“No animal dies of old age in the wild”

True, but that’s not really the relevant question to ask.  In fact, aging has a major impact on mortality in the wild, and this poses a dilemma for evolutionary theory.  In the earliest stages of senescence, already an individual may be losing its competitive edge.  When an epidemic passes through, those with compromised immune function are the first to die.  When a predator is chasing the herd, those that cannot run quite as fast as they used to are caught at the back of the crowd.  In this way, aging can have a big effect on fitness even if no one is “dying of old age”.

In 1951, Peter Medawar put forward the first modern theory for the evolution of aging.  He was a self-made Brazilian giant, 6 foot 5, as charismatic as he was brilliant, and at the age of 36 he had achieved a prestigious appointment at University College, London.  For his inaugural address, he chose to tackle an Unsolved Problem of Biology, and asked how aging in nature could be reconciled with Darwinian evolution.

There had been no evolutionary theory of aging in the 50 years since August Weismann had disavowed his own.  Medawar was astute enough to realize that Weismann was correct to seek an evolutionary understanding of aging.  Aging cannot be understood from thermodynamics or physical processes of attrition.  No physical law requires aging.  Medawar was also correct in judging that Weismann’s proposed solution was no solution at all.  “Weismann caters twice round the perimeter of a vicious circle.  By assuming that the elders of his race are decrepit and worn out, he assumes all but a fraction of what he has set himself to prove.”

Medawar proposed the theory that natural selection can only work on living, reproducing individuals.  But in the wild, there are so many hazards that can lead to death that, past a certain age, there are very few remaining alive.  In nature, everyone dies before they reach old age.  This creates a “selection shadow”.  Bodies are evolved to be healthy, strong or fertile up to the age where there are still survivors in nature.  But at advanced ages, natural selection has never had an opportunity to work her magic, so we should not be surprised that the organism is ill-adapted and falls apart.

We get old and die because of evolutionary neglect.  Natural selection needs living, reproducing individuals to select from, or it is ineffectual; hence we expect that aging takes over and the body deteriorates soon after that age at which predators and disease and other hazards of the wild have thinned the population near to zero.

The rest is history

Very quickly, Medawar’s idea was enshrined in the canon of evolutionary theory.  Building on Medawar, two more ideas were added.  One was the concept of “mutational load”.  If there was no natural selection at work for “late-acting genes”, then random mutations would creep in, and this would account for the organism going to pot.  This became the Mutation Accumulation theory.  The other was the idea that selection at late ages may be weak but not zero, and it could then be overpowered by the drive to maximize fertility early in life, even if it had bad consequences for fitness later on.  This became the Antagonistic Pleiotropy theory.

The idea that, in the wild, no one lives long enough to die of old age made a great deal of intuitive sense.  George Williams (of the pleiotropy theory) added a refinement: that the early stages of senescence would likely have consequences for individual competitiveness, so he based his theory on the idea that selection against aging was weak but not zero.  But everyone was agreed that the fitness consequences of aging were very slight, if not actually negligible.

Evolutionary theory went on to develop on this basis, and continued to be embellished for 40 years.

Fact check

The inconvenient truth came to light gradually, and several decades on.  In physics and chemistry, experimental science is an attractive calling because practitioners get to hang out in a lab and perform magic with nifty apparatus and spiffy electronics.  But experimental ecology is a field science requiring travel to remote locations, and many lonely, patient hours of observation, away from the comforts of home.  The work is often left to doctoral students who are in no position to protest.

So it was 25 more years before evidence started to accumulate that could bear on the question, how many animals in the wild are dying from the (early) effects of aging?

In principle, it is not hard to determine an answer.  Collect carcasses in the woods and use established forensic techniques to estimate the age of the animal when it died.  Once you have enough cases, you can plot a curve:  how many deaths? (on the y axis) vs what age? (on the x axis).  For example:

How to interpret the results?  If there were no aging in the wild, then we must expect that the percentage of individuals dying at every age is the same.  But the number remaining gets smaller and smaller, so the absolute number of deaths would go down with age.  The math tells you that “no aging” corresponds to a falling exponential curve.


If the number that we actually find is flat with age, or even if it declines with age but not as rapidly as an exponential curve, this is evidence that aging is taking a toll on fitness in the wild.

It was 1991 before Daniel Promislow first collected and interpreted the appropriate statistics for 56 different mammals in the wild.  He was a doctoral student at Oxford, and this study launched his career.  In 46 of the 56 species, he found an increasing risk of death with age.  In several species, data were complete enough that he was able to detect a Gompertz curve, meaning that for a given individual, risk of death climbs exponentially with age.


The Gompertz shape of the mortality curve had been known for 150 years—nothing new there.  The surprise was that previous to Promislow, scientists had thought that the Gompertz shape only applies in protected environments, like humans in civilization and animals in zoos.  In the wild, it was expected that (according to Medawar) everyone dies too early to see the rising shape of the Gompertz curve.

The significance of these results was not lost on Promislow.  He boldly asserted that his results conflicted with the accepted evolutionary theories for aging.  He was also modest and tactful enough to allow for reasons that his conclusion might be premature, and that adjustments could be made to permit the evolutionary theories to hold their own.

The Evidence Piles on

In 1998, Robert Ricklefs expanded on Promislow’s results by including more mammal surveys and some birds.  Ironically, he titled his piece Confirmation of a Fundamental Prediction, but in fact the results made all the extant theories for evolution of aging quite untenable.  He fitted mortality curves for each of the species in the study, and reported parameters from these curves.  From these data, it is a small further step to answer the question, What proportion of deaths in species can be ascribed to aging?  Ricklefs set up the equations and provided all the parameters, but he never completed the calculation.  Later, I filled in those numbers, the “percentage of senescent deaths” for each species.  You can read them in the column highlighted in orange.


As you can see, there are no animals for which the impact of senescence in the wild is negligible.  Many are clusted in the range 15-30%.  Some are over 70% — meaning, roughly, aging is reducing fitness in these species by more than 2/3.

Heroic field work

All the above work is based on field studies, data compiled after the fact through searching for remains.  But the cleanest kind of study would be an experiment, planned in advance, where individual animals could be tracked in the wild and their fates determined by direct observation.  As a Canadian grad student in the early 2000s, Russell Bonduriansky set himself the daunting task of individually labeling, releasing, and recapturing thousands of antler flies to answer directly, how did their risk of death change with age?  His doctoral work was stunning enough to be profiled in Nature.  The result: 28% of antler fly deaths were due to aging.


Nature doesn’t care if you die once your fertility is gone

The numbers above present a dilemma for evolutionary theory.  Scientists dealing loosely with this question sometimes say, animals die once their fertility is ended.  It’s no surprise that evolution has permitted these animals to age and die once they have reproduced and replaced themselves.  But the theory can’t escape so easily, for two reasons.

First, this doesn’t answer the question, but only kicks the can down the road.  Yes, there is no selective advantage to be gained by continuing to live on past the end of fertility.  But why should fertility decline in the first place?  Why haven’t we all adopted the growth pattern of trees and lobsters, continuing to grow and produce more offspring with each passing year?  (Or, if there are size constraints that keep land animals from growing forever, at least we should be maintaining our fertility, not losing it with age.)

