data on blood donation suggested to me that something similar was happening, and that there might be synergistic benefit from combining a fast with blood donation. I have been doing Longo’s 5-day Fasting-Mimicking Diet every 4-6 weeks, and it happened that I was FMD-ing when I first read about the benefits of blood donation last week.

I found a Red Cross blood drive on the last day of my FMD within 5 miles of my house.  I chose discretion over valor, and drove out there rather than deploying the bicycle which is my habitual mode of transit.  It had been several years since I have given blood, but I could hardly be surprised that there was 40 minutes of paperwork the Red Cross asked me to read and sign.  Reasons for exclusion include not just infectious diseases but travel  to many regions of the world, intravenous drug use (ever), homosexual activity (ever), cancer (ever), several congenital diseases….I started to feel nervous that they would ask whether I had been on a semi-fast for 5 days, or discover that I hadn’t had a meal in almost 22 hours.  They didn’t ask anything of the sort, and I was able to answer all the questions truthfully.  When I had trouble raising the thermometer above 96 degrees and my blood pressure read out at 85/60, they asked if this was usual for me.  I offered the excuse that ”I am a marathon runner”, which is a stretch.  

Red Cross is strict about the rules, but they really do want our blood.  So I slipped through, stretched out on the table and offered up my left arm.  The procedure itself took only 15 minutes, and went off without a problem.  No light-headedness or weakness–I got up afterward and walked out, hungry and more than ready to re-feed myself after 5 days of minimalist fare.  I might have bicycled after all.


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From Roscoff, with Rotifers

Roscoff is a picture-perfect coastal town in Brittany.  I have just returned from the first Monod Conference on the Comparative Biology of Aging.

Looking toward shore from the quay. My hotel is in the middle, just right of the cathedral.

Looking toward shore from the quay. My hotel is in the middle, just right of the cathedral.

The conference was opened by a theoretical lecture by Tom Kirkwood, father of the popular disposable soma theory of aging.  He admonished us that evolution is a mathematical science that yields specific and quantitative information about what aging can and cannot be.  These provide a powerful mathematical underpinning for the understanding of aging.

The next morning, Annette Baudisch told us that in reality, nature has produced every combination of aging strategy that you can imagine, and some that you probably never imagined.  The kind of aging that humans know is gradual and accelerating, leading to death on a timetable that is predictable within about 10-15%.  But this brand of aging is a small minority in nature.  There are salmon and octopuses and annual plants that reproduce in a burst and then die suddenly.  There are beetles and jellyfish that are able to “age backward”, reverting to a larval state under stress, then beginning life again with a fresh start.  Baudisch coined the term “negative senescence” for a phenomenon that is not the same thing as this:  most trees and some turtles and lobsters just grow ever larger and more fertile over decades or even centuries.  There are giant lobsters that grow to 40 pounds, and there are clams you can hold in the palm of your hand that have over 500 annual growth rings.  Each of these animals and plants grows progressively less likely to die with each passing year, year after year–hence “negative senescence”.

Charming and perfectly diplomatic, Baudisch overtly praises Kirkwood and the contributions he has made to the evolutionary science of aging; but in truth, she has produced more counter-examples to Kirkwood’s pronouncements than all of us combined. 

I was less diplomatic, and in my presentation, I ranted about the many blatant contridictions to Kirkwood’s “precise, mathematical theory”, and in big red Powerpoint letters counseled the assembled scientists, “Don’t let the mathematicians tell you how to interpret your data.”  The mathematical theory for evolution of aging is based on an early 20th Century paradigm of R. A. Fisher, in which gene frequency changes gradually while the population level and the ecology remain ever stable.  We now know that ecologies change hand-in-hand with gene frequencies, on the same time scale.  Furthermore, there are a dozen mechanisms of evolution that were unknown to Fisher, of which the simplistic equations of classical evolutionary theory takes no account:

  • Ecological interactions
  • Horizontal gene transfer
  • Epigenetic inheritance
  • Population cycles
  • Weather cycles
  • Evolvability
  • Social interactions
  • Learned behaviors
  • Phenotypic plasticity
  • Assortive mating
  • Famines
  • Epidemics

In every other subdiscipline of the bio-sciences, experiment is king, and theory is kept in its place.  This, of course, is exactly the way science should be, and especially biology, which is so complicated that theory has only a limited role.  But somehow evolutionists have carved out an exception for themselves, and when they make mathematical pronouncements that manifestly have nothing to do with the natural world, they are nevertheless taken seriously.

(Part of the problem is the illusion created by experiments in laboratory evolution.  Here the theory works beautifully.  But only in predicting outcomes of breeding, where the experimenter dictates the definition of “fitness”.  We have no way of measuring “fitness” in nature, and have every reason to  believe that it is essentially complicated, multifaceted, and completely dependent on ecological context.  I introduced an aphorism that I hope will catch on:  Nothing in evolution makes sense except in the light of ecology.”*)

* Here I am echoing a great evolutionary thinker of the mid-20th Century, who famously wrote that “Nothing in biology makes sense except in the light of evolution.


Worms with Hot Flashes

Researchers in the worm aging laboratory of Meng-Qiu Dong labeled an antioxidant protein with green fluorescent die, and discovered serendipdously that the worms have spots of activity that flash with frequency every few seconds, that you can visualize through a microscope, peaking around day 3 of the worms’ 20-day life span.  Investigation revealed that the mitochondria are producing the flashes, so they’ve been dubbed “mitoflashes”.  Remarkably, the frequency of flashes is correlated with the worms’ date with death two weeks down the road.  Across many different strains, genetic varieties and environmental conditions, the rate of flashes at peak predicts how long the worms are going to live.  Dong had the vision and insight to realize that this implies a longevity plan for the worms that is already in place quite early.  The mitochondria know in advance what the life span is going to be [news article in Nature].  This supports both the perspective of programmed aging, and also the theory that mitochondria act as executioners.

False color picture of young worm, showing mitochondrial hot spots.


