Lamarckian Inheritance:  Passing what you have learned to your children

If you have followed this blog for any length of time, you have probably figured out that I came to the science of aging through evolutionary biology, and that I believe evolutionary thinking is a key to understanding what aging is and how it can be addressed.  So without further ado, I introduce a column that is central to how evolution works, but peripheral to the science of aging.

You know (or perhaps you take for granted or you’ve never thought much about it) that your body is really good at learning.  Whatever it is that you persist in trying to do with your body, day after day over a period of time, your body gets better at it, stronger, more coordinated, more flexible, more skilled and versatile.  (And conversely those potential strengths which you do not exercise will atrophy, and you lose them.)

You also know that you can’t pass these strengths and skills on to your children. They have to acquire them anew with their own effort and their own habits.  Whatever is innate in your own heritage can be passed along with your genes, but whatever you have acquired or developed must be developed afresh by each new generation.

Wouldn’t it be great if we could get past this limitation?  Imagine if you could bust your gut in Pilates class knowing that it wasn’t just your own abs you were strengthening, but a legacy you could pass to future generations?  Imagine if your children could pick up where you left off developing their health and their skills and their coordination and reflexes, each generation building on the last to reach for higher and higher goals.

And what a boon for evolution, this would be – if only it were real!

The process I’m describing is Lamarckian inheritance, an attractive hypothesis, a long-discredited mechanism of evolution.

???  !

Curiously, some temporary kinds of Lamarckian inheritance have become well-established in recent years.  Could it be that permanent, Lamarckian modification of the genome is also a reality?

Here’s how the story is still taught to this day:

In 1809, Jean Baptiste Lamarck’s theory of evolution was that the training and habituation that our bodies undergo when we exercise our muscles, when we endure heat and cold, when we use our brains to solve problems – these abilities acquired in a lifetime affect offspring, so that they are born better able to cope with whatever it is that the parents have coped with during their lives.  Thus the environment and an individual’s response to it helps to shape the character of the next generation, and evolution proceeds efficiently in the directions of those qualities that are required in the environment, and those choices which the parents have made during their lifetimes.

Fifty years later, Darwin’s theory was that offsprings differ from their parents in ways that are purely random.  The direction of evolution is controlled indirectly, because some of those offspring are better able to survive and to reproduce than others.

The difference is whether genetic variation is random or directed by the environment and life choices of the parents.  Darwin said random.  Lamarck said directed.

Darwin Lamarck                                                   
  • Random variation in each offspring.
  • Competition eliminates those individuals less able to survive and reproduce.
  • It is offspring of those individuals who have been most successful at surviving and reproducing that dominate the next generation.
  • Over time, those qualities that aid survival or reporoduction accumulate.
  • The body develops in response to challenges experienced during a lifetime.
  • Some features developed in this way are passed to the next generation.
  • Evolution can proceed without need for natural selection, but natural selection can serve an auxiliary function.

In the 1890s, August Weismann conducted an experiment in which he cut off the tails of rats and then measured the tail lengths of their progeny.  He continued, cutting off the tails of 20 generations of rats, and yet each generation was born with tails just as long as the last generation.  This was a definitive (?) refutation of Lamarckian inheritance, and scientists everywhere have developed the theory of Darwin, and reserved the story of Lamarck as a morality tale about discredited science.

If Jean-Baptiste had been alive to defend his theory he might have said that developing a trait by using the neural pathways and strengthening the muscles is quite different from hacking off a body part.  What Weismann demonstrated had little to do with the heart of Lamarck’s theory.

But it wasn’t Weismann’s experiments alone that gave Lamarckism a bad name.  Austrian Paul Kammerrer set out to prove the reality of acquired genetic inheritance, and was caught in scientific fraud.  In the 1930s, Trofim Lysenko and the Soviet propaganda machine promoted Lamarckism not so much as a science but a political ideology. Communist social practice was destined to change the core of human nature.

The coffin of Lamarckism was sealed by Francis Crick, who not only discovered DNA as the repository of genetic information, but articulated in 1958 the Central Dogma of Molecular Biology:  Information flows from DNA => Messenger RNA => Proteins, always in that direction.  In 1958, there were no mechanisms known by which proteins could feed back to modify DNA, and Crick boldly speculated that no such mechanisms existed.

Here are some facts that don’t fit with that story:

Random variation is extremely inefficient.  The big problem is that two or three or even dozens of genes needto change before a new trait can be acquired.  Suppose that a few mutations appear that are steps in the right direction – how are those mutated genes to be preserved while waiting for other mutations that will complete the set and create something that actually offers some selective advantage?  This problem has been called “irreducible complexity” by the Creationists, Christian critics of Darwinian evolution.  Evolutionary scientists, under seige from the Creationists, have decided to “take no prisoners”, and so they deny there is any merit to this criticism, and pretend that Darwin’s theory of evolution works just fine as is.  But the honest truth is that the Creationists have hit upon the weakest assumption of evolutionary theory as understood by mainstream scientists today.  “Creation science” is in fact not a science at all, but a decision to give up on scientific investigation and accept without question that “that’s the way God made it”.  This is not a path I find appealing; nevertheless, creationist criticism of the version of evolution based on one-mutation-at-a-time is actually quite well-founded.

Evolutionary scientists have always taken it on faith that there is a mechanistic explanation for the origin of every organ, every system, every biological function that we observe.  We have hoped and assumed that the more we learn about the workings of the body, the clearer would be the pathway by which it might have evolved one-mutation-at-a-time, with each incremental step offering some selective advantage that would hold it in place while waiting for random mutation to come up with the other steps.  But in fact, the more we know, the more puzzling cases we see of “irreducible complexity” which strains our imagination to account for a plausible evolutionary pathway.

Darwin knew this.  Even in the first edition of The Origin of Species (1859), he admitted a role for the hfabits of the parents in determining the traits of the offspring.  This idea was coded in the words “use and disuse” in the last paragraph of the book:

It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us. These laws, taken in the largest sense, being Growth with Reproduction; Inheritance which is almost implied by reproduction; Variability from the indirect and direct action of the external conditions of life, and from use and disuse; a Ratio of Increase so high as to lead to a Struggle for Life, and as a consequence to Natural Selection, entailing Divergence of Character and the Extinction of less-improved forms.