Second, responding to the argument about “once they have replaced themselves”…  We should note that this is a flat denial of the dominant “selfish gene” view of evolution.  In standard evolutionary theory, there is no such thing as “enough”, because individuals are in an arms race to dominate the next generation with their genes.  If I have 6 offspring and you have 7, it will not be very many generations before my descendants are completely crowded out by yours (according to the way standard evolutionary calculations are performed).  This perspective highlights the evolutionary paradox that natural selection has tolerated declining fertility and increasing mortality in so many different animal species.

The bottom line

Sixty years after Medawar, it is untenable to maintain that aging exists in a “selection shadow”.  The negative consequence of aging for individual fitness is a force to be reckoned with.  But theorists have yet to face this particular monster.  I still hear Medawar’s hypothesis cited as gospel regularly in papers and at conferences.  The disconnect between theory and observation is stark.

Two footnotes

  1. The idea of “late-acting genes” made sense in the 1950s when Medawar and Williams were formulating their theories, but we now know that all living things have extensive machinery (epigenetics) for deciding when to turn particular genes on and off.  Williams imagined that if a gene is beneficial at one stage of life, we would be stuck with it at another stage, when it is detrimental.  We now know that genes are routinely turned on and off as needed.
  2. The idea that fitness depends on maximizing the number of offspring is enshrined in standard evolutionary theory, which is the “selfish gene” model.  But there are many ways we know this cannot be right.  Producing too many offspring can be just as disastrous for a species as producing too few.  This is the inspiration for my Demographic Theory of Aging.
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Epigenetics of Aging, and Prospects for Rejuvenation

Last week, I attended the tail end of a Keystone conference on Epigenetic Regulation of Aging, followed by a one-day brainstorming session to kick off a project called GILGA-mesh, intended to take this bull by the horns. Though the subjects of the two days were virtually identical, the approach and attitudes of the scientists in attendance set very different tones.  Both days featured smart, creative and careful scientists, but they saw the same material through different frameworks.  Sometimes philosophy makes a difference.

For readers who know me less well, I should introduce my perspective: I believe that aging is an evolved epigenetic program.  When we are young and growing, particular genes are turned on and off with exquisite timing to determine the growth and development of bones, muscles, and organs.  When we are old, the program continues, more slowly and more diffusely, but inexorably nonetheless.  Genes are turned on that destroy us with inflammation and cell senescence and auto-immunity and programmed cell death, while the systems that protect us from pathogens and from free radical damage are gradually shut down.  Evolution has left nothing to chance.

[I first wrote an academic paper about this idea in 2013, excited by a paper by Aviv  Johnson on methylation, but unaware that Tom Rando had written on the same lines the previous year. Jeff Bowles had hinted at similar ideas in a paper more than a decade earlier. Soon the field was broken wide open by the work of a bio-statistician.
Steve Horvath ran a computer analysis on thousands of genes as they are  expressed in young and old humans, and produced an “epigenetic clock” that could accurately report how old a person using measurementis of methylation in 353 DNA sites in particular.]



Epigenetics is a new science in the 21st century.  All the cells in one body have the same DNA (pretty much), but differernt genes are “expressed” (translated into proteins) in different tissues and at different times, and this is what controls the body’s metabolism.  In fact, only 2% of our DNA is genes, and 98% determines how the DNA is folded and spooled, opened and closed at particular times and places, and this in turn controls gene expression.  We are 2% genetic and 98% epigenetic.

There is a language called the “genetic code” which determines how genes are translated into proteins.  It was decoded by Francis Crick and others in the 1950s.  It is as simple as it can be, and is completely understood.  There is another language, the “epigenetic code” that determines gene expression.  It is anything-but-simple, with a convoluted and self-referential syntax that we are just beginning to understand.  The epigenetic code starts with signals embedded in the DNA that serve as “start” and “stop” codons. The stretch in between comprises a piece of a gene, a kind of Gutenberg movable type that is transcribed from the chromosome and then spliced and combined to form functional RNAs and proteins. The complicated part of the epigenetic code is implemented as a pattern of methyl and acetyl groups.  These are little chemical decorations that attach to the DNA and to the “histones” (spools around which DNA is wound up in the cell nucleus for safe storage).  The methyl and acetyl groups are continually being attached and removed according to instructions that come from within the cell and other instructions that are passed through the blood. It is the methyl and acetyl groups that determine how the DNA is folded and spooled, which effectively turns particular genes on and off as needed.

The part of the epigenetic code on which we have the best handle at present is called “methylation of CpG islands”.  Long stretches of DNA have CGCGCGCG… on one strand, complemented by GCGCGCGC… on the other.  Often the C’s in this region get an extra methyl group, turning from cytosine to 5-methylcytosine.  Then this stretch becomes a “repressor region,” a signal to NOT express the adjacent gene.

DNA methylation can be persistent, turning a gene off for decades at a time.  When a cell divides and its DNA is copied, the methylation pattern can be copied with it.  This accounts for some of the persistence of epigenetics, and the way gene expression can be inherited across generations.

DNA methylation has been appreciated for 30 years, but two recent developments make the subject attractive and accessible to research.  (1) There is now a simple lab/computer technique for reading the methylation pattern from DNA.  It relies on commercially available, automated machinery for PCR to sequence a full genome before and after chemical modification of the methylated C’s.  (2) There is now a simple lab/computer technique for changing the methylation state of any chosen target site in the DNA.  It is based on CRISPR technology that is taking genetics labs by storm the last two years.

from Hannum et al., 2013, Genome-wide Methylation Profiles

from Hannum et al., 2013, Genome-wide Methylation Profiles

Epigenetics and aging

Three years ago, Horvath demonstrated that there are specific patterns of methylation associated with particular ages of the body.  It’s not just that the fresh, clear pattern of youthful gene expression becomes muddied and random with age—although there is some of that.  But it’s also true that some genes that are active in youth become inactive as we get older and (especially) that other genes that were suppressed in youth become activated in old age.  What Horvath’s paper says is, “show me  methylation pattern of a person’s cells, and I can tell you how old s/he is.”


Is epigenetics a cause or effect of aging?

The correlation between aging and epigenetic status is established beyond dispute.  But what does it mean?  This is the big question.  Most researchers think of the body as programmed by evolution to be as strong and healthy as possible.  So, when different genes are expressed in old age, they find it natural to assume that the body is protecting itself in response to damage that it has suffered over the years.  We express different genes when we are older because we need different genes when we are older.  This was the predominant attitude at the first conference (where I was present just for the last day).

The other possible interpretation is my own, and it has become common among those who are closest to the field of epigenetics.  It is that epigenetic changes with age are means of self-destruction.  The body is programmed to die, and its suicide plan is laid out in the form of transcribing an unhealthy combination of genes.  This idea flies in the face of traditional evolutionary theory.  (How could natural selection prefer a genome that destroys itself and cuts off its own reproduction?)  Nevertheless, the evidence for this hypothesis is robust.  The genes that are turned on don’t protect the body—quite the opposite.  Genes for inflammation are dialed up.  Genes for the body’s defense against free radicals are dialed down.  Cell turnover is dialed down.  DNA repair is dialed down. The mechanisms of programmed cell death (apoptosis) are strengthened in healthy cells, at the same time that they are perversely weakened in cells that are a threat to the body, like infected cells and cancer cells.


How will we determine who is right?