Sex and the Single Rotifer

Standard evolutionary theories of aging tells us that reproduction and longevity are on a see-saw, so that whenever one goes up, the other must go down.  I don’t believe this, and for years I’ve been collecting exceptions.  My favorite is David Reznick’s guppies.  From the river pools of Trinidad, he identified two varieties of the same species:  one with high fertility and long life span, the other with low fertility and short life span.  It turns out that life span is determined not by individual competition to make as many offspring as fast as possible, but rather by adaptation to the local ecology.  Guppies are the little kids on the block, and where there are prerdators present, their death rate can be so high that selective pressures drive them to mature more quickly, swim faster, lay more eggs, and also age more slowly.  Where there are no predators, they can’t afford to be so prolific.  There isn’t enough food in the small pools to finance a population explosion, and overcrowding risks the spread of fungal and bacterial epidemics

This, of course, is group selection of a kind that mainstream evolutionary theorists still deny, as they have since 1966.  But in recent years, some prominent evolutionists [ref, ref, ref] have defected from the orthodoxy, and have caused a stir with the announcement of what every high school biologist knows in his gut:  that cooperation and competition both have a role to play in evolutionary dynamics, and much of what we see in the biosphere is the result of a tug of war between what is good for the individual and what is good for the community.

In Roscoff, I was privileged to hear Heike Guber, a talented young experimentalist from Max Planck Institute, describe her experiments with rotifers raised in tanks.  Rotifers eat algae and protozoans which they filter from the water.  In different tanks, she supplied various concentrations of food, then followed them through generations to see how they evolved.  The ones with lots of food evolved long life spans and high fertility; those with the slimmer diet evolved short life spans and low fertility.  I was saddened but not surprised to hear that she had trouble getting her results published, simply because they went against the established dogma.

Clearly, what Gruber observed is an outcome that is adaptive for stabilizing the community of rotifers.   But dogma says that evolution always seeks to maximize the reproduction of the individual, no matter what the consequence for the community.  Hence the official skepticism of her results:  if the rotifers harbor this capacity to both to produce more eggs and to live longer, then what could keep that trait from quickly rising to dominance?  (The answer, of course, is group selection; but peer review is often influenced by gatekeepers who deny the reality of group selection.)


What is a rotifer?

Rotifers, it turns out, are all around us.  They occupy that size regime (along with mites and nematodes) that so frequently escapes our attention: much larger than single-cell species, but still too small to see.  The oceans, every pond, every stream and many puddles are full of rotifers.  Even mossy patches in a wet forest carry rotifer populations.  Wherever there is water, they thrive; and where water is intermittent, they go into a state of suspended animation, waiting for the next rain. There are 2,200 known species of rotifer, and counting.  The largest are about 2mm long, the smallest are but a speck to the eye.

Rotifers are an important part of the freshwater zooplankton, being a major foodsource and with many species also contributing to the decomposition of soil organic matter.[ref]

photomicrograph from Wikipedia’s article on rotifers

At banquet dinner, Gruber filled me in on the sexual versatilty of rotifers.  When conditions are stable, they just clone themselves.  They lay eggs that are exact copies of the mother.  No sex.

Under stress, mother rotifers lay eggs that can also develop into females.  Females lay eggs that develop exclusively into males in the next generation.  Some of these are males, and they can mate with their own mothers or others of her generation; in this case, the eggs produced will always become female.  

To summarize: the parthenogenic form reproduces more parthenogenicists or females.  Females can reproduce as males with the exact same genome as the female.  Female + male can combine to produce another female, with genes that derive half from each parent.

Gruber also told me that a male rotifer is not so impressive a specimen as a bull or a peacock.  In fact, males are tiny tiny, only about 1/10 the size of the female of the same species.  Males cannot eat or grow.  They live for just one thing, and they don’t live very long.  They latch onto the female body and inject their sperm in any place that happens to be near at hand.  It doesn’t seem to matter; the sperms navigate through the female body, and find their way to the ovaries.     

There are more curiosities and mysteries associated with rotifers.  The bdelloid family of rotifers have no sex at all, and have not known sex for at least tens of millions of years.  Woody Allen asks why they bother to get up in the morning. Evolutionists ask, how do they manage to keep their genomes from succumbing to inexorable accumulation of deleterious mutations. (This is Mueller’s Ratchet).  

And rotifers are usually found in extended colonies.  What do they get from one another?


Keynote by Austad

Closing the conference was a keynote address by Steven Austad.  Austad gets along with everybody.  He is widely knowledgable, and famous for his radical common sense.  He described his induction into the field, as a grad student in the 1970s.  The central dogma of his time was that aging could be observed only in protected environments like a zoo, but that animals in nature died of other causes before they could die of old age.  But, working with an island population of opossums as a young student, Austad captured many that were old, some that were clearly very impaired and not long for this world, yet still reproducing.  

 Austad warned us that much of what we have long assumed about the biology of aging is not to be taken literally without exception; and some of it is merely persistence of myth.


Life spans of mammals (y axis) vs body mass (x axis) in a log-log plot

He showed us the classic log-log plot of animal size vs lifespan.  In mammals, life span rises slowly, with about the 1/4 power of an animal’s weight, which corresponds to a slope of 0.25 in the log plot.  There are outliers where animals have managed to find strategies to suppress their death rates from predators and disease.  Most birds live longer than comparably-sized mammals, and the most dramatic examples are people and bats.  

I had known that mice are outliers on the downside.  Since mice provide food for a great number of predators, and they freeze to death over the winter; their life spans are below the trend line.  What I learned from Austad is that the exceptions extend to all small rodents.  For rodents less than 8 kg, there is no correlation at all between size and life span.  No one, to my knowledge, has explained this.

The hard thing for me to hear was that, as a way to extend life, caloric restriction is far from perfectly robust and universal.  He reminded me of an experiment a few years ago with 41 diverse strains of out-crossed mice.  The mice were “recombinant inbred” = first generation crosses between different purebred strains.  Under 40% caloric restriction, about a third of these showed life extension, a third showed no significant life extension, and a third actually lived shorter when restricted.  There were more mice with shorter life spans under CR than with longer life spans!

