GDF11—Not So Fast

A research report from Novartis may temper our excitement about GDF11, which was a runner-up for Science Magazine’s 2014 Breakthrough Of the Year.

Bakground

“Heterochronic parabiosis” is the sanitized word for sewing together as Siamese twins two animals of the same species but different ages.  Modern implementation as a research technique was pioneered by Clive McCay in the 1950s, the same McCay who brought us caloric restriction in the 1930s.

The two animals share a common pool fo blood.  What is clear is that the older animal in the pair benefits from young blood.  Healing is improved, and some tissues are rejuvenated.  What is less clear:  what are the elements in the blood that are responsible for the rejuvenation?  Is there a “youth serum”, transferred from the young animal to the old; or in fact is there a blood factor responsible for deterioration, and the old animal is benefiting from dilution of his elder toxins?  Are there a few such blood factors, or too many to form the basis of a practical therapy?

In the last ten years, there has been a diaspora of researchers from the Stanford lab of Tom Rando, young researchers now at Berkeley and Harvard who are pursuing advanced techniques of blood transfer, seeking to isolate the active ingredients.  A consensus is emerging that

  • It is not the red or white blood cells, but dissolved proteins in the blood that make the difference.
  • There are both pro-aging and anti-aging factors in the blood.

The big questions remaining:

  • There are at least several factors of each kind, pro- and anti-aging.  Is the number of essential blood factors small and manageable, so we might hope to make a “bloody Mary” cocktail?  Or is the number so large this is impractical?
  • Will these blood factors reboot the body’s epigenetics so the old body starts producing the young mix itself?  How long must the body be exposed to the young mix before it starts to produce the young mix itself?

Last year in particular saw eye-popping results from the Berkeley lab of Irina and Mike Conboy, and from the Harvard lab of Amy Wagers.  The Conboys claimed that oxytocin is a blood factor promoting longevity.  [ref, my blog]  Wagers identified GDF11 as a blood factor that declines with age, and enhances strength and endurance when administered to muscle tissue in mice.  [ref, my blog]  In humans, GDF11 has been shown to increase nerve growth.

 

Cousins of GDF11

A rejuvenating role for GDF11 was a surprise because it is in the TGFβ class of hormones, which generally have negative effects on muscles.  In a 2013 blog, I identified TGFβ as one of the blood factors that we have too much of as we age.  Myostatin is the best-known member of this group, and it inhibits muscle growth.  Mice lacking the myostatin gene grow double-size muscles and have better insulin sensitivity.  Creatine is a myostatin inhibitor that is popular among muscle-builders.

Genes for GDF11 and for myostatin are 90% identical.  But mice lacking GDF11 don’t have bigger muscles, and in fact they die soon after birth.  So it’s possible that GDF11 is good and myostatin is bad.

 

The latest news

Last week, David Glass and a team at Novartis report that they have failed to reproduce Wagers’s results about GDF11.  From a Nature News report by Sara Reardon:

Glass and his colleagues set out to determine why GDF11 had this apparent effect.  First, they tested the antibodies and other reagents that Wagers’ group had used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11. When the Novartis team used a more specific reagent to measure GDF11 levels in the blood of both rats and humans, they found that GDF11 levels actually increased with age — just as levels of myostatin do. That contradicts what Wagers’ group had found.

Glass’s team next used a combination of chemicals to injure a mouse’s skeletal muscles, and then regularly injected the animal with three times as much GDF11 as Wagers and her team had used. Rather than regenerating the muscle, Glass found, GDF11 seemed to make the damage worse by inhibiting the muscles’ ability to repair themselves. He and his colleagues report their results on 19 May in Cell Metabolism.

Woops.  The Wagers results may prove to be an error, or it may be that the story is more nuanced.  It would not be surprising if there is such a thing as too little GDF11 and too much GDF11.

Wagers, however, stands by her findings. She says that although at first glance the Novartis group’s data seem to conflict with her team’s results, there could be multiple forms of GDF11 and that perhaps only one decreases with age. Both papers suggest that having either too much or too little GDF11 could be harmful, she says. She adds that the Novartis group injured the muscle more extensively and then treated it with more GDF11 than her group had done, so the results may not be directly comparable.