Through the development of Darwin’s thought after The Origin, the idea of Lamarckian inheritance gradually gained ground.  In 1876 he wrote in a letter (published after his death):

In my opinion, the greatest error which I have committed has been not allowing sufficient weight to the direct action of the environments, i.e. food, climate, etc., independently of natural selection. . . . When I wrote the “Origin,” and for some years afterwards, I could find little good evidence of the direct action of the environment; now there is a large body of evidence.
— From a letter to Moritz Wagner, 1876

Savor the irony that the version of Darwinism that is best accepted today is ultra-orthodox, far more narrow than beliefs and writings of Charles Darwin.  If Darwin were submitting his papers to the journal Evolution today, he would receive a patronizing letter of rejection, criticizing his unfocused thinking, and warning him that Lamarckian inheritance is not a credible mechanism, and that he must re-frame his theory in terms of known, validated laws of inheritance.

This kind of censorship in the name of scientific orthodoxy is bad enough when it is well-grounded in empirical science.  But in the case of Lamarckian inheritance, it is the mainstream scientists who have missed the boat.


Epigenetic inheritance is now un-controversial, mainstream science

The term “epigenetic” refers to any inheritance mechanism that is not coded directly into DNA.  The best-established kind of epigenetic inheritance occurs through decorations and markers that surround the DNA and affect which genes are expressed and which are held in reserve for another time and place.  Methylation of the DNA and acetylation of the histones are two of the best-studied markers that affect gene expression.

Methylation and acetylation patterns can change in response to habitual activities and to the envirnoment.  These patterns are copied with the DNA – not quite so faithfully as the DNA itself – and can be passed from parent to offspring through multiple generations.  This is a kind of temporary Lamarckian inheritance.  It is indisuptably Lamarckian, but seems to last four or five generations at most, if it is not re-inforced.


  • Children of obese mothers have greater risk of insulin resistance and diabetes [Ref].  (This inheritance is both genetic and epigenetic, and we have to trust that the authors of the studies cited here correctly separated the two with their statistical filter.)
  • Traumatized mother mice are affected in their metabolic as well as their psychological responses, and these effects are detectable in the offspring of the traumatized animals out to the fourth generation [Ref].  Just this last week an article was published about male mice that transmit the effect of trauma to their young, and two more generations beyond.
  • “One of the most dramatic examples is with diethylstilbestrol, a synthetic nonsteroidal estrogen prescribed in the 1970s to prevent miscarriage in women with prior history. While the drug helped pregnancies to go to term, it induced severe developmental abnormalities and increased the risk for breast cancer and a rare form of adenocarcinoma in girls whose mothers were exposed to the drug during the first trimester of pregnancy. Furthermore, the risk of cancer appeared to be transmitted to the following generation. A clinical study reported that a 15-year-old girl whose maternal grandmother was exposed to diethylstilbestrol during pregnancy was diagnosed with a very rare case of small cell carcinoma in the ovary. Many more of maternal granddaughters than expected also developed ovarian cancer. Although these findings are among the first and need to be confirmed by further transgenerational studies, they suggest that the detrimental effect of a drug can be transmitted across generations. Such transgenerational effect of diethylstilbestrol was also observed in mice. Similar to humans, perinatal exposure to the drug induced abnormalities in uterine development and uterine cancer in first and second generations. These abnormalities were suggested to result from aberrant DNA methylation in a gene that controls uterine development and in uterine cancer genes.” [from Franklin and Mansuy, 2009]
  • Here’s an example that’s not really Lamarckian, but that clearly demonstrates epigenetic inheritance.  There’s a mutation in a gene called Kit that causes brown mice to have white spots.  One copy of the gene is enough to cause the spots.  So experimenters crossed a mother mouse with one copy of the gene with an un-mutated father mouse that had no spots.  According to standard Mendelian genetics, we would expect that half the offspring of the cross would get the Kit mutant gene from their mother, and half would get the mother’s normal gene.  So they expected half the offspring to have spots.  The surprise was that all the offspring had spots.  With DNA tests, they checked and, as predicted, only half the offspring had the mutated Kit gene.  Still, they all had spots.  Epigenetics!  The experimenters figured out that the mutated gene signals the body to silence the other copy with methylation.  So the offspring mice inherited a methylated version of the normal gene from their mothers.  The methylation was copied along with the DNA. [Ref]

Here is a Stanford study that isolated the epigenetic component of longevity inheritance in worms.

Eva Jablonka is an Israeli geneticist who realized early the importance of epigenetic inheritance, and has been writing about the subject for 20 years.  Here is a review article from 2009 in which she lists hundreds of examples of epigenetic inheritance.


But where did epigenetic inheritance come from?

A question which I have not seen asked in the literature is this:   The epigentic inheritance mechanism is itself permantly installed, presumably with a basis in the genome.  So how did the mechanism of epigenetic inheritance come to be?  Here is a prime example of irreducible complexity!  Copying the methylation state requires a whole different set of enzymes from copying the DNA bases.  Epigenetic inheritance offers many potential advantages over the long term, but it is not an adaptation that offers fitness benefits in immediate neo-Darwinian terms (survival or fertility).

In addition, it is agreed that mutations increase in response to stress

Epigenetic inheritance is a well-accepted Lamarckian mechanism, but it is temporary, and doesn’t affect the DNA itself.  Is there also Lamarckian influence on the DNA?

Normally, DNA is replicated accurately, with negligible errors, but in times of stress something different happens.  It was once described as a breakdown of the cell’s proofreading facility under stress.  But it has now become a mainstream idea that this is no accident, that the cell flails at random, trying wild cards when it is clear that the standard strategy is not working so well.  Jim Shapiro goes further, and describes “conservation in times of successful growth as compared to active restructuring in times of stress.” [my emphasis]  Shapiro’s position stands out as an extreme, but he has credentials that suggest we ought to listen.

For example, it was once thought that UV radiation damages chromosomes, a purely physical effect of high-energy photons.  The truth that has emerged is that the cell detects the UV as a stressor, and mutates its own DNA, under metabolic control, as part of an adaptive response.  Whether the mutations are random or whether they are part of a directed response to the radiative environment remains controversial.  This was disovered already in the 1950s by Swiss microbiologist Jean Weigle.

