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.

Print Friendly

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.

 

Print Friendly

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.

Print Friendly

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.

Print Friendly

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.

Print Friendly

‘one of the most important aging discoveries ever’

The science news circuits have been buzzing about Jan van Deursen’s recent paper, in which mice stayed younger, longer when their senescent cells were removed.  They’re right to call this technology a game changer for anti-aging medicine.  They’re wrong to say this is new—in fact, the recent paper advances only incrementally over van Deursen’s stunning results from 2011.  But what they don’t explain very well is that so far this technology only works for specially-prepared mice.  The mice are genetically engineered (before birth) to make their senescent cells vulnerable to a trigger that can be administered later, when they are old.  We don’t yet have a way to selectively kill senescent cells in a natural mouse, or a natural human.

(Background is in my blog post of last spring.)

As we get older, a tiny minority (~1 in 10,000) of cells becomes senescent, usually through telomere shortening that goes so far as to compromise the integrity of the chromosomes.  The number of cells is small, but they do outsized damage, by secreting signals into the surrounding region and even into the body as a whole that turn on inflammaging, which is one of the primary modes by which the body destroys itself.  Chronic, systemic inflammation is linked to all the diseases of old age, especially arthritis, cancer, arterial diseases and Alzheimer’s.

The original paper from 2011 reported on a novel idea to test the hypothesis that getting rid of this tiny number of cells could have a positive impact on the whole body.  The experiment required genetically engineered mice.  That means their genes were modified in the egg stage, when the incipient mouse is still a single cell, and there’s only one set of genes to modify.  Mice could be prepared in such a way that a particular gene called p16 was associated with an added gene that made the cells extremely vulnerable to a drug that wouldn’t otherwise have damaged them.  This was done because senescent cells express p16, while normal cells don’t.  So administration of the drug would kill just the senescent cells, while leaving normal cells alone.

The results of the experiment were dramatic.  Animals that had their senescent cells removed lived 20-25% longer, and were healthier and more active at an age when other mice were in steep decline.  In the recent paper, life extension was bumped up marginally to 24-27%.

From my perspective as theorist, I take this as confirmation of the idea that aging is part of the developmental program, not an unavoidable side-effect or “accumulated damage” as standard thinking allows.

  • The body is assassinated by signaling, not by damage.
  • Much of the signaling comes from a tiny minority of cells that the body could eliminate, but doesn’t.
  • And furthermore, there is no need for this minority to become senescent in the first place.  They become senescent for want of telomerase, despite the fact that every cell in the body includes the telomerase (TERT) gene, and has the potential to produce telomerase, if it were instructed to do so.  (There are many species that DO produce telomerase through their lifetimes, including mice, pigs, and cows.)

Most scientists have yet to assimilate this paradigm shift, and the popular press glosses over it with glib quotes.

This seems perverse, but there’s method to the body’s madness. Cells undergo senescence because they accumulate damage that could potentially lead to cancer, and the molecules they secrete prompt the immune system to come over and clear them. “It’s a very potent anti-cancer mechanism,” says Baker. But as we get older, the immune system falters, and senescent cells accumulate. Now, the molecules they secrete become problems rather than solutions.

Even then, senescent cells have benefits. Last year, Campisi showed that these cells help to heal wounds. And sure enough, Baker and van Deursen found that their mice heal more slowly after such cells were removed. [quote from TheAtlantic]

But (1) the cancer hypothesis has been abandonned even by its principal proponent, Judith Campisi.  Senescent cells cause a net increase in cancer deaths.  And (2) the idea that secretions from senescent cells may marginally increase wound healing efficiency cannot explain their evolutionary provenance if the small good is outweighed by a larger harm.  The net result is that they kill us.  (I wrote a related column last year.)