Finally, strain-specific lifespans under CR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of CR exhibits wide variation amenable to genetic analysis. They also show that CR can shorten lifespan in inbred mice…

Strikingly, the majority of strains showed no extension of lifespan under the level of DR used in this study (Figs. 1C, D). Only 5% of the strains for males and 21% of the strains for females showed statistically significant life extension under DR (p values < 0.05)…

Of note, the longest lifespans achieved under DR did not exceed the longest achieved under AL feeding.  [ref]

Differences in life span between CR and full-feed, male (left) and female (right) strains.

Differences in life span between CR and full-feed, male (left) and female (right) strains.


Austad himself did a study of CR for mice captured from the wild.  

Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups. [There was] higher mortality in CR animals early in life, but lower mortality late in life.   A subset of animals may have exhibited the standard demographic response to CR in that the longestlived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents

This study demonstrated an increase in maximum life span, but not mean life span under CR.  Many people in life extension are very interested in extension of maximum life span, because, as they say, it demonstrates that the fundamental biology of aging has been affected.  I agree, but note that increase in maximum without mean life span is the nightmare we have here.  It means that the biology of aging has been affected, but not in the same direction for everyone.  There are just as many mice in this study whose life span is shortened by CR as the ones whose life span is lengthened.  This is what I find most troubling.  I once had a graduate advisor who nailed a particular human tendency when we relate ourselves to what we know about others: “Statistics are for everyone else; dumb luck for me.”

As in his past work, Austad offers so much useful good sense in his keynote…And yet he clings to a view that aging is driven by an accumulation of damage, that it can be slowed but never reversed, that there are no genetic mechanisms that have evolved solely for the purpose of assuring a fixed (shorter) life span.  The three points are related but not identical.  Curiously the idea that damage is the root of aging is not the influence of evolutionary theorists, but far older, rooted in ancient concepts of impermanence.  

I have written an academic article [ref] and two blog posts [one, two] in opposition to “wear and tear” theories, and devoted a chapter of my forthcoming book to the subject.  It is the most common misconception in the field that aging in biological organisms is akin to physical wear and chemical entropy, and that it has something to do with the Second Law of Thermodynamics.  

I know it is theoretically possible, and hope that it will prove generally true in practice, that the body knows how to repair all the important kinds of damage that accrue in aging, and is capable of restoring itself to a youthful state, given the appropriate signaling environment.

Austad’s present research is based on the observation that misfolded proteins tend to accumulate in our cells, and are related to dysfunction and disease, most prominently Alzheimer’s.  Long-lived varieties need to keep proteins in the right conformation, with “chaperone” molecules that are particularly effective.  Austad is isolating and transplanting some of these chaperone molecules from his menagerie of 500-year-old clams.

Despite differences in theoretical perspective, I have found the community of aging biologists to be especially personable and gracious.  I have known Austad and Kirkwood in the deep past,  and Baudisch more recently because she belongs to the next generation.  Before I had any reputation or credibility in the field, all of them responded to me personally and respectfully.  The most promising thing to come out of the meeting for me personally is that I told Austad privately of my idea to test hundreds of combinations of life extension treatments, in order to learn how they interact (see my blog from last month).  He told me about an NIA program that evaluates proposals for experiments with mice, deadline later this year.  The program is not terribly oversubscribed because it offers no funding to the winning proposals; however winning proposals will be assigned each to three separate mouse labs around the country that will replicate the experimental design in triplicate.  I’m pumped!

Privately, Austad also told me that a previous winner had proposed combining rapamycin with metformin and the test was successful.  In yet unpublished results from three labs, the combination of metformin and rapamycin extends mouse life span more than the sum of the benefits from the two separate treatments.  

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Can Botanicals Replace Metformin?

Gymnema, Jiaogulan and Berberine: Can herbs replace metformin?

We all lose insulin sensitivity with age, and this is is a primary mechanism by which we become more vulnerable to all the diseases of old age.  But there is much that we can do to retain insulin sensitivity: diet, exercise, drugs and herbs.  Because these act differently on the metabolism, there is reason to hope that combining treatments will yield combined benefits (this is theoretical–there is no data available on combinations.)

While emerging anti-aging technologies are still emerging, the best-tested treatments we have for the present all rely on the insulin metabolism.  Our bodies are evolved to sense stress–especially food scarcity–and adjust our rate of aging to compensate for those around us who may be starving to death.  (This is the demographic theory of aging, and though the theory may still be controversial, the fact that we can address the rate of aging through the insulin metabolism is undisputed.)

Insulin manipulation works much better in mice than in larger animals like us, but it’s the best-studied, surest way to improve your odds for a long and healthy life, and there are vitality, alertness, productivity, freedom from infectious disease–almost every aspect of your quality of life is improved with more exercise and less food.

The best measure of diabetes risk is glucose tolerance.  The body is challenged by swallowing a dose of sugar, and glucose levels in the blood rise immediately.  Over several hours, follow-up blood tests measure how quickly the blood levels come back to normal.

(IDDM means insulin-dependent diabetes mellitus)

Fasting glucose is a secondary predictor, not so robust as glucose tolerance [ref].   


For anyone who doesn’t choose to maintain the most rigorous program of exercise and caloric restriction, metformin can make up the difference.  Metformin is a fifty-year-old drug, long out of patent and cheap.  Mice fed metformin live longer.  We have a great deal of epidemiological data on metformin, because tens of millions of people have been taking it for decades.  Diabetics who take metformin have much lower rates of cancer, heart disease, and AD.  Arguably, their survival statistics may even be better than non-diabetics who don’t take metformin.  There are researchers who are proposing that Alzheimer’s Disease should be regarded as type 3 diabetes.  (FightAging! led me to this article.)

The numbers look so good that Nir Barzilai (Einstein Hospital, New York) has banked the future of FDA policy on a clinical trial to demonstrate that aging is a risk factor that can be mitigated, and that aging should be recognized as a treatable condition.  Last month, there was a major article in Science Magazine about his program.  It is hardly a radical claim, from a scientific perspective.  But government policy lags science, and what Barzilai is doing will be a boon for us all, if it works.

Metformin is a safe drug, without serious side-effects except rarely among people taking high doses.  I have recommended it to anyone over 40 who is overweight, or over 60 even if you’re not overweight.  