In my opinion, the existing evidence heavily favors the hypothesis that aging is caused by epigenetic changes, rather than the other way around.  When we look at the kinds of changes that occur, they seem to be pouring fuel on the fire, not putting it out.  Protective genes are turned off and inflammatory genes are turned up.  I also think that
parabiosis experiments provide a strong clue.  Three researcher groups (at Stanford Harvard, Berkeley) have shown that injecting blood plasma from a young mouse into an old mouse makes the old mouse healthier, and relieves some problems associated with age.  The blood plasma contains no cells—only signal molecules that are the product of gene expression.  This is powerful evidence that youthful gene expression is supporting a strong and youthful body, and (conversely) that the kind of gene expression that characterizes old age is not doing the body any good.

But the ultimate experiment will be to re-program gene expression in an old mouse and see if there is a rejuvenating effect.


My proposal

As of now, the GILGA-Mesh project is dominated by numbers geeks (like me) who practice the “Google approach” to bioinformatics.  Huge databases of gene expression are screened for epigenetic candidates that seem to be well-correlated with good outcomes.  I think what we need is an infusion of biolochemists who understand something about the body’s signaling networks, and can orient us toward “upstream” and “downstream” molecules.  Here’s my proposed program:

  1. Repeat Horvath’s (human) analysis for mice.  In other words, identify several hundred places where methylation is different in young and old mice.
  2. Determine which genes are associated with these regions.  (Map needed for this should already be available.)
  3. Look at the set of genes and identify transcription factors. These are likely to be “upstream”, in that they control other genes.
  4. Start with old mice.  Use CRISPR to change the methylation status in a handful of promoter regions that control transcription factors, making them match the methylation status of young mice.
  5. Measure metabolic functions to see if the old mice are more healthy or less after these procedures.  Look particularly for changes in inflammation, propensity for cancer, and especially life span.

If this experiment goes as I expect, we will be ready for rejuvenation experiments in humans.


How does the body know how old it is?

Even further upstream, is there a central master clock that dictates the body’s epigenetic expression, and thereby determines our biological age?  Logically, it seems that the body would need an accurate clock to time the events of growth and development.  Evolution likes to re-use the parts she has created, and it would not surprise me if the developmental clock morphs into an aging clock.

have reasoned that there are two possibilities.  It may be that there is a timekeeper, probably in the neuro-endocrine regions of the brain, that controls the processes of development and aging.  This possibility is supported by works of Kasper Daniel Hansen and Claudia Cavadas.  If this pans out, it would present the handiest target for true rejuvenation in humans.  But it also may be that epigenetic expression itself is a kind of clock that is diffused through the body.  Today’s gene expression includes transcription factors that control tomorrow’s gene expression, and so epigenetic state may be a feedback loop, or self-contained clock.  This may also be a target for rejuvenation, but a little accessible, harder to address or to tinker with.

Random notes—other things I learned last week

I was tickled to find how many members of the GILGA-mesh team already support the
programmed aging perspective that I have advocated.  I was particularly gratified to receive encouragement from Caleb Finch, a grand old man of the field who wrote the
encyclopedia of aging in 1990, and continues a very active research program today.

From Finch, I learned that infections in childhood and even in the womb can have a serious effect on diseases of old age, decades after the fact.  He hypothesizes a lifelong burden of inflammation.  Evidence includes an elevated incidence of heart disease for the cohort born just after the influenza epidemic of 1918.

I was chagrined to learn that air pollution, especially particulate matter, is associated with increased risk of dementia.  This poses a personal dilemma for me, as I plan to spend the summer at the lab of Meng-qiu Dong in Beijing.

I learned that hospital errors are the third leading cause of death in the US, accounting for about 10% of all deaths, about the same number as smoking.  Maybe you already read that in the New York Times.


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Aging is a Military Coup

The military forces of the United States are not to be deployed within the country.  Many people think it’s a clause in the Constitution, but actually it was an afterthought, enacted into law in 1807, strengthened and clarified by the Posse Comitatus Act of 1878.

The Founding Fathers reasoned that government is always in danger of assuming imperial powers, escaping from democratic control.  If ever our government were to turn against the people and treat them like a domestic enemy, they would not start from the ground floor to assemble an occupying force; rather they would be tempted to use the existing military forces, the standing army, grotesquely turned against the American people whom they were sworn to defend and protect.

Evolution as conceived by Charles Darwin has no forethought and no central direction, but often the results of natural selection are elegant and economical, as though they had been planned.  If evolution found it necessary to regulate the individual’s life span for the larger good of the community or the ecosystem, there would be no need to invent a new and specialized death program.  It would be far easier to coopt the body’s existing armies, and redirect them in a suicide mission.

The science of aging in the last twenty years has made one discovery after another of the body’s protective armies turned inward, repurposed to destroy the self.  In each case, researchers specialized in one particular disease notice that the body is attacking itself; they imagine that this is a unique case of “something gone awry”, and they write about “dysregulation” of this system or that system.  But when generalists in gerontology step back and see many examples of the same pattern, they suspect an evolutionary purpose.  In the same sense that the purpose of our eyes is to gather visual information and the purpose of our kidneys is to filter waste from our blood, we may say that aging has an evolutionary purpose, and that purpose is to eliminate the individual for the larger good of the community. All for one and one for all — only the “one” in this case is not the individual animal but the whole population, which if it grows too fast can crash the ecosystem on which all depend.

Arthritis.  The old view of arthritis was that the cartilage that cushions and lubricates our joints wears away with years of use.  Now it is recognized that osteo-arthritis has the same roots as rheumatoid arthritis.  It is an auto-immune disorder, the body’s immune system turned traitor against our bones and cartilage.

Atherosclerosis.  The old view of coronary heart disease was that over many years, cholesterol deposits on the artery walls in the same way that mineral deposits build up inside a water pipe and gradually come to clog the pipe completely.  Now it is recognized that inflammation plays an essential role.  When we are injured, inflammation is the body’s first line of defense against invading microbes; but in old age inflammation attacks healthy tissues, and the delicate linings of our arteries are among the most vulnerable.  Inflamed pieces of the artery walls break off, clog the artery and cause heart attacks.

Cancer.  The old view was that there are random mutations in a particular cell line, a series of unfortunate accidents that cause the cells to disregard regulating signals from the body and just continue replicating and growing out of control.  Now we realize that cancer is a failure of the body’s immune defense system.  When we are young, our white blood cells search and destroy incipient cancers, but as we get older the immune early warning system is gradually shut down.  The thymus gland, where these white cells are trained for their task, gradually atrophies with age.  And the cancer mutations themselves are not steady and random, but are ramped up as we get older by chronic, systemic inflammation.  Further, the deadliness of cancer comes not from the selfishness of uncontrolled growth, but from malicious “oncogenes” that create toxins, poisoning the body from the inside out.

Alzheimer’s Disease.  This is the latest paradigm to shift, highlighted in an article this week in the MIT Technology Review about the work of Harvard Med School Professor Beth Stevens.  The old view was that plaques and tangles accumulate in the brain from cellular waste products.  Now we are beginning to see that glial cells are the culprits.  When we are infants, the brain is sculpted by subtraction.  It is the glial cells that decide which nerve connections to keep and which to prune.  But in old age, this article reports, the cells “go rogue” and begin—unexplainably—to destroy nerve connections that are healthy, even essential for the brain’s function.  Could it be that this, too, is not a random dysfunctional behavior, but part of evolution’s program to reliably fix our life spans?