From here, Shapiro takes another giant leap into full-blown Lamarckism

Shapiro has a thin, dense book called Evolution: A View from the 21st Century, in which he makes the case for a radical departure from the notion that evolution takes place by natural selection on random mutations.  He cites evidence that the “mutations” that appear under stress are far from random, that in fact the cell is re-arranging its own DNA, and doing so in a way that is much more likely thant “random” to produce ana daptive response to the particular stress at hand.   “Natural genetic engineering”, he calls it.  He has spent much of his career documenting this effect in bacteria, but he claims that animals and plants have far more sophisticated abilities to re-arrange their own DNA – it’s just that these are more difficult to see in the laboratory.

If Shapiro is right, then perhaps we can begin to understand the mystery of how evolution is so miraculously efficient as it seems to be.  But we will have left traditional limits of neo-Darwinian evolutionary theory far behind.

pf button Lamarckian Inheritance:  Passing what you have learned to your children

No, the body doesn’t just wear out as we get older.

Friends often look at me quizzically when I tell them this.  One says, “But I can feel myself wearing down.” And another: “Nothing works the way it used to.  Isn’t that the definition of wearing out?”  And again: “Do you mean it’s all in my head, it’s not really happening?” and then a moment later, “do you mean it doesn’t have to be this way?”

This last formulation is getting a little closer to what I mean.

Of course, loss of function with age is not just in your imagination, and it is very common (though not universal!) in the Animal Kingdom.  But aging is not caused by wearing down.  It is more accurately an orderly program of self-destruction, orchestrated by gene expression.  Some aspects of aging appear as accumulated damage (e.g. cartilage worn away from joints, or build-up of cross-linked sugar-protein complexes), but on closer inspection even these are seen to be entirely avoidable consequences of the body shutting down its repair systems.

This column is devoted to the reasoning and the evidence that tells us aging cannot be, at root, a process of wear and accumulated damage.  First, the theory: why there is no physical necessity for aging; second, a few examples of animals that age very slowly or not at all, and others that age super-fast; third, some familiar facts and a few unfamiliar facts about aging that tell us “wearing out” does not provide a helpful perspective.


1. The Physical Theory, and Why it Doesn’t Apply to Living Things

There is no physical necessity for aging.

Man’s earliest conception of aging was that the process was akin to physical wear and tear. Knives get dull – why shouldn’t our teeth?  Wheels get rusty and squeak when they turn – isn’t that what happens to our joints?  Water pipes fill with sediment over the years, just like our sclerotic arteries.  It’s a theory with a great deal of intuitive appeal.

But the analogy between living body andmachine is flawed.  Living things are fundamentally homeostatic.  They can repair themselves.  They build themselves from a single egg cell, and simple animals can rebuild when damaged.  A car takes in energy in the form of gasoline and uses the energy to propel itself forward.  An animal takes in energy in the form of food and uses it to perform all the feats of metabolism, locomotion, foraging, signal processing, and evasion of predators; and a small portion of that energy is devoted to the “capital budget”: breaking down and rebuilding damaged tissues; replicating cells; looking for copying errors in DNA and setting them right, detecting malformed protein molecules, breaking them down into constituent peptides for recycling into new molecules.  This small part of the energy budget is all that is needed to keep the system in good repair indefinitely.

The Second Law of Thermodynamics says that entropy (disorder, degeneration, damage) must increase in any isolated physical system.  But living systems are not isolated.  Living things draw free energy* from their environment, use it internally, then dump waste entropy back into the environment.

This isn’t some lucky feature, tacked on to living bodies, rescuing them from an ironclad law of physics.  The capacity for homeostasis is built into the form and function of living things.  To a physicist, a living body is defined by its ability to create and maintain itself using ambient sources of free energy.  The very function of the living machine is homeostasis (along with reproduction).

Q:  Even though the body is able to repair itself, the repair can’t be perfect.  Isn’t that the root cause of aging?

A:  The repair doesn’t have to be perfect.  The body built itself from seed, created a robust, young individual in the prime of life.  But the body wasn’t perfect when it was young.  Repair can be accomplished to that same standard.  In fact, it’s always easier to repair a body than to build a new one from scratch.

Q:  When a car gets old, it becomes more and more costly to repair.  Eventually, the mechanic tells you that it’s going to cost you more to fix all the things wrong with your car than to buy a new one.

A:  This is an artifact of mass production.  A new engine is made on an Asian assembly line, with low labor costs and automated manufacture.  Repair requires local, skilled labor, paid at a rate reflecting professional service.  Cars are loss-leaders, artificially cheap; replacement parts are expensive when the manufacturer knows you’ve got no place else to go.  Most important, an engine must be disassembled bolt-by-bolt to get at the worn piston rings deep inside, then meticulously rebuilt; but living tissues are repaird from the inside by efficient molecular machines.

Q:  But think in terms of information.  The DNA is like a book that needs to be copied over and over.  If a single letter is mis-copied, and it evades the error-checking machinery, that represents lost information that can never be recovered. In the long run, the errors have to accumulate, and eventually they will degrade the cell’s ability to function.

A:  This is true, and was the basis of a promising theory of aging in the 1960s.  Experiments were done to test this theory, and it didn’t pan out.  It turns out that DNA replication is designed to be accurate enough that the errors accumulating over one lifetime are not a significant problem.  I wrote up this topic recently, as a new study was done based on 100-year-old twins, and found that only an insignificant handful of mutations over a long lifetime.

When stem cells divide to form new, differentiated cells, the old, original strand of DNA stays with the stem cell and the newly-copied strand goes consistently with the differentiated cell.  It seems that Nature has been thinking about DNA copying errors, and has taken care of the problem.

So yes, some loss of information is inevitable over long enough times but no, this is not relevant to aging.  Read more here.

Aging can’t be explained by inevitable accumulation of chemical damage, or DNA copying errors that accumulate, or physical wear and tear, or the accumulated toxic effects of reactive oxidative by-products of the energy metabolism (ROS).  Actually, this much was understood already at end of the 19th Century, when August Weismann wrote a book attempting to explain aging from an evolutionary perspective.