Many people prefer a natural alternative, and I’m witing today about three good ones.  The reasons for preferring “natural” may transcend science.  There is a general feeling that natural products are safer, though in this case we know a heck of a lot about the safety of metformin.   There are decades of epidemiological data for metformin, vs centuries of traditional wisdom for the herbal products.  Readers of this column are accustomed to my periodic rants about the fact that capitalism has distorted funding priorities for medical research, hence we know a lot less about natural products than about patentable ones.



Thanks to Bill Sardi for introducing me to Gymnema.  Here is a review of limited evidence for Gymnema and diabetes that was available as of 2007.  Gymnema has a long pedigree through the Indian ayurvedic tradition of life extension, in which it is called mesasrngi [sic].  Gymnema reduces uptake of sugar from the small intestine, and also increases generation of insulin in the pancreas.  The former is definitely beneficial; the latter is helpful for diabetes type 1, but not for type 2 which is associated with aging.  In this study, Gymnema improved cholesterol profiles, fasting glucose, and also results from the (most predictive) glucose tolerance test.  This study found similar benefits in obese mice.



Berberine is a chemical, not a plant, though it is extracted from several different plant sources.  The best source is goldenseal.  Berberine has a 5,000-year legacy in Chinese medicine–even longer than Gymnema has in Indian medicine.   

(It may look complex, but still counts as a “small molecule,” and compared to proteins it is tiny. Insulin is considered a small protein, but it is 18 times the molecular weight of berberine.)

Metformin reduces blood glucose by shutting off the source (in the liver), while berberine reduces blood glucose by augmenting the sink (glucose uptake in muscle and nerve cells). Berberine affects cells in much the same way as insulin, increasing the uptake of glucose from the blood into the cell.  This means that if you take berberine before exercise, it might (theoretically) enhance your performance, while taking metformin before exercise might (theoretically) reduce your performance.  

This study compared metabolic benefits from berberine with metformin head-on in a three-month trial.  500 mg berberine had benefits equal to 500 mg metformin, with fewer reported stomach upsets and better triglyceride control for berberine.  

This column by Frank Shallenberger raves about the advantages of berberine.      

“Berberine has low rates of absorption when taken orally due to both being subject to P-Glycoprotein (ejects Berberine back into the intestines) and increasing the activity of P-Glycoprotein (augmenting its own ejection), but absorption is greatly increased when taken with P-Glycoprotein inhibitors such as Silymarin from Milk Thistle.” []



This traditional Chinese herb () has recently been marketed by LEF under the name “AMPK Activator”.  The latin name of the plant is Gynostemma pentaphyllum. It is sometimes known as “southern ginseng” because it contains some of the same active ingredients as ginseng, deemed the king of all Oriental medicines.  But the anti-diabetic benefits of jiaogulan derive from constituents that are not found in ginseng.  In parts of Southeast Asia, jiaogulan has a reputation as an “immortality herb”.  

Like Gymnema, jiaogulan shows promise, both theoretically and in limited human trials, but there isn’t yet enough data to know how well it works.  In one study, it improved both fasting glucose levels and (more important) tolerance.

In promoting its new product, LEF has made a case that low AMPK is part of a keystone aging pathway.  We have less AMPK as we get older.  Both fasting and vigorous exercise increase AMPK levels.  Less body fat leads to more AMPK expression, and, even better, more AMPK leads to burning more fuel, storing less as fat.  This is a positive feedback loop that can work in either direction.  AMPK → faster metabolism → less fat → more AMPK or low AMPK → slower metabolism → more fat → less AMPK.  By adding AMPK, they claim, we can be sure to go around the circle in the right direction. Like many LEF reports, I find this one to be well-rooted in truth but a bit breathless in presentation and overstated in its significance.


(click to enlarge)


Other measures

Weight control is still your first line defense against the creeping insulin resistance that affects all of us as we get older, and only is diagnosed as diabetes in its more severe form.  There’s a school that says low protein diet offers best protection, and another that favors low carbs.  (I have favored carb restriction, but I may be tipping toward low protein.)  You can’t do both without raising fat intake, and there is good agreement that dietary fat shouldn’t be more than 40% of your calories.  

Exercise prodigiously.  Exercise right before eating can change your body’s insulin response to the sugar challenge.  Even a minute of high-intensity exercise can make a difference [ref, ref].

Vegan diets are associated with much lower incidence of diabetes.  In this study, vegans had half the incidence of diabetes, even after controlling for the fact that they had lower BMI.  Non-vegan vegetarian diets were not far behind.

Almost all of us can benefit from magnesium supplements.  Zinc [ref, ref] and tiny quantities of chromium might also help.  Resveratrol extends life span in fat mice.  There is some evidence for thiamin (vit B1).  Large quantities of cinnamon may or may not be helpful.  One small study showed a substantial benefit from boswellia=frankincense.  


The Bottom Line

Loss of insulin sensitivity is so closely intertwined with all the diseases of old age that it is hardly distinguishable from “normal aging”.  It’s an issue that we all face, and there is a whole Chinese menu of measures you can take to better your odds for health, vitality and a long life.

The mechanisms of metformin, berberine, jiaogulan and Gymnema are quite different, and there is reason to think that combining them offers more benefit than any treatment separately; but there is as yet no data on combined therapies.

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Growth & Aging; Creatine & Health


Promoting growth is dangerous, especially if it is done in an un-natural way.

Hormones and growth signals are tightly constrained, and highly optimized by evolution.  Too little and the body atrophies over time, failing to renew muscle and nerve tissues.  But too much and the body risks overstimulating some rogue cell, which may turn cancerous.  Navigating between these two risks is a treacherous game, and the channel of safety is narrow.  Eventually, the body falls to one side or the other, and so we must die.”*

I have read this narrative in different contexts and in countless variations.  It is the central rationale of aging according to the mainstream of Western medicine.  But we know it cannot be true.  When we are infants, every endocrine growth signal is dialed up to the max, growth hormone is through the roof, cells are dividing like crazy, and yet cancer risk is very low.  When we are old, growth hormone has dropped to nearly undetectable levels, cell division is lethargic, stem cells are few and less active–and yet the risk of cancer is at an all-time high.