Evolutionary biologists have been the last to recognize this paradigm shift in our understanding of aging.  Since the 1960s, they have been committed to the idea that natural selection cares only about the individual, never the community.  This is the theory of the Selfish Gene.  But a growing wing of academic scientists has been gathering evidence that natural selection works both on individuals and on groups.  The new view is that evolution occurs simultaneously on multiple levels, so that both selfish and cooperative behaviors appear.  Communities and entire ecosystems may evolve in a way that is integrated for the good of the whole.  Only in this context can we make sense of the body’s civil insurrection that is aging.  We die individually as part of nature’s regulation of the ecological community.

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Retrotransposons: The Lamarckian Link

Today’s offering is not directly related to aging, but I’m an evolutionary biologist and these ideas about the fundamental mechanisms of evolution are compelling to me.  I think a deep shift in the foundations of evolution is imminent.  If some of the following is unfamiliar, I hope you’ll find it worth learning about.

Jean-Baptiste Lamarck, 1744-1829

I came out of the closet as a Lamarckian two years ago in this space.  I believe that experiences and adaptations that occur during an individual’s lifetime can affect the genetic legacy passed on to her offspring.  Darwin believed this, but it was excised early from Darwin’s legacy.  Though Lamarckism has been heresy for over 100 years, a Lamarckian mechanism would go a long way toward explaining how evolution manages to be as efficient and directed as it is.  Just in the last 15 years, Lamarckian epigenetic inheritance has been documented in lab animals and in humans.  These are temporary modifications to the chromosome that affect gene expression, but not the genes themselves. Effects can last for multiple generations, but they are not as “permanent” as modifications to the DNA sequence themselves.  In addition, James Shapiro has documented full Lamarckian inheritance in bacteria.  Yes, bacteria edit their own DNA.  

The last step toward full Lamarckian inheritance would be: Do multi-celled organisms also edit their own genomes?  Why shouldn’t we be as sophisticated as bacteria in this regard? The problem with this idea has been lack of a plausible mechanism.  How can information about adaptations in this lifetime filter back to affect the DNA within sperm and egg cells that carry genetic information into the next generation?

To this question we now have a tentative answer.  Last month, Science Magazine featured an extensive and quite technical article on retrotransposons, which suggests a possible mechanism for full Lamarckian inheritance.  (The article is not framed this way, and nowhere does it mention Lamarck.)



When you use a muscle, it becomes stronger.  When you practice thinking in a particular way, or playing a musical instrument or solving crossword puzzles or writing with pen in your right hand—any of these can lead to specific adaptations that improve your proficiency for that particular task.  Conversely, if you don’t practice remembering your dreams or riding a unicycle, then your dreams become increasingly inaccessible and your potential to learn unicycle skills diminishes over time.  But, of course, none of these adaptations affect your children.  They get a clean slate, a fresh start in life quite independent of anything you did or didn’t do before they were born.

Of course.

Darwin didn’t think this was a matter “of course”.  Though he is most famous for introducing the idea of natural selection as the primary driving force in evolution, he also wrote about what he called “use and disuse” of a trait, contributing to enhancement of that trait not just in an individual but also his offspring and descendants.  Late in life, he wrote

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]

Twenty years after Darwin, August Weismann cut off the tails of five generations of mice to seee if their descendants would be born with shorter tails.  The experiment showed no effect.  Though Weismann regarded the test as definitive, we might object that this is hardly a representative example of “use and disuse”.  It came to be regarded as Strike one against Lamarckian inheritance in the halls of theoretical biology.  Strike two came in the year 1900 when Mendelian inheritance was rediscovered, and biologists learned to distinguish the body, or soma, from a line of cells sequestered and destined for the next generation, the germ line.  It was difficult to imagine a mechanism whereby experiences of the soma could feed back to affect the information stored in the germ line.  Twenty more years passed, and Trofim Lysenko in the nascent Soviet Union performed his infamously tainted experiments, motivated by Lenin’s ideology to validate Lamarckian inheritance.  If Lenin and Lysenko believed it, it can’t be true.  Strike three.

So it became part of the evolutionary canon that all mutations are blind, that the experience of an individual is not passed to her offspring, that Lamarck was wrong and that Darwin was wrong to include a Lamarckian element in his theory.  This became a widely-held premise of evolutionary genetics, though there was never a fair experimental test of the question.

By the time that Franklin, Crick and Watson found the structure of DNA and elucidated the replication  mechanism, it only remained to seal the coffin of Lamarckism with one more nail, a conjecture that Crick called the Central Dogma of Molecular Biology.  The Central Dogma says that DNA is an invariant repository of information for the cell.  DNA is transcribed into RNA and thence to proteins, and information flow is always in this direction, never backwards from protein to RNA to DNA.


Cracks in the Ideological Wall

In th 21st century, the experimental situation has changed drastically, though the genetic dogma has not yet caught up.  First, the epigenetic changes that contribute to adaptation during an individual lifetime have been found to be heritable over multiple generations.  Second, experiments have confirmed that bacteria are able to edit their own DNA.  Third, and the main subject of my story here, is a mechanism by which large, multi-celled critters like us change our DNA routinely during development and through the lifetime.

Heritable Epigenetics

Subjecting lab animals (or humans) to one form of stress or another produces adaptations that not only persist for the individual’s lifetime, but can be passed down at least several generations in the future.  This effect began to be observed in the 1990s.  A decade later, DNA methylation was discovered. Methylation of a region of DNA is a signal that suppresses expression of nearby genes.  Methylation is programmed by proteins called transcription factors, and is carried out by methyl transferase enzymes.  When DNA is copied, often (but not always) the methylation state is copied along with it.  This is the best-understood (not the only) mechanism by which epigenetic adaptations are passed from one generation to another.

This is a subject that has been the life work of Eva Jablonka.  She has been writing about heritable epigenetics at least since 1989, and she has a 1999 book on the subject, and a broader perspective, updated 2014.  Here is Jablonka’s best recent summary of the evidence (2009).  She emphasizes that many aspects of the cell carry information, and that epigenetic inheritance is not limited to the programmed modifications of DNA that controls gene expression.


“Genetic engineering” in bacteria

This is the term used by Shapiro to describe diverse mechanisms by which bacteria restructure their own genomes.  It was found experimentally in the 1980s that bacteria up their mutation rates in times of stress, but it was assumed that mutations are still random, and the organism is merely motivated to take big changes when it is in danger.  But Shapiro shows us that the changes are not random, and that they are far more likely to generate new and useful functions than if the mutations were by chance.  All changes to the DNA of bacteria are heritable, because it has only one copy.

Protists are single-celled eukaryotes, much more complex than bacteria, from which all multicelled life is descended.  Protists also splice and dice their own DNA.


Do animals and plants edit their own genomes?

We are taught in school that our bodies have developed from a single fertilized egg, and therefore every cell in the body has the same DNA as that egg.  The DNA in every cell in our bodies is identical (except for rare, random mutations).

This has been assumed without experimental support until four years ago, when a team of researchers from Yale decided to test it out.  They were surprised to find substantial variation from one tissue to another in the DNA of a single individual.  They looked in particular for copy number variation, in which segments of the genome typically a few thousand BP long are duplicated.  They found examples wherever they looked, and they unconvered evidence that this is not random but functional.  For example, genes that are expressed in the pancreas have extra copies in pancreatic cells.  Regulatory genes that operate at a high level were more likely to be duplicated than downstream genes or regions of non-coding DNA.