 

The Future

This technology holds up the possibility of a quick avenue toward life extension in humans that could be delivered in a treatment starting in middle age or even later. But promising as this idea is, it remains an idea and not a treatment that can be tested.  Up until now, it only works in genetically engineered animals, and not in natural mice or you or me.  What we need is a medication that will kill senescent cells while leaving normal cells undamaged.  This is akin to the idea of chemotherapy, but perhaps somewhat easier because we have already identified a single genetic marker (p16) to identify the cells we want to kill, and because the cells are not proliferating and mutating as they are in a cancer patient.  Nevertheless, there is a substantial challenge in finding the medication that can kill almost all senescent cells while leaving almost all other cells undamaged.

The word for such an agent is senolytic.  Last year, two effective senolytic agents were reported: quercetin, a common botanical extract, and Dasanatib, a chemo drug [my blog post from last spring, including reference].  Though they prove the principle, they don’t distinguish senescent cells efficiently enough to offer an attractive therapy.

Some promising anti-aging technologies are being ignored by researchers and pharmaceutical companies, but this isn’t one of them.  The good news is that there is a race on to test senolytic agents, with at least half a dozen labs competing to find powerful and non-toxic senolytic agents.  Oisin Biotech is a start-up with a liposomal technology.  Van Deursen and Campisi have their own for-profit spinoff, called Unity Biotechnology.  This is now a problem of synthetic chemistry and testing, and we should know within a year or two if they are finding success.

 

Print Friendly

Is Aging Controlled from the Brain? NPY and ALK5

For more than a decade, Claudia Cavadas of the Center for Neuroscience in Coimbra, Portugal has been on the trail of a signal molecule that comes from a region of the brain associated with timing.  It’s a small protein called Neuropeptide Y, and Cavadas has recently collected the body of evidence that it is a central determinant of aging in the brain and throughout the body.  Whether or not NPY proves to be the Philosopher’s Stone, I think she’s on the right track to be investigating neuroendocrine origins of aging.

The present column also contains a (belated) update on ALK5 and TGFβ.


Since the genetic science of aging began to take off in the 1990s, the biggest surprise has been the extent to which aging is centrally orchestrated. ”Regulated” is the accepted word, but I don’t hesitate to say “programmed”.  For those of us interested in intervening to slow or reverse the process, the burning question is: how is the program implemented?  If the process is centrally orchestrated, where is the orchestra’s conductor?  

We have the same genes when we are old as when we are young, but different genes are turned on and off in different stages of life.  How genes are turned on and off is the science of epigenetics, and we are just beginning to untangle the set of chemical add-ons that bind to the chromosome or to the histones, protein spindles around which the chromosome is spooled.  Chemical signals that turn whole suites of genes on and off are called transcription factors, and these can be big molecules or small, proteins or RNAs, very specific and targeted to a single gene, or aimed more generally at large swaths of the chromosome.

At the least, transcription factors are able to regulate the body’s rate of aging.  But I see evidence that the chemical signals have even more power—the chemical signals tell the body how old it is.  Change the signals, and the body can change its age.

When we think this way, the questions “what are these signals?” and “where do they come from?” become exciting and highly charged.  The most intuitive and logical place to look for a source of age signals is in the brain.  Here are four reasons to look to the brain’s hormone center, the neuroendocrine region, as a source of aging signals.

  • We know that aging is highly plastic and adaptive depending on behavior and environment.  To sense many factors and make a decision about aging, it seems that the combined forces of the nerves and endocrine signal transducers in the brain are best equipped for the job.
  • The hypothalamus is a neuroendocrine region of the brain already known to house the seat of the 24-hour clock that synchronizes our circadian rhythms, the suprachiasmatic nucleus.  
  • The hypothalamus is also responsible for flooding the body with at least one of the transcription factors that increase destructive inflammation late in life (NFkB).
  • In a worm experiment fifteen years ago, genes for aging were modified in different systems of the worm, and the modifications were effective in changing the worm life span only when the genes were modified in the nervous system (not in skin or muscle or digestive system).

This mode of thinking suggests that Cavadas has been digging at the taproot of aging, and that the signal she has identified may be of central importance.  In a recent paper, Cavadas lays out the case for a central role in Neuropeptide Y in dictating the age of the body.  