Mainstream evolutionary theory says that the body is forced to make compromises, and this this is the ultimate reason for aging.  The body doesn’t want to fall apart, but its first priority is to leave as many offspring as possible in the here and now, secondarily to preserve the body to continue to create offspring later on.  Here-and-now is safer and also more effective, because of the earlier start generating grandchildren.  So the body errs on the side of short-changing the infrastructure.  

Why should the body have to compromise?  The most popular and most standard theoretical answer is that its energy is limited.  There just aren’t enough calories to do everything perfectly.  This is the Disposable Soma theory of Tom Kirkwood, a beautiful theory that fails spectacularly when confronted with the real world.  In theory, more energy should help the body avoid the need for compromise.  We should live longer the more we eat.  The truth is the opposite.  In theory, spending energy on exercise should generate damage that needs repair, while consuming energy that could have been spent to protect from old age.  Theory says that exercise should shorten life span, but the truth, again, is just the opposite.

Even if energy isn’t the limiting factor, it sounds so reasonable that the body should be forced to compromise because we so often encounter tradeoffs in different areas of our lives.  Tradeoffs involve time and money, can’t be in two places at once, can’t have children and a career, must choose between two lovers who each fulfill parts of us.  But it doesn’t always work this way.  Computers become smaller and faster and cheaper and more energy efficient with each passing year.  Filling our lives with love and fulfillment and a sense of gratitude and wellbeing also is the best single thing we can do to enhance our life expectancies.  Sometimes you can have your cake and eat it, too; compromise isn’t always required.

So the question whether enforced compromises are implicated in aging must be answered by experiment and observation–it is not a matter of theory.  

The root of the theoretical problem is the assumption that the body is doing its best to live as long as possible, and that aging and death represent failures of a system trying heroically to avoid them.  But in this case, evolutionary theory leads us astray: the body is trying to kill it self on a schedule, as it is programmed to do.

The truth is that the body knows how to be young, and it knows how to be old.  It does an exemplary job of both, each in turn.  When the body is young, it is perfectly capable of growing, healing, producing offspring and repairing molecular damage, all accomplished simultaneously and without compromise.  When it is old, it does all of these things imperfectly, if at all, as it gradually degrades and dismembers itself, using some of the same tools that were deployed for health and protection early in life: immunity, inflammation, apoptosis and cell senescence.  

This view leaves open the possibility that medical science may find the body’s epigenetic clock, may learn how to talk to the body in its own language and fool it into thinking it is forever young.

So I am motivated to leave theory behind and look to the lab experiments for the answer:  is it possible to boost growth and simultaneously to enhance longevity?



Creatine is a very simple and common molecule with nitrogen and a COOH group like an amino acid.  It occurs in all animal cells, more not plants.  1% of our blood is creatine.  Biochemistry of creatine has been studied since 1832.

Creatine promotes creation of ATP, the cell’s short-term energy storage molecule.  The way it works is this:  ATP is adenosine triphosphate, and the 3 phosphates make it a high-energy molecule.  In muscles and neurons that consume energy intensely, ATP is tapped, and one of the phosphates is degraded in the process, leaving ADP, or adenosine diphosphate.  Creatine then steps in to recharge ADP back to ATP.  It takes on a phosphate to become phosphocreatine, and then transfers the phosphate to ADP which is restored to its high-energy form, ATP.  In times of rest, the process is reversed, as ATP gives up a phosphate to creatine, and an enzyme called creatine kinase generates phosphocreatine.  Phosphocreatine can then serve as a short-term energy reservoir.

At any given time, there is something in the neighborhood of 100g creatine in our bodies.  The amount varies widely.  We make our own creatine in the kidneys and liver.  But a substantial portion of our creatine is ingested, except that those of us who eat a plant-based diet get very little creatine. “Normal reference values for creatine are lower in vegetarians [ref]”  We make less as we grow older, but it’s easy to lose the difference because of wide natural variation in creatine levels at all ages [ref].  

Creatine was first discovered to improve athletic performance in 1912.  Since stories emerged from the 1992 Olympics, creatine has been an increasingly popular supplement among body-builders.  Creatine works especially well In combination with exercise, enhancing the benefit for strength and lean muscle mass.  I found one study demonstrating these benefits in older men.  I personally have been experimenting with creatine the past 5 months, and have noticed I can do more push-ups and chin-ups, and have gained a few pounds that I flatter myself to imagine are muscle.  I have had a minor issue with cramping which might be a side-effect

But it is only since 2010 that creatine has been known as an inhibitor of myostatin (aka GDF-8).  Myostatin is a hormone that increases with age and degrades tissues, especially muscle tissues.   Inhibiting myostatin leads to more strength and muscle mass, including a stronger heart.  The action is not through more activity of muscle satellite (stem) cells, but of less wasting [ref].  

Myostatin also promotes resting levels of growth hormone while suppressing spikes of growth hormone during exercise.  This is generally thought to be a good thing, but the reasoning is indirect.  

The best effect might be the increase in muscle satellite (stem) cells, but evidence is still thin [ref], and the effect may be temporary [ref].  There is limited evidence for creatine’s benefit to cognitive performance, especially in vegetarians and the elderly [another ref].  It has been mentioned in the context of treating Parkinson’s Disease.  One study showed a decrease in the inflammation that comes after intense exercise.  


The Bottom Line

100% of people in their 60’s and beyond develop sarcopenia=loss of muscle strength.  No one likes it, and (if you need a clinical reason) sarcopenia increases risk of injury and very gradually closes the door to a world of benefits that derive from exercise.  Exercise itself is the best way to slow sarcopenia, and creatine synergizes with exercise to help in maintaining muscle mass, strength and endurance.

Strengthening the heart is likely to be a good thing, and I have a belief that endurance and motivation and exercise and longevity are all so closely linked that I’m inclined to think there are ripple benefits from creatine. Some studies show that effects fade, so I’ll  take it intermittently, one month on, a few months off.  Drink much extra water while you’re taking creatine.

Long-term effects of creatine supplementation in humans have not been studied, except for one safety study that lasted a year and found no adverse side-effects and a small 4-year study that looked at a limited number of biomarkers.

You can purchase creatine as a powder, and it is not expensive.  It is tasteless, and can be added to drinks (but not OJ), yoghurt, or smoothies.  There is no consensus on dosage.  I have seen recommendations ranging from 1 to 20 g per day.  