Most of the biological community still believes what they were taught in school, but this finding suggests that the body is capable of editing its own genome for functional purposes.  The article says nothing about the mechanism by which it is accomplished, but whatever it is, it is not hard to imagine that that same mechanism is harnessed for a Lamarckian function.


Retrotransposons: A candidate mechanism for Lamarckian Inheritance. .

This brings us to the article from three molecular biologists at University of Rochester that provided my inspiration for writing this page.  It’s titled Retrotransposons as regulators of gene expression.

Retrotransposons are regions of DNA that can copy themselves to RNA, which then picks a site in the genome and inserts another copy of itself.  “Retro” refers to RNA ⇒ DNA, which is opposite to the normal order of things, which was once called Crick’s “Central Dogma”.  Retrotransposons are able to invert the Central Dogma because the particular sequence of RNA includes a binding site for an enzyme that copies RNA backward to DNA, and inserts into a chromosome. “Long” retrotransposons, or LINEs, actually contain a region that codes for the requisite enzyme; “short” retrotransposons, or SINEs, depend on the protein provided by LINEs.

LINEs and SINEs together constitute 30% of human DNA.  By far the most common are a kind of short stretch known as Alu elements.  There are over 1 million Alu elements, together making up 11% of human DNA.

Most researchers writing about transposable elements (TEs) regard them as random or (worse) “parasitic DNA”, existing just to duplicate themselves and go along for the ride, while persisting in genomes passed from species to species over tens of millions of years.  I suspect that evolution is more efficient than this, and that anything lasting tens of millions of years has a purpose, whether or not we are yet able to divine what that is.  In the case of Alu elements, the purpose is to affect DNA transcription, not just epigenetically but by locating strategically, so as to promote or suppress particular genes.  This can  happen in the soma, changing gene expression from one tissue to another, or in the germ line, making long-lasting changes to the genetic legacy.

Curiously, the article begins and ends with the assumption that TEs are parasites that have learned to copy themselves, and that organisms have learned to work around them.  But in between, the article cites a great deal of evidence that TEs have acquired functions, and have evolved to be essential for life. I think it probable that anything that has survived tens of millions of years of natural selection has an adaptive purpose.  I think of mitochondria as an analogy.  Mitochondria began as parasites that invaded the first, primitive eukaryotic cells, but over time they became fully integrated into the cell’s energy metabolism, and eventually became essential for the cell’s survival.  Perhaps retrotransposons had a parasitic origin once upon a time, but now they are part of the structure of DNA and part of the machinery of evolution.

Alu elements tend to be rich in methylation sites (CpG islands) which are places where the most common, best-understood kind of epigenetic regulation takes place.

Retrotransposons actively copy themselves, thereby restructuring chromosomes, during development.  This accounts for some variation in DNA in tissues (documented in the Yale article mentioned above).  There is also active copying throughout life within the brain, which makes me wonder if learning might be accompanied by restructuring DNA in the brain.

Carl Zimmer recently featured Job Dekker on a short video that explains the importance of the intricate way that DNA is folded over on itself, helping to determine which regions are transcribed and which remain locked up as heterochromatin.  The stretches of TE DNA certainly affect transcription, and they are re-programmable during an organism’s lifetime.  We might expect as a matter of course that the number and placement of TEs has been subjected to natural selection, and has become highly adaptive in a way that responds to experience during a lifetime.

Of course.

We know for a fact that methylation programming extends back to the germ line, and accounts for heritable epigenetics.  Now that we have a glimpse of the retrotransposon mechanism, why wouldn’t we expect it also to feed back and restructure the germline DNA?


The Bottom Line

Scientific bias against Lamarckian inheritance is an anachronism.  Some modes of Lamarckian evolution have been firmly established.  The most general and most permanent form has never been tested competently.   The last remaining argument against it was the difficulty of imagining a plausible mechanism.  What we have learned about retrotransposons and genetic variation among different tissues of the same body removes that objection.

The time is ripe for a well-planned exploration of Lamarckian inheritance in various circumstances, with a variety of animal and plant species, coordinated over multiple laboratories worldwide.   At this point a “surprising” result is to be expected.


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Politics Drives a Promising Nutraceutical Underground

The plural of “anecdote” is “data”.  When Anatabloc was taken off the market two years ago, customers bemoaned the loss of the only product they had ever found that relieved their arthritic symptoms.  One of them contacted me through this blog, and told me that before it disappeared, he stockpiled three years’ inventory, which he is still taking now.

Anatabine is a naturally-occurring chemical constituent of eggplant, tomatoes and (especially) tobacco.  The chemical structure is similar to nicotine

Anatabine is interesting because

  • Inflammation is one of the primary means by which the body self-destructs as we get older.
  • NFκB is the best-known pro-inflammatory hormone that increases with age, to our detriment.
  • Anatabine is reported to block the action of NFκB.

Beginning more than 10 years ago, anatabine was promoted by Star Scientific Co as a nutraceutical under their trade name, Anatabloc.  Impatient with the steady rise of sales, Johnnie Williams of Star Sci used political influence with Virginia’s Gov Bob McDonnell to get Medicaid to pay for anatabine as a drug.  A scandal two years ago brought down Williams and McDonnell both.  (Jon Stewart skewered the story at the time, and though his take on the politics may be well-grounded, his implication that any chemical found in tobacco must be poison is silly.)  Anatabine was dragged down with the two, and now research on a promising chemical is foundering.  Anatabine is no longer available for purchase in the America or Europe.

In the only published clinical study of anatabine, it was found useful for an obscure auto-immune syndrome of the thyroid.  In the government web site ClinicalTrials.gov, there are three more completed trials for which I was unable to find publications as yet.  The most interesting relates to the effect of anatabine on C-Reactive Protein in the blood, which is a well-established marker of inflammation.  That study was conducted by Michael Mullan of Roskamp Inst.  In this video, he reviews a mouse study suggesting anatabine might be useful for slowing progress of Alzheimer’s Disease.  Psoriasis is another disease of inflammation gone awry for which it may be useful, and reportedly Rock Creek Pharmaceuticals is banking on psoriasis for their first clinical approval, from which they might leverage research on other applications.  Smoking cessation is another promising early application.  But in the long run, Rock Creek scientists have their sights set on Alzheimer’s Disease.  (I’ve been unable to raise a response from Rock Creek’s principal scientists to find out more.)

What’s the evidence for blocking NFκB?

These three studies [1, 2, 3] all claim to observe that NFkB activity is lower in mice taking anatabine.  The mechanism is to block phosphorylation of NFkB, which is an energizing stage in the biochemistry that initiates its activity.  Dosages were injected, at 2mg/kg.  These studies followed from cell studies in vitro observing the same chemistry.

All studies come from the same team of scientists, associated with RockCreek Pharma and the Rosskamp Inst, both in Tampa, FL.  I wish there were independent groups replicating their findings, and I suspect that it is the political scandal that has driven them away.

I learned from Examine.com of two more herbs that block NFkB, to wit Boswellia (frankinicense) and Feverfew.



Anatabloc contained a dosage of only 1mg per pill, but rodent studies suggest that the effective human dosage is likely to be at least 10 times higher than that.