 “We look forward to addressing the differences in the studies with additional data very soon,” Wagers says.

Rando expects that researchers will now investigate the finding2 that GDF11 affects the growth of neurons and blood vessels in the brain. “I’m not sure which result is going to stand the test of time,” he says.

Two Unrelated Items of Interest

Life Extension magazine for June claims that fear of Testosterone has been unwarranted, that the benefits of T for strength and heart health do not come at a cost in increased cancer risk or decreased longevity.  (June edition is not yet on-line at LEF, but has been uploaded to Dropbox by a colleague here.)

Low endogenous bioavailable testosterone levels have been shown to be associated with higher rates of all cause and cardiovascular-related mortality…

Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics and to lower the BMI in obese patients. These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.


Here is an intriguing news release from Yale about a protein found only in primates that is useful for making ordinary cells into stem cells.

 

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Pterostilbene

I have a new article at Pterostilbene.com.  The bottom line is that pterostilbene may be a “better resveratrol”.  It is better absorbed, stays in the blood stream longer, and has a stronger effect on insulin metabolism and SIRT-1 than resveratrol.  But resveratrol got there first, and there has been much more study of resveratrol in actual animal tests, so it will be a few years at least before we know for sure.  Len Guarente’s MIT lab is where resveratrol got its start, and Guarente has recently launched a corporate spinoff to sell a pterostilbene formula.

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Vital Questions — A Book Review

The Vital Question, by Nick Lane, 352 pp, Profile Books, April, 2015

Life has been on earth about 4 billion years.  If we think of each billion as a term at college, then for its Freshman, Sophomore and Junior years, life majored in chemistry.  Every possible chemical environment was probed, drawing its first energy from the warm, hydrothermal vents at the bottom of the ocean, leaving the alkaline silos where life got its start, colonizing the sea and the land, the atmosphere, places cold and hot, wet and dry, acid and base, high in the clouds and deep in rock miles under the earth.

Life as an underclassman was just one cell at a time, and a small cell at that, maybe a micron across, a “prokaryote” that despite its impressive chemical virtuosity had little physical structure and the simplest life cycle.  Divide and conquer.

Before his Sophomore year was over, the precocious chemists had figured out how to use the sun’s energy to pull carbon right out of the air, and the entire atmosphere had been processed, molecule by molecule, from (inert) CO2 to (energy-laden) Oxygen.  The energy economy of the earth was transformed.

Then, about a billion years ago—life was a rising Senior—a once-in-a-lifetime event occurred, a wild fluke.  One of these chemists that specialized in membranes and electrochemistry was invaded and colonized by a parasite that specialized in combustion chemistry—oxidation of sugar, to be specific.  The invader put all that atmospheric oxygen to good use, then spewed out toxic ROS (reactive oxygen species) that almost killed the host, as it had killed many archaeons before.  But this time, the host survived and, over an amazingly short time of just 2 million years, learned not just how to coexist with the invader, but also to domesticate the parasite and put him to work.  The host was already using ATP as an energy source, and the parasite had a talent for producing copious quantities of ATP/energy—more than any archaeon had ever seen before.  Stick with me, kid and we’ll go far.  By the end of Senior year, every plant and animal on earth, every fungus and amoeba, toadstool, jellyfish and (by the way) you and me—every cell in our bodies, all of them are descended from that one sick, infected “hopeful monster”.  Her name was LECA, the Last Eukaryotic Common Ancestor.  Everything we think of as macroscopic biology comprises her progeny, in so many different guises.

Because it was in its Senior year that life first got interested in engineering, cell upon cell.  Pipelines and networks of roadways, electrical circuits, information processing within and between cells. Muscles, bones, shells, levers, motors and other mechanical devices that were made out of living cells!  Locomotion in the sea, on land and air.  The greening of earth and sea, predators and prey, webs of interconnected life—all of this is the realm of eukaryotes.