* Not a literal quote from anywhere, but I place this introduction in quotes just as a warning that I don’t believe it, and I don’t wish you to believe it.

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Promise of Novel Alzheimer’s Treatments

Last year, I blogged on a CDC report that Alzheimer’s Disease is more prevalent than previous epidemiology had acknowledged.  Last month at the Rejuv Biotech conference, I heard Chas Bountra tell us that

  • Alzheimer’s Disease is currently #3 among diseases of old age
  • Demographics are increasing the prevalence of AD at an inexorable rate
  • Far more than cancer and vascular diseases, AD is unknown to us–medical science really doesn’t have a clue

Boutra is in a position to direct many millions of research dollars for AD, and he says he won’t go near either of the two large branches of research on the disease.  Study of (1) beta amyloid plaques and (2) tau proteins has absorbed tens of billions of research dollars over half a century, and yet there is no agreement even about what ultimately causes AD, let alone a program for cure.  So he will only fund long-shot ideas at the fringes of Alzheimer’s research.

There is no shortage of dark horses in this field.  In recent blog posts, I described two:  Tony Wyss-Coray is beginning clinical trials using plasma transfusions from young donors, and Bioviva will soon be trying gene therapy to activate telomerase.

Further along than either of these is Dale Bredesen’s innovative approach based on the sustained application of common sense.  Bredesen reports on a trial with just 10 patients, but 9 of them showed major improvement.  This was not the kind of result that you need a cognitive test to measure; the patients came out of nursing care and went back to their jobs.  He calls the program MEND, for Metabolic Enhancement for Neurodegeneration.  

Bredesen’s starting point is a model in which AD results from a change in hormonal signaling.  There is turnover of neurons throughout our lives (this alone is a relatively new acknowledgment), and late in life, the destruction of neurons outpaces the growth of new ones.  Bredesen defines AD as the tail of the distribution, in which the destruction of neurons has become so severe as to precipitate obvious cognitive decline.  He draws an analogy to osteoporosis, which is understood as a loss of the healthy balance between the creation and destruction of bone cells (osteoblasts) that renews bone tissue and keeps bones strong.  Nerve cells in the brain do not turn over as frequently as bone cells, but the principle is the same.

Body homeostasis is maintained generally by signaling with negative feedback loops.  Biology derives its robustness from  processes that are self-limiting.  But positive feedback loops act like “switches”; they can take the body from one state to another.  Beta amyloid is at the center of a positive feedback loop; it is a mis-folded protein that tends to cause more proteins to misfold, similar in dynamics to a prion, though the feedback of beta amyloid is not so direct as in prion diseases.

In the case of beta amyloid, the protein that is misfolded is called APP, for amyloid precursor protein.  Bredesen sees APP as a switch that turns AD on, and can just as well turn AD off.  It is both a signal protein and the gunk that accumulates around neurons in the Alzheimer’s brain.

The (missing) punch line

So what is the program that Bredesen has used so successfully to reverse Alzheimer’s symptoms in ten patients?  It is multi-faceted, not easily summarized, addressing multiple risk factors through multiple modalities.  The program is also personalized, as a doctor works with each patient’s particular symptoms and particular strengths, desiging a program the patient can commit to.  This is not traditional allopathic medicine, and prescription drugs play a minor role.  Bredesen describes a program for one of the 10 patients.

(1) she eliminated all simple carbohydrates, leading to a weight loss of 20 pounds; (2) she eliminated gluten and processed food from her diet, and increased vegetables, fruits, and non-farmed fish; (3) in order to reduce stress, she began yoga, and ultimately became a yoga instructor; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; [5] she took melatonin 0.5mg po qhs; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin 1mg each day; (8) she took vitamin D3 2000IU each day; (9) she took fish oil 2000mg each day; (10) she took CoQ10 200mg each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated HRT (hormone replacement therapy) that had been discontinued following the World Health Inst report in 2002; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week. [same ref above]

(Do you ever wonder about the code language used by doctors on their prescription pads, that only pharmacists can read?  “po qhs” is prescription-ese for “by mouth at bedtime”.  Methyl cobolamin is vitamin B12.)

Bredesen’s results

The good news is that AD was dramatically reversed, especially in its early stages, with a low-cost program that does not require superhuman life style changes.  This worked in 9 cases out of 10, and the 10th case was advanced AD.  The bad news is that crafting an individualized program for the patient requires a doctor with broad knowledge both of medicine and of the patient’s history and temperament, as well as blood tests and cognitive tests.  Patience.  This is likely to be expensive and difficult to replicate in modern, assembly-line medicine where doctors are fungible cogs in a health care factory.  But then, perhaps the bad news isn’t bad–it’s pointing in the direction of the future of medicine.


This is just vibration, but at a higher frequency than human ears can hear.  Ultrasound is commonly used (at low intensity) as an imaging tool

Prof. Jürgen Götz and Gerhard Leinenga of the Clem Jones Centre for Ageing Dementia Research, Queensland, Australia have pioneered the use of ultrasound at higher intensity to break up the beta amlyloid plaques in the brain, with dramatic benefits in mice.  Mice normally don’t get AD, but they can be genetically engineered to come down with AD reliably.  It was these mice that the Queensland doctors worked with, and in most mice they were able to clear up the plaques.  There is still controversy (after 40 years) whether amyloid plaques actually cause AD or whether they are a symptom or side-effect.  So it was important to verify that the mice showed actual memory improvements, and not just better results on the diagnostic tests.  The next step is to get experience in larger animals, before the first human trials.  [Read more from Medical News Today]  [In-depth nterview with Norman Swan.  The episode also includes an interview with Saul Vileda of Stanford about planned plasma transfusion experiments in Alzheimer’s patients.]


Alzheimer’s as an Immune Disorder

A promising line of research regards AD as an immune attack on nerve cells that producers amyloid plaques as a side-effect.  It is not the neurons byt glial cells, the “in-between” cells in the brain, that trigger the immune attack.  In active brains with lots of nerve firings, the glial cells are kept in check, while inactive neurons allow the neighboring glial cells to turn themselves into immune provocateurs.