2. Aging in nature: fast, slow, and backwards

Aging appears in nature in an amazing variety of forms.  Some of these were abstracted as graphs in a paper I reviewed last month.  In our anthropocentric view, we might imagine that all animals grow up, reproduce in the prime of life, then gradually lose fertility and strength, and suffer accelerating decline leading to death.  This is the way it is for people, guppies, and sea birds.

But salmon and octopuses reproduce all in a burst and quickly die.  The thing that kills the salmon is a burst of corticoid hormones that deranges the fish’s hormonal balance.  What kills the octopus is that its mouth seals closed, and it can no longer eat.

Sharks and clams just keep growing larger and more fertile and stronger and less vulnerable to death as they get older.  The oldest ones are rare and large, and it takes a great accident to kill them, because they are not about to die of old age.

Cicadas spend 17 years maturing underground, then come out, mate and die in a single day.  The adult has no organs for eating or digesting food.

Some jellyfish and beetles have been observed to regress when starved.  Their bodies shrink, then progress backward through previous stages of development until they are larvae once more.  As larvae, they can exist in a kind of hybernation, and when food becomes available, they can grow again and start life over.  In the lab, they have been manipulated to go through many cycles of getting older, getting younger, and on and on.

Rockfish are medium-sized, deep water dwellers.  Though most rockfish live 10 to 20 years, occasionally one is caught that is over 200 years old, as determined by annual growth rings in an ear bone.

The fastest life cycles in nature (yeast cells) suffer aging and death in a matter of hours.  The slowest (sequoia trees) aging processes unfold over thousands of years.  If aging is an inevitable physical process, why would it occur a million times faster in some species than in others?

It would appear that aging is a common but optional part of the life plan.


3. Response to stress:  Aging doesn’t act as we would expect

If you keep your car in the garage six days a week and drive only to church on Sundays, it will last a long time.  Drive it like a hot rod and it will wear out a lot sooner.  But our bodies last longer the harder we work them.

Exercise generates free radicals like crazy, but the body’s native anti-oxidant defenses overcompensate.  Muscles suffer little tears, bones tiny fractures, and yet the body repairs these better than new, and the result is that we live longer if we exercise.

One of the three mainstream evolutionary theories (the “disposable soma”) holds that aging results from budgeting of energy.  The body apportions its food energy for maximal fitness, not for maximal longevity, so more of it goes to survival and reproduction, less to repair and maintenance.  This theory is utterly untenable in the face of caloric restiction experiments.  Animals quite generally live longer ther less they are fed.  If aging were enforced by the energy budget, a larger energy budget would cause us to live longer.

Finally: Some of the biochemistry of aging is understood now, and its basis looks like self-destruction, not like attrition.

  • Stem cells cease replicating when their telomeres become too short, all because the enzyme telomerase is withheld.

  • Inflammation, which protects the young body against invading microbes, is turned against healthy tissues in old age, damaging arterial walls in particular and triggering cancers everywhere.

  • Apoptosis is cell suicide, which works to protect us against diseased and dangerous cells in our youth, but as we get older we lose healthy, functional cells to apoptosis.  This is the underlying cause of sarcopenia, and is related to the cause of Alzheimer’s disease.

  • The thymus is a tiny gland at the base of the throat, responsible for training white blood cells so that they are smart enough to attack invading pathogens and refrain from attacking the body’s own tissues.  As we age, the thymus shrinks in size and loses its functionality, so the immune system makes errors Type I and Type II:  It attacks the self, causing auto-immune diseases including arthritis, and it fails to attack invaders, making us increasingly vulnerable to infectious disease.


The bottom line

Since 1889, mainstream evolutionary science has rejected the idea that the body ages for the same reason that a tool or a machine wears out.  In this case, evolutionary science has it just right.


* “Free energy” is a technical term in thermodynamics.  It means that portion of total energy which is available for work.  Ambient warmth is energy, to be sure, but not useful energy.  “Free energy” has a well-defined quantitative meaning.  Electric energy is 100% free energy.  Energy in boiling water is about ¾ free energy and ¼ ambient warmth.  Likewise, chemical energy is partially free energy and partially warmth.

Total energy cannot be created or destroyed, but free energy becomes degraded into warmth as it is used.  Both living things and non-living machines take in high-grade forms of free energy, use some of that for their various functions, and discard the same total amount of energy as low-grade chemical energy and warmth.

pf button No, the body doesn’t just wear out as we get older.

Build exercise into your day

Here is a perfectly-matched pair for adding exercise to your daily schedule without taking time, while (probably) improving your mood and increasing your energy and concentration: Bicycling for low-intensity aerobic exercise, stairs for bursts of speed and strength.  This would be a great addition to your life even if it weren’t the second most effective path to long-term health and lower risk of all causes of mortality.


ds73 Build exercise into your day

Skip the elevator

The two greatest fitness inventions of all time (in my humble opinion) are the bicycle and the stairwell.  Both fit into our city-dwelling lives, adding bursts of energy without taking time from our routines.  Taking the stairs instead of the elevator is often quicker, and even for ten flights or more adds only 2 minutes or so, and starts your meeting or your workday with tension released, heart pumping, brain in high gear.

Similarly, a bicycle commute is almost always quicker than a bus or even a commuter train, when you take wait times into consideration.  And bicycling may well be competitive with driving, if you include the time for parking and walking the last block or two to your destination.

Urban cycling III Build exercise into your day

Commuting in Vienna

Take a break from work every hour and run up a few flights of stairs.  Stairs are conveniently available to most of us, and a minute of climbing is just the right scale for a high-intensity exercise break.

Celebrate the spring by bicycling to work one morning.  Experiment with a new commuting routine.


pf button Build exercise into your day

Salt is good for you

Last year, the Federal CDC backed off from 50 years of advising everyone (and especially heart patients) to limit their salt intake.  A meta-analysis of many studies showed that eating salt was not associated with increased risk for any disease.  Here is my blog on the subject from last June.