Accumulating evidence suggests that neuropeptide Y (NPY) has a role in aging and lifespan determination. In this review, we critically discuss age-related changes in NPY levels in the brain, together with recent findings concerning the contribution of NPY to, and impact on, six hallmarks of aging, specifically:

  • loss of proteostasis
  • stem cell exhaustion
  • altered intercellular communication
  • deregulated nutrient sensing
  • cellular senescence, and
  • mitochondrial dysfunction

NPY is a small protein, with 36 amino acids, found in the nervous systems of all higher animals.  It is one of the most abundant neuroendocrine proteins, but since these chemicals are very powerful signal molecules, the body’s total inventory is measured in μg (millionths of a gram).  NPY has various roles related to appetite, anxiety, memory, and circadian rhythm.  Levels of NPY decline with age, especially in certain regions of the brain.  Caloric Restriction also elevates levels of NPY.  High blood sugar levels tend to inhibit NPY.  And there is a bit of evidence that NPY is necessary for CR to extend life span:  Mice in which the NPY gene has been knocked out don’t respond to CR. NPY is also associated with cancer suppression in mice.

Autophagy is the process by which cells break down and recycles damaged molecules.  As we age, autophagy slows down and damaged molecules accumulate:  misfolded proteins, cross-linked sugars, lipofuscin and amyloids.  A central function of NPY is in promoting autophagy, especially in the brain.  

The NPY gene can be read in a way that transcribes only the second half, and the result is a protein that binds to mitochondria and improves energy efficiency, reduces ROS damage.  Some studies suggest that NPY can extend the useful life of stem cells, and delay cellular senescence.  Links to anti-inflammatory chemistry are less well established.

 

Why NPY probably is not the Philosopher’s Stone

All this suggests a role for NPY in aging, and the possibility that increasing NPY might increase life span.  But it is not easy to increase the body’s transcription of a target protein.  (It is easier to block a protein that is bad than to promote one that is good.)  And my guess is that we will find signals further upstream from NPY that are even more effective points of intervention.  The guess is based on the fact that NPY is a neurotransmitter, an “end-use” molecule.  I suspect that the upstream source of aging will be found in transcription factors, the molecules that bind to DNA and determine which genes are expressed.

 

Other Signal Molecules from the Brain

TGFβ might be a good candidat for the first brain signal to become a target for anti-aging therapy. TGFβ is a not a transcription factor but a cytokine, a signal protein that affects the energy metabolism and, in particular, inflammatory response.  It comes not from the hypothalamus, but from the hippocampus, another part of the brain, an inch or two underneath.  TGFβ works against us, i.e., we produce more and more of it as we age, and it rallies the inflammatory legions that promote arterial diseases and cancer.  We would want to block its action, and that might not be too difficult.

One of the targets, receptors into which the TGFβ molecule plugs to do its work, is called ALK5.  Jamming ALK5 has been promoted by the Conboy lab at Berkeley and others as a strategy to test further.  ALK5 inhibitor can be injected deep into the body cavity, where it has already been shown to promote new growth in both muscles and nerves in mice.  This function is apparently related to its role as antagonist to TGFβ.  Remarkably, stem cells retain their ability to regenerate new tissue well into old age, but they receive signals telling them to stand down.  Simply changing the signaling environment can make an old stem cell act young.  This has been a major theme of the Conboys’ work.

What good is TGFβ?  The story is complicated.  The molecule can apparently be pro-inflammatory or anti-inflammatory, also pro-cancer or anti-cancer.  This relates to the GDF11 controversy, too.  GDF11 is in the TGFβ family.  To me, the Conboys are a trusted source, and they have systematically built a case that too much TGFβ in later life is a big factor leading to more inflammation and less stem cell activity.

Their ALK5 inhibitor has only been tested for short-term benefits.  The next step is to do life span studies in mice with ALK5 inhibitor.

 

Print Friendly