This is a link between decline of the immune system with age, increase in inflammation, and AD.  Strong circumstantial support for this perspective comes from the fact that anti-inflammatories such as NSAIDs and curcumin offer some of the best protection against Alzheimer’s risk that we currently have available.

Conversely, the healthy immune system attacks amyloid beta and breaks it up.  Biogen Corp purchased a drug based on antibodies produced by healthy humans that attacks A-beta.  Just this year, a new drug called Aducanumab, aka BIIB037, was reported to be effective in reversing cognitive decline in small, initial trials with human trials–not just mice.


DFMO and Arginine

Arginine is one of the 20 amino acids used to build proteins, and it has been found that the AD brain consumes inordinate quantities of arginine.  This begs the question whether arginine is part of the problem or part of the body’s natural solution.  Carol Colton and her Duke Univ lab are betting on the latter.  DFMO=difluoromethylornithine is a drug that blocks arginase, the enzyme that breaks down arginine.  In case that’s too many negatives for you: more DFMO means more arginine.  DFMO has already been approved as a cancer treatment, and now it has been tested in mice, and found to both decrease plaques and improve cognitive performance. [News article, Research article]

Another protein component called taurine was found last year to be beneficial for the mice genetically engineered for susceptibility to AD.  Taurine was added to their drinking water in quantities huge by human standards, equivalent to more than 2 ounces per day of pure taurine.  But improvements in cognitive performance were dramatic.  Results were reported from the Korean lab of YoungSoo Kim.   


Current “best practices”

There are currently 5 FDA-approved drugs for AD, but all of them provide symptomatic relief only, and work only for a few months.  None is able to slow progression of the disease.  [Read more from Carl Sundquist]  Last year, there was a breathless announcement by Eli Lilly about early successes with a new drug called solanezumab, but later results deflated the bubble.


What you can do to lower your long-term risk of AD

  • Regular and sufficient sleep
  • Anti-inflammatories: NSAIDs, fish oil, curcumin=turmeric
  • Weight control
  • Mental and emotional engagement
  • Yoga and meditation
  • Vigorous exercise
  • mega-doses of Vitamin D
  • Melatonin at bedtime
  • DHEA, Vit B12 and SAMe, especially for people with MTHFR genetic risk
  • Low carb diet
  • CoQ10

Fortunately, the greatest risk factors for AD are the same as for other diseases of old age, so there are broad benefits from the above program.  General risk factors are cholesterol levels in the blood, insulin resistance, and inflammation.


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Untested Treatments for Longevity, and How to Test Them

Tests with human subjects require decades, and are impossible to control, so the  gold standard for testing claims for treatments that delay aging is the controlled trial with rodents, usually mice.  Each treatment is applied to about 50 mice for their 2-3 year life span, and an equal number of controls is housed in identical circumstances.  The total cost for a single experiment can run over $200,000, and what we get for this is two full mortality curves, with and without treatment.  

You already know that aging research is the most cost-effective in medical science.  Medical costs rise steeply with age, and delaying aging by even a small amount carries enormous benefits in avoided suffering, in lives, and in medical costs. Research on life extension treatments in mice is grotesquely underfunded by any reasonable accounting of costs and benefits.  

So there is a backlog of treatments that show promise, but we just don’t know yet whether they work.  I’m going to list a dozen of my favorites and then propose a novel scheme for testing them at minimal cost.  The proposal is to run a rough screening for important increases in lifespan, using a small number of mice, and later to determine the full mortality curves for only the most promising treatments.  Further gains in cost-effectiveness can be realized by testing the treatments 2 or 3 at a time.  This leaves a lot of disentangling for the statisticians, but math is cheaper than mice.

And there is an important fringe benefit: What we really want to know is how to combine treatments to extend health span longer than is possible with any single treatment.  Almost nothing is known about how various life extension treatments interact, and it’s high time we started learning.

Here’s my suggested list

  1. Epitalon/Epithalamin
  2. MitoQ/SkQ
  3. Lapachone
  4. Spermidine
  5. Berberine
  6. Dinh lang (Policias fruticosum)
  7. Pterostilbene
  8. Gynostemma pentaphyllum (sold as “AMPK Activator” by LEF)
  9. NAC
  10. Ashwagandha
  11. Turmeric/curcumin
  12. C60


Where do these ideas come from?

The most creative science is also the highest risk, and for that reason is underfunded in today’s economic environment.  There are herbs and roots from traditional Chinese medicine and the Indian Ayurvedic tradition; there are experiments run in small, low-budget labs and experiments from Russian universities that will not be given credence until they are validated in Western labs.  The ones I am featuring today are substances that I happen to know about, and the universe of promising treatments could be greatly expanded by any expert in Oriental medicine.

A new database of life span studies has recently been announced, to be hosted at  There is an existing catalog of life span studies in animals at, which seems to be unavailable as I write this.



Decades ago, Vladimir Anisimov of the Petrov Institute in Leningrad began testing purified extracts from pituitary glands for health and longevity benefits.  In a lifetime of research, he has found many promising substances.  At the top of the list is an extract from a region of the brain known as the epithalamus.  The natural extract is known as Epithalamin.  The active ingredient is thought to be a short peptide or micro-protein with just 4 amino acids, which Anisimov named Epithalon.  In a series of experiments over the years, Anisimov finds life extension in rodents ranging from a few percent to 30%.  Treating 70-year-old humans with the extract, Anisimov reports that their mortality rate is cut in half.



This is a molecule akin to CoQ10, attached to a positive charge which causes it to be pulled into mitochondria. I have written about it previously here and here.  The molecule was developed as a research tool in the 1970s by Vladimir Skulachev and Russian colleagues, and later was recognized for potential health benefits by Michael Murphey and Robin Smith in New Zealand.  Skulachev has tested his product SkQ in mice and claims modest life extension.  A New Zealand company began selling their version, called MitoQ last year, based on experiments that show improved wound healing and neuroprotective benefits in mice.



Beta Lapachone

Tomas André introduced me to Lapachone a few weeks ago.  His French company has begun to promote the science on a web site, though they do not offer it for sale as yet.  It is a tri-cyclic molecule extracted from bark of the Pau d’arco tree in the Amazon rain forest.  In preliminary studies, it has shown potential promoting arterial health, as a cancer treatment and modifier of the energy metabolism.  Most impressive is one study in which the survival curve of mice treated with beta lapachone seems to improve over caloric restriction.