Put Down that Saltshaker Salt is good for you

Feel free…

Now that the doors have been opened to question long-established medical advice, a bit more of the truth has emerged:  Cutting back salt is dangerous.  Risks for mortality and various cardiovascular outcomes were 10-15% higher for people who cut back on salt, compared to people who salted their food to taste.  That’s a lot of excess disease, and the number of people who have been affected is many millions.  In my opinion, it is a major scandal that epidemiologists have failed to correct their stand over a period of 50 years.

Results were consolidated from 25 different published studies, using different criteria and different age ranges.  It took some fancy statistical footwork.  Even more challenging is the fact that most people who are limiting sodium intake are doing so because doctors have told them they have elevated risk for heart attacks.  So it’s not straightforward to compare the risks among low-salt and normal-salt groups, because they’re not comparable populations.  The authors of this study understand this, of course, and claim to have done the statistics appropriately.  My guess is that there was a tendency to under-state the difference, both because the results are so damning to the medical establishment, and because larger claims expose the authors to more criticism.  For these reasons, it is likely that the reported cost of lowering salt intake may rise further from 10-15% reported here in coming years.

The article was titled Compared With Usual Sodium Intake, Low-and Excessive-Sodium Diets Are Associated With Increased Mortality: A Meta-Analysis

Lead author of the study, Dr Niels Graudal of Copenhagen University says, “The good news,” he says, “is that around 95% of the global population already consumes within the range we’ve found to generate the least instances of mortality and cardiovascular disease.”
Read more

pf button Salt is good for you

Life Extension Supplements: A Reality Check

In a paper published late last year, a cautious and expert biochemist reports that none of the most popular “life extension supplement” mixes actually extend life span in mice.


Stephen Spindler, biochemistry prof at UC Riverside, has been warning us for years that supplements, herbal extracts and nutraceuticals are, on the whole, ineffective for healthy adults, and that some may actually shorten life expectancy.  Spindler’s lab has done many life extension studies on mice (summary), almost always with negative results.  One recent report included separate life span tests on extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin.

One of the themes in his papers is that caloric restriction is the only thing that works consistently, and that many of the treatments that seem to offer life extension are subtley inducing caloric restriction, (and this goes unreported by the investigators).  But there are so many substances to test, and each lifespan test in mice is so expensive, that Spindler has suggested gene expression profiles as a shortcut to identifying candidates for further testing.

Another approach is to test many substances at once in a mouse life extension cocktail.  Another rationale for this kind of testing is that we know that natural fruits and vegetables contribute to a long and healthy life, so perhaps it takes a complex combination of nutrients to be effective.  Late last year, Spindler reported on his experiments, feeding commercial “life extension” mixes to hybrid mice.  The results are a bracing cold shower for those of us who take a variety of carefully-chosen supplements each day – and a personal caution to me, since I have recommended supplements on my Aging Advice web page.  [Link to Spindler combinations paper]



Seven of the eight graphs of survival time in the paper look like this.

Spindler Fig1 Life Extension Supplements: A Reality Check

The mice that ate the supplements and the mice that ate ordinary mouse chow had exactly the same pattern of mortality.

(The agreement between treatment and control is so perfect that, if it were a scientist of less integrity, I would suspect the data had been doctored.  But in Spindler’s case, I think the consistency of the results bears witness to his expertise in all aspects of mouse husbandry and experimental desgin.  Clearly, his lab has benefited from a lot of experience, and has adopted methods of caging, feeding, watering, temperature and light control that eliminate a lot of the usual experimental scatter.  Even choice of the mouse strain was subject to thoughtful analysis.)

The eighth treatment group showed slightly shorted life span.

Spindler Fig8 Life Extension Supplements: A Reality Check


Our results do not support the hypothesis that simple or complex combinations of nutraceuticals, including antioxidants, are effective in delaying the onset or progress of the major causes of death in mice. The results are consistent with epidemiological studies suggesting that dietary supplements are not beneficial and even may be harmful for otherwise healthy individuals. [Spindler]


What substances were tested?

There were eight test groups with different mixtures of supplements, one control group fed only standard mouse chow, and one calorically restricted “positive control” that got less mouse chow (and lived longer).  There was some overlap among mixtures of compounds in the eight test groups.  The list of substances included is long.  Here are highlights:


Alpha Lipoic Acid
Blueberry extract
CoQ10 (ubiquinol)
Green tea
Many minerals
N-Acetyl Cysteine
Pomegranate extract
Silymarin (milk thistle)
Vitamin A complex
Various B vitamins
Vitamin C
Vitamin D3
Vitamin E
Vitamin K2

Two of these substances (metformin and melatonin) have a credible history of life extension potential in past experiments with mice.  Spindler doesn’t comment, and I leave this as an open question.  There is credible data in humans for two more (vitamin D and aspirin), both of which have been shown to lower all-cause mortality.  I am not aware of rodent life span studies of vitamin D or aspirin, but I trust that one of you, my readers, will point me to a reference.

Notably absent were prescription drugs that have been shown to lengthen mouse life span in the past: deprenyl, metformin, and rapamycin.  The first two are, in my opinion, suitable for general human use.


Fish oil responsible for shortened life span

Why did experiment #8 actually shorten life span (by about 9%)?  Spindler speculates that it might be due to the way mice respond to omega 3 fatty acids (fish oil).  He cites not-yet published data in which fish oil alone was found to shorten life span.  Another possibility he mentions is the well-established fact that plant compounds can mimic the effects of mammalian hormones, and that indiscriminate overdoses of plant extracts can throw the metabolism into dysregulation.


Caveats: Mice are not humans

Some things about aging metabolism in mice are the same as humans, and some are different.  One principal difference is that aging mice die predominantly of cancer, while aging humans die of cardiovascular disease, cancer, and Alzheimer’s disease.  Aging mice, like aging humans, are flooded with hormones that dial up inflammation that destroys healthy tissue and heightens risk of cancer [ref].  So the failure of anti-inflammatory ingredients (e.g. omega-3 fats, aspirin) in these mixes to have a life extension effect is particularly puzzling.  Unlike humans, aging mice do not suffer from short telomeres, so we might hope that telomerase activators (e.g. silymarin, astragalus extracts, ashwagandha, bacopa) would benefit human life span even if they do not help mice.