Safety, and the Bottom Line

Reported side-effects of anatabine include headache and stomachache.  Perhaps this is why the dosage in Anatabloc was kept so low.  Rock Creek Pharma claims that a phase-1 trial of oral anatabine found no side effects, but anecdotal evidence suggests that some people have serious responses.

The best evidence we have may be from a user survey conducted by scientists affiliated with Rock Creek, and written up as a journal article.

Of the 78 respondents who stopped taking the supplement for some period of time for any reason, 83% experienced a noticeable return of their joint pain symptoms. Forty-four of 65 (68%) respondents indicated that their symptoms returned within 2–3 days or less, and 64 of 65 (98%) indicated that their symptoms returned within one week or less (Fig. 3). Almost all of the respondents (64 of 65, or 98%) who had stopped using anatabine and felt their joint pain symptoms return subsequently felt those symptoms decrease once they resumed using the supplement.

The survey indicates a lot of satisfied customers, but does not touch on the issues of dosage or side-effects.

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Cholesterol and inflammation; Statins and alternatives (Part II)

Last week, I cited evidence that statins work to lower risk of heart disease, but their benefit is probably independent of their design function, which is to deprive the body of cholesterol. I believe the benefits of statin drugs come from anti-inflammatory action. Their effect on cholesterol is at best a subsidiary benefit, at worst a cause of multiple systemic problems. Reviewing a handful of studies over 30 years, I didn’t find any consistent relationship between heart risk and blood levels of cholesterol (HDL, LDL or TC). The only exceptions were at the very extremes. Both the top ½% and the bottom ½% had elevated risk of heart attack.

This 1994 study was titled Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. But if you read past the abstract to the data tables, you’ll find that people with low cholesterol had twice as many fatal heart attacks as people with high cholesterol [sic]. Deaths from other causes than heart disease were higher in subjects with high cholesterol, and this added up to a negligible difference in overall mortality rates for high or low cholesterol. (This was pointed out to me by Uffe Ravnskoff, a Danish doctor and researcher, author of The Cholesterol Myths.)

Statins tamper with body chemistry that doesn’t need tampering. This line of thinking suggests that alternative anti-inflammatory strategies might avoid the side effects while lowering risk of heart attacks as much or more than with statins.


CV mortality rates are falling

If our NIH had declared “war on heart disease” in 1965, they would be well-justified in crowing today. Since a peak in the 1960s, cardiovascular mortality in the Western world has been declining steadily.

Age-adjusted CV mortality, 1950 - 2006

Age-adjusted CV mortality, 1950 – 2006

The decline is the more impressive in that it has fought twin headwinds in the form of an epidemic of obesity and an aging population. The rise of statin prescriptions may be part of the story, but statins only came into widespread use beginning 1995-2000. The prevalence of smoking started declining steeply in 1965, and this is surely a contributing factor. Other than that, experts can’t seem to agree on the cause of our good fortune.


Side effects of statins

Statins don’t just affect blood chemistry, but interfere with the manufacture of cholesterol. But cholesterol is an important ingredient in cell membranes and nerve sheaths; it is also a substrate from which other essential molecules are manufactured, including vitamin D. It is no surprise that statins carry powerful complications. All the side-effects come from the cholesterol metabolism, and not the anti-inflammatory action, so they may be completely unnecessary.

  • Lowering inflammation ought to improve insulin sensitivity. But most statins are associated with elevated risk of diabetes. Since loss of insulin sensitivity is a primary driver of aging, even marginal effects on insulin resistance could be important. Diabetes is an independent risk factor for heart disease [ref]. Simvastatin seems to have the worst effect on insulin sensitivity, and pravastatin may actually improve insulin sensitivity [ref].
  • Cognitive impairment is of great concern for most of us, but it is difficult to measure reproducibly. There are enough subjective reports of cognitive impairment from statins to be worrisome [ref, ref] but there may be a slightly lowered risk of dementia (as you would expect from an anti-inflammatory) [ref].
  • Muscle cramping (myalgia) is reported in some industry-sponsored studies to be 18% or 5% or even as low as 3%. But in my small sample, everyone I know who takes statins notices muscle cramps. This rises from being a nuisance to a clinical risk when it interferes with patients’ ability to exercise, which is potentially a more powerful heart protector than statins.
  • Probably related, people on statin drugs report fatigue and intolerance to exercise. Statins interfere with the energy metabolism, and in particular reduce the concentration of CoQ10=ubiquinone, which already declines with age and is essential for mitochondrial function. Everyone who chooses to take statins should be supplementing with CoQ10.


Alternatives for lowering CV risk without statins

  • Exercise. The #1 most cardioprotective form of exercise is interval training. The #1 most difficult discipline to maintain is: interval training. Establish an exercise program you can live with, and then live with it.  Intense exercise makes a world of difference, but even taking a walk a few times a week has significant benefit.
  • Lose weight.
  • Less meat, more Mediterranean in your diet. Vegan seems to help. If you can tolerate it, a raw foods vegan diet is all-purpose for weight loss, heart health, anti-inflammation, and anti-cancer.
  • Daily aspirin or ibuprofen after age 50. (A reader has recently made me aware of a link between macular degeneration and daily aspirin. No such link seems to be documented for ibuprofen. If you have AMD in the family, you may want to substitute ibuprofen for aspirin, or lower the dosage. There is no evidence that a full aspirin daily is better for your hear than ¼ aspirin, but it does seem that the full pill is worse for AMD.)
  • Other anti-inflammatories include turmeric, fish oil, boswellia, cat’s claw. A reader has alerted me to the potential of anatabine citrate. This is an alkaloid compound found in small quantities in nightshade vegetables and tobacco. Some people who have taken it say it is the best anti-inflammatory ever, but it was taken off the market 2 years ago based on a scandal that was purely political and had nothing to do with the biological merits of anatabine.
  • Supplement with CoQ10 [Ref1, Ref2, Ref3, Ref4] or ubiquinol, which is offers enhanced absorption for a closely-related molecule.
    * Caveat: CoQ10 may interfere with the (larger) benefits of exercise. More research is needed. Until we know more, we may hedge by taking CoQ10 during rest times (when not exercising).
  • Both kinds of dietary fiber decrease heart risk. (The reasons for this are still debated, and may include intestinal flora, appetite control, and speed of food absorption.) Wheat bran and leafy greens are the best sources of insoluble fibre (“roughage”). Oat bran, beans and nuts are the best sources of soluble fibre.
  • 8 cardioprotective foods (garlic and ginger should be on this list, but were not as I found it)
    • avocado
    • lentils
    • edamame
    • nuts
    • olive oil
    • pears
    • tea (black is good, green is better)
    • tomatoes
  • Get your vitamin D blood levels up to 70 (In people like me, this can require 10,000 to 30,000 iu daily. Whole body sun exposure can help, too, but it ages the skin.)
  • Supplement with niacin (vit B3). Niacin raises HDL and cut risk of heart attacks by 30% in people not taking statins in a meta-analysis. Mechanism of niacin explained here.
    Am I being inconsistent in saying that cholesterol has nothing to do with heart risk and then recommending a vitamin that raises HDL (good cholesterol) levels?  Perhaps so, or perhaps I’m hedging my bets.  In include this recommendation because there is independent evidence linking niacin not just to HDL but also to a lower rate of CV events.
  • Hawthorn(e) berry seems promising, and some naturopaths have had good results prescribing it for congestive heart failure.
  • Don’t worry about salt.
  • Trans fats (or partially hydrogenated vegetable oils) do not exist in nature, but are created in food processing because they retard spoilage. Trans fat consumption is associated with heart risk as well as all-cause mortality, and should be avoided. (I’ll bet you already knew that.)
  • Cut sugar and grains to keep up your insulin sensitivity. Diabetes is a heart risk factor.
  • Avoid foods high in iron. Don’t supplement iron, unless you have been diagnosed with a deficiency. [Ref1, Ref2] Donate blood.