Autophagy is the name of the cell’s main clean-up process, eliminating accumulated wastes.  Spermidine promotes autophagy, and is found in many foods.  As an anti-aging agent, it has been championed by Frank Madeo of University of Graz. He reports dramatic life extension in worms and flies, and smaller life increases in life span for rodents.



Metformin is a diabetes drug that increases insulin sensitivity and dramatically lowers cancer risk. Mice fed metformin live longer.  Berberine is a naturally-occurring polycyclic molecule that reportedly has many of the same benefits.  It is extracted from the goldenseal root, which has been used in Native American and other cultures as a natural remedy and has been championed by Jonathan Wright,  In some studies, berberine improves on metformin both in its effect on glucose metabolism and in improving the lipid profile in the blood.  Like metformin, has anti-inflammatory benefits, but it is not known whether it can slash cancer risk as metformin has been shown to do.  Recently, concern has been expressed about increased risk of Alzheimer’s in patients taking metformin, and we don’t know how berberine might do on that score.  


Dinh lang (Policias fruticosum)

Dinh lang is the Vietnamese name of a traditional herbal remedy. The Parkinson’s drug sold presently as Selegiline or Eldapril or Emsam began life with the name deprenyl.  In the 1960s, it was studied by a Hungarian doctor named Joseph Knoll.  In one of Knoll’s studies, dinh lang was combined with deprenyl, with the result that each separately extended life span in mice, and two together synergized so that life extension with both was more than the sum of the two separately.  I have not seen other studies of dinh lang, and do not know where it can be purchased, or whether it has a place in traditional Chinese medicine.



Pterostilbene is a chemical cousin of resveratrol.  Both are naturally-occurring, with trace amounts in grapes, wine, blueberries and other berries.  Both are a kind of natural anti-biotic, produced by plants as a self-defense when they are threatened by fungal infection.


In 2003, Resveratrol made a splash in the press after an MIT lab discovered that it activated a class of SIR genes associated with longevity.  There were high hopes for resveratrol when it was found to lengthen life span in yeast, worms, fruit flies and fish.  Performance in mice, however, was disappointing, with life extension only for obese mice on a high fat diet.  Pterostilbene appears to have similar activity to resveratrol, but it is much better absorbed and has greater affinity for its target, so it is used in smaller quantities.  Pterostilbene deserves to be tested for life extension potential in rodents.


Gynostemma pentaphyllum

This is the powdered leaf of a traditional Oriental medicinal herb, recently popularized by Life Extension Foundation, which promotes it under the name “AMPK Activator”.  In human and rodent studies, it improves insulin sensitivity and lowers blood sugar.  In studies with fruit flies, it modestly increases life span, but it has not yet been tested for life span effect in rodents.


N-Acetyl Cysteine

Glutathione is a first-line mitochondrial antioxidant, and it is the only antioxidant for which there is any evidence of life span extension.  Unfortunately, we cannot absorb glutathione orally, and NAC has been promoted as the next best thing, as the body uses it to make glutathione. A study from Jackson Lab reports significant life span extension from NAC in male mice, but it comes with a warning about reliability of experimental protocol.  Here is a study that reports that NAC can slow the loss of brain cells in aging mice.



Withania somnifera is an Indian root herb that is used as a longevity aid in the Ayurvedic tradition, and is reported to have anti-cancer benefits.  It is a common ingredient in those herbal mixtures that promote telomerase without astragalosides (Product B, PrimalForce, Telo-100, ProxyStem)



Curcumin is an extract from the curry spice turmeric that has been used in traditional Ayurvedic medicine.  It is one of the best herbal anti-inflammatory agents, and has been found to extend life span in flies and worms.  Based on epidemiology and cell cultures, a role in preventing Alzheimer’s Disease has been proposed for curcumin.



Buckminsterfullerene is a spherical molecule made of 60 carbon atoms that was hiding in plain sight before being discovered in the 1980s.  Based on one spectacular report of life span extension in rats three years ago, it has been adopted by people willing to experiment on themselves, who share their experiences, for example, on the Longecity web site.

Pathways and Interactions

In some cases, we expect combining treatments to be a kind of duplication of effort.  It may be that the net benefit of A and B is just A.  For example, many of the treatments that are known to extend life span work through the biochemical pathway of insulin sensitivity and the glucose metabolism.  There are only a few years of human life available from this pathway, and once we add those years, no amount of tinkering with the insulin pathway will get us any more.

Conversely, if we can indeed address two pathways that are fundamentally different, then we expect positive synergies.  It may be that the net benefit of A and B together is greater than A+B.

We have a handful of interventions that reliably extend life span in mice:  besides dietary treatments such as caloric restriction, protein restriction and intermittent fasting, there is rapamycin, metformin, aspirin, maybe TA-65, some short peptides and various anti-inflammatories.  Very little is known about their interactions, and yet there are humans (some of whom read this column) who are not waiting for the data, but doing all these things at once.  


Experimenting with multiple treatments

I think it is important both to gather information about new treatments individually, and to begin collecting information about how they combine and interact when applied together.  So I have put together an experimental plan using pairs of treatments.  Since the number of pairs is much larger than the number of treatments, I propose using a small number of mice for each treatment.  For example, with 12 treatments, there are 66 pairs of treatments.  If there are just 5 mice assigned to each pair of treatments, that’s 330 mice in all–a manageable number.  This is a modest experimental effort compared to the potential for new information about 12 treatments and their interactions.  With just 5 mice for each treatment pair, the statistical power for each combination is low.  But there will be 55 mice receiving each one of the 12 treatments, so information is there, and the math can extract it.  With so few mice, we will not be able to get the clean survival curves that have become the gold standard for testing treatments in mice.  But with a technique called incremental multivariate regression, it is possible to untangle the data and determine which are the most promising treatments, and how they are likely to work in combination.

I have begun to circulate this proposal with people who are best able to implement it, and others who are best able to find funding for the project.  In coming weeks, I’ll let you know what happens.


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