A partial explanation for the null results is that some of the combinations include anti-oxidant vitamins, which have been shown generally to shorten lifespan.  This could be counteracting the benefits of some ingredients that might provide benefits on their own.  Likewise for the fish oil that was included in one of the ineffective combinations.


What does this leave us?

There is epidemiological evidence for mortality reduction in humans from small doses of NSAIDs (ibuprofen, aspirin) and for large doses of vitamin D.

There is evidence from rodent experiments that melatonin, metformin and deprenyl extend life span.  There are reports from one lab in Russia that SkQ should be added to this list, but it is not yet commercially available.

There is anecdotal evidence and theoretical support for telomerase activators:  astragalosides, silymarin, other herbs, carnosine, etc.  We expect these might work better in humans than in mice, though evidence is yet thin.

Everything else is speculative, and many anti-aging supplements will help some people but not others.  There is also the disturbing potential for actual harm, as Spindler emphasizes.  None of us wants to think that the mix of supplements we take might be shaving years off our life expectancies.

pf button Life Extension Supplements: A Reality Check

A one-man experiment in radical anti-aging

One reason that there is still so much uncertainty in anti-aging medicine is that we can’t do experiments on humans the way we do on mice.  So we are grateful for a few human guinea pigs who put their own bodies on the line as early adopters.  There is the Caloric Restriction Society, people who are losing weight in the hope of gaining years.  There is an on-line community of people experimenting with Buckyballs in olive oil (this may sound like a joke if you haven’t read about it before).

And then there is Jim Green of Wichita, KS.  Since 2007, Jim has been pursuing experimental strategies and claims to have set his body clock back by 15 to 20 years already.  The core of his program is telomerase activation herbs, particularly astragalus, taken in much larger quantities than the label recommends.  Jim has quite a story to tell, and this week I have interviewed him, an exclusive for ScienceBlog.

(You can read more about Jim’s career here and his anti-aging program here.)

 A one man experiment in radical anti aging

Jim Green in 2007

 A one man experiment in radical anti aging

Jim Green in 2013

What gave you the idea that growing younger was possible?

According to the telomere position effect data I saw early on back in 2007, telomere length impacts youthful gene expression, and gene expression is more youthful the longer the telomeres are. Furthermore, since 1998 it has been realized that senescent cells can often be restored to the youthful phenotype by transfecting them with a virus that improves hTERT transcription and boosts levels of telomerasee in the cell. In 1998, Michael Fossel published an article on this in the Journal of Anti-Aging Medicine (now Rejuvenation Research). [Another Fossel article -JJM] So there were definite grounds for optimism that lengthening telomeres with telomerase could result in rejuvenation transformations.

On the other hand, as telomeres got shorter, patterns of gene expression became more elderly and the likelihood of the onset of diseases of old age increased, according to many scientific studies. For instance, microglial cells in the brain that clean up amyloid beta plaque leading toAlzheimer’s disease fail when they become senescent. If senescence in the microglial cells (derived from hematopoietic stem cells) could be prevented, then Alzheimer’s disease due to the onset of senility might also be prevented. Similarly, when the lining of the vascular endothelium becomes senescent, it becomes more adhesive to monocytes and more likely to develop atherosclerotic plaque leading to attacks or strokes.  So taking small molecule telomerase activators effective at increasing the telomere length of components of the blood was a very good bet for effective life extension. Similarly, when dermal fibroblasts go senescent, they begin to attack the extracellular matrix, producing wrinkles. This does not happen at once to all of the fibroblasts, but gradually in a way that produces more and more defects in the extracellular matrix behind wrinkles. Thus a telomerase activator effective on dermal fibroblasts should prevent observable signs of old age such as wrinkles.


When did you start your program?  What was your program in the beginning?

I started taking telomerase activators on May 1, 2007, after reading material on TA-65 from TA Sciences.  I also had an exchange with Greta Blackburn of TA Sciences in which she emailed me promising results obtained by using TA-41, an astragalus extract which they believed would be similar in effect to TA-65.

At first I expected to be able to set back my telomere clock by up to 8 or 9 years per year, but subsequently revised this to about 5.1 years per year.

The astragalus extract actually finally turned out to work rather better, in fact, than TA-65.

I was also reading Life Extension Magazine since 2004, so I was familiar with supplements recommended by LEF to prevent diseases of old age, such as acetyl L-carnitine with alpha lipoic acid for mitochondria, L-arginine as a nitric oxide booster for rejuvenating the vascular endothelium, anticancer supplements such as garlic and ginger and turmeric, and so forth.

At first I took astragalus extracts such a Solaray Astragalus Extract, and tried GAIA Herbs astragalus extracts.  Later, I got the idea of using colostrum skin creams for telomerase activation. However I seem to have used astragalus extracts both orally and on my skin in the beginning.  This was done for two weeks before switching to a telomerase-inhibiting anticancer phase of treatment for the next two weeks, when I took medicine like curcumin, which is anticancer. If my telomerase activators tended at all to encourage cancer, I was going to squelch that every monthZin November 2009 I presented a short description of my program here For 2 1/2 years, I had relied primarily on astragalus extract for telomerase activation. However, I also got 5 grams of arginine per day to improve my nitric oxide levels and improve the length of endothelial progenitor cell telomeres.  By June of 2009 I concluded after studies of Vida Institute literature that 33 grams/day of astragalus root would serve as well or better than the 5 mg/day of astragalosides from astragalus extract that I computed I was taking. So I switched from pure astragalus extract like TA-41, which worked fine according to Greta Blackburn at TA Sciences, to astragalus root in capsules from NOW FOODS. However, I was still applying astragalus extract directly to my scalp.

[Editor’s note: Astragalus is a woody root which can be found in Chinese groceries for about $10/lb.  Traditional use would be to boil strips of astraglus to make a tea. -JJM]

What is your supplements regimen at present?  Is it still evolving?

I have posted a short summary of my present program and photo news here. It is still evolving, and by now I have 173 items at least on my list of telomerase activators that I am exploring. The numbers of the activators chronicle the order in which I found them in the literature, or were tipped off to them by other investigators, except for sub-items, which I have sometimes found more frequently.

