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.

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.)


 

Background

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.

 

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.

 

Dosage

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.