Chinese medicine

Despite high rates of smoking (men 62%), Chinese has a low rate of heart disease (less than a third of the US). The rate in cities has begun to climb to rates more typical of Western societies, but remains low in the countryside [read more]. Part of the reason may be the Chinese diet and traditional Chinese medicine. Astragalus and ginseng are considered to be cardioprotective in TCM. Auricularia (木耳=“wood ear” ) is a mushroom-like fungus common in Chinese soups, which also is used in traditional Chinese medicine. It tends to raise HDL and prevent inflammatory damage to blood lipids, and it mitigates damage in the event of a heart attack. Oyster mushrooms are a natural source of simvastin. [Read about traditional Chinese medical approach to heart disease]

If you have a heart attack, the Chinese herb Fuzi (附子=aconite) is both toxic and protective in case of traumatic tissue damage. Definitely not to be added to your daily supplements, but it may mitigate damage to your heart after a heart attack. It is the single red pill packed with Yunnan Baiyao.  Meldonium is a promising plant extract in early stages of testing for power to mitigate heart damage.  (It is claimed that statin drugs also mitigate heart damage.)


The Bottom Line

Heart disease is no longer the #1 Killer that it was decades ago. Doctors are still looking at blood cholesterol to tell people when they are at high risk, and in fact, for most people, cholesterol levels are not related to risk of heart disease. BMI, physical activity and blood pressure are much better predictors of heart risk.

Statin drugs lower your risk of heart disease, but there are other measure you can take that are both more effective and have less side effects. John Aronson says the only proven benefits for statins are for males who have already had one heart attack.

Keep in mind that everything I have reported here is based on a general population, averaged over all genetic types. A number of different genetic variations may make you more or less vulnerable to heart disease in a particular way, and may mandate a particular treatment. Take your 23andMe profile to someone who knows how to interpret it.



Appendix: Why do doctors prescribe drugs that don’t work?

A friend of mine recently retired after working as a VA doc for 25 years. She saw her most effective role as getting patients off some of their many medications. When a student of mine told me that her doctor was prescribing statins, I asked my friend for a doctor who would give her a different perspective. She said she knew of no one who would advise against statins?

How could that be? The explanation involves liability law. There are no guarantees from any treatment, and every doctor knows that some of his patients will have heart attacks. If a patient suffers a heart attack and sues the doctor who had managed his regimen, the doctor can be liable even if he has given the best advice and prescribed the best course. He cannot be liable if he does the same thing that everyone else does. The doctor’s liability depends not on whether he did the right thing, but whether his advice conforms to the prevailing standard of care.

It gets worse. Suppose a brave doctor decides that he’s going to do the right thing and, he’s willing to take the risk that his patients might sue him later. His insurance company won’t let him do that. He becomes uninsurable, and without insurance he dares not practice medicine.

This is how liability law and insurance economics work to effectively suppress diverse diverse approaches and hold back innovation for decades after the consensus of the medical community may have shifted.

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When your doctor suggests statins (Part 1: Mechanism of Action)

High blood pressure is statistically associated with cardiovascular risk. Avoiding salt lowers blood pressure, but it does not affect cardiovascular risk.

Inflammation is statistically associated with cardiovascular risk. NSAIDs lower the body’s inflammation, and also lowers cardiovascular risk.

Statin drugs reduce LDL cholesterol levels in the blood and also quell inflammation. Statins seem to reduce cardiovascular risk.  Does this have to do with cholesterol or with inflammation?

For almost everyone, LDL cholesterol levels rise during middle age.  Most doctors will prescribe statin drugs as your first line of defense to lower risk of heart attack. The link between LDL cholesterol and heart disease is not well-established.  And in any case, there are many things you can do to lower heart risk that are both more effective and have less side-effects than statins.  I have become convinced that statins are over-prescribed.

(Too many doctors are still telling patients to cut back on salt.  They are out of touch with an emerging consensus.)


Two years ago, I spent a few weeks reading the literature on cholesterol and heart disease, and I reported finding a deep split in the community [Part 1, Part 2]:  There are two camps in the research field, one saying that lowering cholesterol levels is the most effective way to control heart risk, and the other saying that cholesterol levels are completely unrelated to heart risk.  At the time, I didn’t take sides; but now I’m inclined toward the latter group, based on politics as much as science.

It is difficult to get a man to understand something, when his salary depends upon his not understanding it.
         — Upton Sinclair

John Abramson, a professor at Harvard Med and author of Overdosed America, lists statins as America’s #1 most overprescribed drug class.  Even for the class of patients most at risk, he estimates that of every 140 people are taking statins, only 1 of them avoids a heart attack. He tells a story of an entire sub-field of medicine that has been touched by money from the pharmaceutical industry.  Most scientists are smart, honest, and independent.  But I have found in several areas that scientists are not immune from herd mentality.  We tend to be trusting creatures, specialized in a narrow field, with faith to accept others’ findings in areas where we are less expert.  Hence, it is not as difficult as you might think for money to influence a scientific paradigm.  This is especially so in epidemiology, where large studies of diverse humans are amenable to various interpretations.  The specialists in physiology are not good at statistics, and the statisticians are not senior authors, but are hired to put numbers together in support of a thesis  The predominance of private money from drug companies over public money from NIH makes pharmacological science especially vulnerable.

Abramson’s advice is that statins are appropriate therapy only for men who have already suffered one heart attack.  For your reference, I’ve posted the key pages from Chapter 9 of his book here.  What he reports is enough to foment a rebellion against for-profit health care, and especially the corporate role in health research.  After reading it, I was moved to write a column dismissing statin drugs as a well-funded scientific fraud.  I did not find evidence to support that.

What I did find, is that the prevailing theory about LDL cholesterol and CV disease has very little support.  I believe that statin drugs work to lower CV mortality, but that the mechanism for the benefit has more to do with inflammation than with cholesterol.  This leads to the question:  Are there better ways to lower inflammation that do not impose the substantial side-effects of statin drugs?


What is a heart attack?

Heart attacks result when an artery feeding the heart muscles becomes obstructed.  Most commonly, deposits (“plaques”) build up on the insides of artery walls over many years, and sometimes pieces of placque break off and become seeds for blood clots that can block the artery enough to cause an attack.

  1. The placques are predominantly cholesterol.
  2. The breakage of the plaques is an inflammation process.
  3. Clotting of blood is frequently the step that pushes the attack over the edge.

Viable therapies interrupt the process at any of these three stages.