I have continued a four-week cycle featuring telomerase activators for two weeks followed by anticancer telomerase inhibitors for two weeks.  I do things that permit cells to recover from the senescent state that are a little unusual now: I use folic acid in my colostrum solution with an amphipathic alcohol to improve absorption (rubbing alcohol = isopropyl alcohol). [Isopropyl alcohol is moderately toxic. - JJM]  I take carrots and exercise to inhibit P16INK4A, which can stop senescent cell recovery.

I have many ideas about medicine I would like to include, such as tocotrienol-rich fraction. [These are chemical cousins of vitamin E derived from grains -JJM]  For bodybuilding, I take whey protein and creatine monohydrate, although I am not attempting a championship program. I can more easily resemble a gymnast.

Besides supplements, what are you doing to stay young?

Exercise improves circulation in the brain, elevates nitric oxide levels that dialate vessels, and provides numerous growth factor telomerase activators that can be separately enhanced by various nutraceuticals. So I work out with weights, about 6 sets per muscle, using a split routine that takes 3 or 4 days.  This might be dangerous to a person with too much atherosclerotic plaque, or someone with glycation stiffening in the veinous system from high levels of sugar from ice cream. However, it tends to lower triglycerides and improve the lipid profile, and also to improve confidence and mood.

I take a slice of Swiss cheese often to get a higher vitamin K2 level to avoid calcification of the arterial system and aortic stenosis.

In what ways do you feel younger than 7 years ago?

May 2007 was my starting date, and we are now approaching May 2014.  I would say that my confidence has improved that we can finally master aging, although there is still a fair amount of suspense involved.  My physical condition oscillates somewhat, and is subject to minor perturbations. I work to get leaner in the Spring, like most people, and my self-image improves then. I look better in photographs, although I invariably puff up a bit in the Winter. In the Summer I can do pull-ups on outside chinning bars, and I get more V-shaped.     In general, I seem to look somewhat better to myself in photographs an I did 7 years ago. Last Summer I did 130 pushups, which was    an all-time record for me. I am hoping that it will go back up to that this summer.

I notice you pay attention to appearance as well as health.  Do you think there’s a connection between anti-aging skin treatments and longevity?  Or a psychological effect whereby looking younger helps you to feel younger and programs your mind to live longer?

I could dress better to improve my appearance, but my funds vanish into supplements.  Wrinkles are definitely symptomatic of the formation of senescent cells which begin to excrete factors that attack the extracellular matrix and weaken it. A weaker extracellular matrix leads to more than cosmetic problems, eventually, and less resistance available to UV radiation from the sun.  So keeping the skin healthy and young is very important for survival as well as for image. Skin cancer kills. Thin skin and failing veil cells around veins can produce bleeding, finally, perhaps even dangerous internal bleeding.

Of course, looking younger creates a sense of optimism about what may be possible, and helps reinforce a positive attitude.

What evidence do you have that your body is really younger?

Unfortunately, I was unable to do measurements of my blood component telomere lengths because of funds could not be mobilized in time. Therefore, about all I have is my collection of photographs online. There are many measures of aging and senescence that may be applied to the problem of measuring the effect when funds are available.  See .


* I wish I could say, “Testing experimental drugs on unsuspecting humans is off the table, out of the question, never done.”  The truth is that it is not as exceptional as we might wish.  And the institutions that resort to surreptitious experimentation are usually up to no good. [MK-Ultra, Nazis, antibiotics to children, Tuskegee syphilis experiments]

pf button A one man experiment in radical anti aging

Mitigating risk of Alzheimer’s Disease: More important than we thought

Recent re-analysis suggests that Alzheimer’s Disease ought to be ranked with cancer and heart disease as one of the most important mortality risks for older Americans.  Some of this risk is under our control.

In a study published last week, Bryan James and colleagues at Rush Univ. Medical Center in Chicago tell us that Alzheimer’s Disease has been greatly under-reported as a cause of death.  According to current statistics, cancer and heart disease are tied for the top spot, each contributing almost ¼ of all deaths in the US.  The new study says that AD should be right up there with heart disease and cancer, accounting for about ⅕ of US deaths.  If they are right, then these Big 3 diseases of old age together account for 70% of all deaths – not just deaths among the elderly.

Previously, AD had been listed as number 6 by the US Center for Disease Control, and the new study would move AD up to the #3 spot, which had previously been claimed by emphysema.  Emphysema is way behind cancer and heart disease, and predominantly affects smokers.  It’s almost certainly true that AD has been under-reported, and it wouldn’t take very much to move it up to #3; but whether AD really accounts for a 20% risk factor overall is less clear.  Let’s take a look at their methodology.  (or if you like you can skip ahead: What can you do about your AD risk?)

What’s wrong with this study?

The methodology of the study was straightforward.  For eight years, they tracked a group of about 2500 seniors, average age 78.  They learned if each person was diagnosed with AD, and if he died.  People diagnosed with AD had on average less than 4 years to live.  The mortality rate for people diagnosed with AD under age 85 was 4.3 times higher than otherwise (and 2.8 times higher if over 85).  These numbers (4.3 or 2.8) are called “hazzard ratios”, and as it turns out, they are an easy statistic to work with, and translate straightforwardly into inferences about the mortality risk of a diagnosis of AD.

The authors make the leap that this many deaths were attributable to AD, whether AD was listed as the cause of death or not.  Is this justified?  Think about it.  They are assuming that AD is the underlying cause and (for example) heart disease might be listed as the cause of death, but the heart disease was caused by an earlier diagnosis of AD.  But isn’t it just as likely to be the other way around?  People in danger of a heart attack may undergo bypass surgery, as a result of which the brain is deprived of oxygen during surgery and cognitive impairment results.

Or maybe there are underlying conditions (e.g., high inflammation, metabolic syndrome) that put the patient at higher risk for both AD and cancer, and then the patient dies of cancer.  It’s not right to assume that AD caused the cancer, or that this patient really died of AD.