  1. LDL the form of cholesterol in the blood that is most likely to form plaquest, while HDL can actually dissolve the plaques and re-metabolize choleserol.  Statin drugs lower LDL.  Exercise, weight loss, a Mediterranean diet, and niacin (vit B3) can raise HDL.
  2. Anti-inflammatories can help keep the artery walls intact.  Lowering inflammation also lowers risk of cancer, stroke and AD.  Common anti-inflammatory agents include NSAIDs, fish oil, curcumin, boswellia, and cat’s claw.  Statin drugs are powerful anti-inflammatories, and there is a school of thought that says that their anti-inflammatory action is more important than their cholesterol-lowering action for preventing heart attacks.
  3. Anti-coagulants, including NSAIDs and fish oil, protect against heart attacks as well.  Side effects include risk of internal bleeding, stomach ulcers, and hemorrhagic stroke.  (13% of strokes are hemorrhagic and come from blood flooding the brain; the rest are ischemic, which means that they are caused by a clogged artery, via mechanisms closely analogous to heart attacks.)

Congestive heart failure is a condition that sometimes precedes or predicts a heart attack, and is a health problem in its own right.  The cause is often partial blockage of arteries feeding the heart, causing the heart to become weak.  Common symptoms include decreased stamina, shortness of breath, fluid retention and swelling in the limbs.


Statin Drugs Interfere with the Manufacture of Cholesterol

Starting sixty years ago, medical thinking was that it was most powerful and sensible to interrupt this cycle at Stage 1 by lowering the cholesterol in the bloodstream.  Statins go a step further by actually interfering with the body’s manufacture of cholesterol.

The trouble with this reasoning is that cholesterol is not some unwanted byproduct of the metabolism like lipofuscin or glycated proteins.  It is not, like adipose tissue, the origin of pro-aging signals in the body.  Rather, cholesterol is an essential ingredient in the cell metabolism, which the body manufactures abundantly and uses in diverse waves.  Cholesterol lives in cell membranes, and cholesterol is concentrated in nerve cells, where it plays an essential role as insulator.  Cholesterol is a chemicl precursor to vitamin D and sex and steroid hormones.   Our brains have more cholesterol than any other part of us.  Cholesterol is the substrate for producing the bile acids that we need for digestion.  Here is a tutorial on the biochemistry of cholesterol in the body, its manufacture, uses and dangers.

It should be obvious that shutting off the body’s cholesterol factory is likely to cause many unwanted side-effects.  A smarter, more focused attack on the particular chemistry of deposits in the arteries is needed.


Choesterol and CV disease

Here are results from a classic epidemiological study, based on the Framingham Heart database [1993] :

The relationship between total cholesterol level and all-cause mortality was positive (ie, higher cholesterol level associated with higher mortality) at age 40 years, negative at age 80 years, and negligible at ages 50 to 70 years.

[Note: there are a lot more people dying at age 80 than at age 40.  The negative relationship at late ages is both more important and better established – JJM]

The relationship with CHD mortality was significantly positive at ages 40, 50, and 60 years but attenuated with age until the relationship was positive, but not significant, at age 70 years and negative, but not significant, at age 80 years.  Results for the relationship between low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and mortality help explain these findings. Non-CHD mortality was significantly negatively related to cholesterol level for ages 50 years and above.

[Translation: People under 70 who had higher levels of cholesterol had a greater chance of dying of heart disease, but this was compensated by a smaller chance of dying of other causes. – JJM]

In this study, funded by the life insurance industry which ought to have a neutral interest in prediction, only small relationships were found between cholesterol and mortality risk,* and risk was elevated both for low cholesterol and for high cholesterol.  LDL levels had no consistent relationship to mortality.  Average levels of HDL were better than either high or low.  High levels of total cholesterol (TC) presented no additional risk, but very low levels corresponded to a 50-75% increase in mortality.  These findings may be of limited utility because they are uncorrected for smoking or diet or statins, and are only very crudely stratified by age. The “sweet spot” for total cholesterol was about 180-230 for men, 170-220 for women.

These two graphs represent all-cause mortality risk for women and men over 60, graphed against their cholesterol level.  1.5 million life insurance applicants (yes – a huge subject pool) have been grouped by percentile.  The middle half is all lumped together, and the ends of the curve are finely divided.  What I get from this picture is consistent with noise from the 5th through the 95th percentiles.  There is no apparent relationship between mortality risk and either total cholesterol or HDL.  The exception seems to be at the extremes–the highest 1% and the lowest 1% both seem to be at higher risk.  The highest 1% corresponds to about 334 mg/dl (F) and 308 (M).  The lowest 1% corresponds to 146 (F) and 138 (M).  (There is no corresponding graph for LDL in the article, but the authors report, “Using LDL or non-HDL cholesterol instead of total cholesterol does not improve mortality risk discrimination; neither does using total cholesterol or triglyceride values in addition to the total cholesterol/HDL ratio”

Mortality_vs_Cholesterol_Fgt60 Mortality_vs_Cholesterol_Mgt60


Anti-Inflammatory action of Statins

  • Of potential interest is the statin-induced reduction of C-reactive protein (CRP), a marker for inflammation; recent data suggests that the CRP-lowering effect of statins might, in addition to lipid lowering, be relevant for progression of disease.
  • Data from experiments in cell culture and animal models show that statins can induce the cellular accumulation of endothelial nitric oxide synthase; inhibit the expression of adhesion molecules and chemokines that recruit inflammatory cells; inhibit expression of pro-coagulant factors and induce anti-coagulant substances; inhibit proliferation and promote apoptosis of vascular smooth muscle cells; and ameliorate platelet hyper-reactivity.  [ref]


Evidence for Benefits of Statin Drugs

(1) Here’s an example that is well-researched and well-reasoned with a British pedigree:

Reduction of LDL cholesterol with a statin reduced the risk of major vascular events , largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories. [Lancet, 2012]

The size of the benefit they find is a 22% reduction in risk of heart attack for a 40 point drop in LDL.

This finding, solid as it appears to be, is actually not inconsistent with the thesis that LDL cholesterol has nothing at all to do with risk of heart disease.  Statin drugs are both powerful anti-inflammatories and also lower LDL cholesterol.  People who take statin drugs may indeed have lower LDL and also lower inflammation.  The incidental correlation between LDL and inflammation would only show up in people taking statins, but it could completely account for the results of this meta-analysis.

(2) Here’s a trial of Rosuvastatin in which heart attack rates were slashed by more than half and stroke by almost that much, and the trial was stopped after just two years because it could no longer be justified to keep people on placebo.  These were people without elevated LDL going in.  Rather they were chosen on the basis of high C-Reactive Protein.  CRP is an inflammatory marker.

So this study is more evidence, perhaps, that statins are very effective anti-inflammatories, and can be read as consistent with the idea that LDL is a red herring.  Reporting included both CRP and LDL levles, but the body text emphasized LDL.

The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%…(hazard ratio for rosuvastatin, 0.56; P<0.00001)…Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. [review of JUPITER study]

Tentative Conclusion

I believe that to resolve questions about statins, their mode of action, and whether their benefit justifies the side-effects, what we need is a large scale study in which patients at high CV risk are randomized to a program of statins or to other anti-inflammatory agents.  There has not been such a study, and at present it would be considered unethical, so large is the presumption in favor of statins.

Next week, I’ll have more cholesterol stories, and suggest some alternatives to statins.

Caveat: I’m speculating on health advice out of my field.  I could well be wrong.  I invite readers who know things I don’t know to please comment, or contact me privately.


* In this context, “small relationships” mean less than a factor of 2 in death rate.  A doubled risk might not seem a small concern, but ratios less than 2 are difficult to distinguish from noise in actuarial studies. An easy-to-remember rule of thumb: a factor of 2 in mortality corresponds to about 10 years in age.

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