So the authors’ conclusion that AD causes half a million deaths in the US every year is certainly overstated.  Nevertheless, they’ve got a point, and AD almost certainly should be moved up to the #3 slot, especially for non-smokers.  I believe there’s a lot of truth in the idea that mortality from AD is under-reported because the proximate cause of death is frequently something else.  If nothing else, depression and institutionalization frequently follow from dementia, and both are major mortality risk factors, under many guises.  Also, I believe in an “aging clock”: regulation of the rate of aging that derives from hormones secreted in the brain.  It is not hard for me to believe that deterioration of the brain has a direct effect on aging, and through aging on other aspects of health.


Blood test predicts AD

Also reported this week was a blood test that can predict (10 false positives out of 100) who will develop AD in the ensuing three years.  The work was reported in Nature Medicine by Howard Federoff of Georgetown University.  Does the test offer a clue about the etiology of AD?  Not at all.  The test was developed using formal statistical methods.  They made lipid blood profiles for several hundred people over the age of 70, testing the specific types of fats present in the blood plasma.  Then they waited three years to see which of the people might be diagnosed with AD.  Then, after the fact, they went back and used a blind, brute-force computer search to test millions of combinations of different features in the lipid profiles to look for ways in which the people who developed AD might be consistently different from the people who didn’t.  They then tested the test, applying it to a completely different group of people to see if the same test would work to predict AD for them.  It did.

There is no biology in this approach; only mathematics, and authors of the paper do not try to parse the significance of their results.


What causes AD?

Medical science is not in agreement about the cause of AD, and it may be that the symptoms of cognitive impairment come from several causes, separately and together.  Up until a few years ago, there was a theory about amyloid plaques in the brain, tiny accumulations of misfolded proteins that the body has failed to recycle.  But that theory has faded in popularity with evidence that the plaques may be an effect rather than cause of AD.


Apoptosis of otherwise healthy neurons?  or  is it
Amyloid plaques triggering an inflammatory attack on the brain?

Everyone agrees that the proximate cause of dementia symptoms is the loss of nerve cells in the brain.  Curiously, it seems that healthy neurons may be “committing suicide”, eliminating themselves via apoptosis [ Ref1 , Ref2 , Ref3 ].  For people of my school, this is yet one more instance of the body’s suicide program, the finite life span that has been programmed into our genes by natural selection for the purpose of leveling the death rate and stabilizing ecosystems.  People who believe that aging is not programmed tell the story in terms of the amyloid plaques triggering an immune response, and it is the inflammation that leads to apoptosis.  In any case, we all agree that inflammation is a risk factor for AD, and that anti-inflammatory supplements and drugs can lower the risk of AD.  (Anti-inflammatories also offer protection against cancer and heart disease.)


What can you do control your risk of AD?

The usual stuff.  Weight control, exercise, and most everything else you do to extend life expectancy lowers risk of AD along the way.  Remaining mentally active, learning new skills, putting yourself in new situations and taking on new challenges – these are ways to keep ourselves alive and aware, and they also reduce risk of AD

Anti-inflammatories are especially helpful.  Curcumin (turmeric) is an herbal anti-inflammatory that deserves special mention because of the many studies finding a protective effect in test tubes, mice, and humans.  In India, dementia is only ¼ as common as in Europe and America, possibly because of turmeric in the diet.  There is evidence to recommend fish oil, and also studies in which fish oil does not work.  Daily, low-dose ibuprofen lowers the risk of AD, and there are mixed reports of whether aspirin does as well.

A great number of traditional herbs have been shown to be neuroprotective.  This review of neuroprotective herbs mentions Ashwaghanda, Bacopa, Carnitine, Melatonin, CoQ10, Garlic, Vitamin D, Ginseng, and Ginkgo biloba. Here is another review of herbs that might be useful for AD.  None of these is a cure for AD, but there is some clinical evidence for benefit from each.  Readers familiar with my AgingAdvice page know that I like melatonin and vitamin D for other reasons as well.

Blueberries and perhaps other berries are protective.  A substance called fisetin (chemical cousin of quercetin) found in fruits and berries may be partly responsible.  Soy products contain phytoestrogens – chemicals which resemble female hormones.  Twenty years back, it was noticed that east Asians who moved to America and adopted an American diet had lower risk of AD, and it was hypothesized that phytoestrogens from soy might increase risk of AD.  But more recently several studies seem to point in the opposite direction, that soy might protect against AD [ Ref1 , Ref2 , Ref3 ].

I’ve reported (here and here) that since November I’ve been taking deprenyl (~1mg daily) and I find that it’s making me happy and increasing my energy, much to my consternation since I’m constitutionally anti-anti-depressant.  Deprenyl (sold as Selegiline or Emsam) is neuroprotective and it’s on the short list of drugs that consistently augment the life span of rodents in the lab.


And what is the payoff for avoiding AD?

According to the new hypothesis of James, 20% of mortality risk at all ages comes directly or indirectly from dementia.  Based on a 20% reduction in mortality, I calculate (using CDC life tables for 2010) that if we can greatly reduce risk of AD with all the above measures, starting (for example) at age 50, we might add 2½ years to life expectancy. Mitigating risk of Alzheimers Disease: More important than we thought


A horrible way to die, for some

The stereotypical AD patient is depressed and isolated by failure of his memory and inability to communicate.  And sadly, this is the norm as patients become disoriented and frustrated with inability to function.  But some AD patients become happy and grateful, detached from the worries that tied them down, occasionally euphoric.


Who will I be after I die?  Who was I before I was born?

We think of life and death like 1 and 0, like on and off, without a gray zone.  But it took time for our physical selves to develop, and our brains to connect up in ways that support the conception of a separate self.  In AD, the self takes about the same amount of time to disintegrate as it took to form.

Most of us have no memories before we were three.  Perhaps it takes three years for the brain to organize itself around time and events, inner self and outer world.  All that individuation that happened during the “terrible twos” is no longer part of our remembered life.  All that bewilderment, the wonder and constant questioning, a state of deep becoming.

I think of AD as the mirror image of the child’s individuation, the gradual dissolution of self.  For many of us, that prospect is terrifying, but remember that the infant also found it terrifying to become a separate self.  If there’s any benefit we can hope to derive from a lifetime of accumulated wisdom, let it be the ability to know fear for what it is: merely a genetic program, evolved to protect the individual genome and improve our chances of passing

pf button Mitigating risk of Alzheimers Disease: More important than we thought