This story wasn’t written by Nick Lane, but he certainly tells it with a flare.  The story was written by biological visionaries of the last century.  Richard Goldschmidt, Francis Crick, Lynn Margulis, Carl Woese are biologists that I know.  Also Stephen Jay Gould and E. O. Wilson—I’m sure there are others who are equally eminent with whom I am unfamiliar.  Erwin Schroedinger and Freeman Dyson were physicists who also contributed to the canon, speculating about the Great Questions.

In our generation, Nick Lane is the only one I know who is making a bid as heir to these giants.  (I hope that readers of this column will use the comments section to make me aware of others.)  He is a biological visionary who happens to be a great storyteller.  In a series of books since 2005, he is asking the Great Questions about life, how it began, why it is the way it is, how much of life’s history is pure chance, and if we should run into an extraterrestrial life form, how much can we expect it to be like us?  His latest book is called The Vital Question.  Like his previous books, this one takes a bioenergetic view of life. The centerpiece of the present volume is that singular event at the beginning of Senior year:  The fusion of (probably) several bacterial and archaeon individuals to form that one “hopeful monster”, the mother of us all.

Among the traits that all eukaryotes have in common (but distinct from prokaryotes) are

  • a cell nucleus, with multiple linear chromosomes.  (Prokaryotes, by contrast, have their DNA in a single loop and many smaller loops.) “The nucleus is an exquisitely adapted structure, no mere repository for DNA.”
  • genes coded piecemeal, interrupted by introns, a catch-all word for the 95% of DNA that does not code for a protein, and may have many different functions, or possibly none at all
  • within-species genetic exchange (sex) with crossover of parts of chromosomes.  Before eukaryotes, genetic exchange was rampant, promiscuous, and willy-nilly.  Every type of bacteria exchanges genes with every other type.
  • energy generation in mitochondria (the parasites mentioned above)
  • endoplasmic reticulum, a network of membranes that guides transportation of molecules within the cell
  • Golgi apparatus, there are many within the cell, and they serve as post offices, addressing and dispatching packages or protein to their appropriate destination
  • soft, permeable cell membranes that can take in selective nutrients or even engulf and absorb another cell in its entirety (phagocytosis).

Eukaryotes are about 100,000 times bigger than prokaryotes, and there is much more structure and machinery.  Right from the start, Lane frames his narrative with a question about eukaryotes, why they are so different from everything that came before, why they were able to do things that in 3 billion years the prokaryotes never attempted, and why there are no extant “missing links” by which we might trace the evolution from prokaryote to eukaryote.

There is a black hole at the heart of biology. Bluntly put, we do not know why life is the way it is. All complex life on earth shares a common ancestor, a cell that arose from simple bacterial progenitors on just one occasion in 4 billion years. Was this a freak accident, or did other ‘experiments’ in the evolution of complexity fail? We don’t know. We do know that this common ancestor was already a very complex cell. It had more or less the same sophistication as one of your cells, and it passed this great complexity on not just to you and me but to all its descendants, from trees to bees. I challenge you to look at one of your own cells down a microscope and distinguish it from the cells of a mushroom. They are practically identical. I don’t live much like a mushroom, so why are my cells so similar? It’s not just that they look alike. All complex life shares an astonishing catalogue of elaborate traits, from sex to cell suicide to senescence, none of which is seen in a comparable form in bacteria. There is no agreement about why so many unique traits accumulated in that single ancestor, or why none of them shows any sign of evolving independently in bacteria. Why, if all of these traits arose by natural selection, in which each step offers some small advantage, did equivalent traits not arise on other occasions in various bacterial groups?

This story, the merging of very different life forms to create evolutionary revolutions,  is associated most closely with Lynn Margulis.  Lane acknowledges the deep legacy of Margulis, and also parts company with her and diverges from her Story of Life to offer his own version.

Something odd seems to have happened at the very origin of eukaryotes. It looks like the first eukaryotes picked up thousands of genes from prokaryotes, but then ceased to ply any trade in prokaryotic genes. The simplest explanation for this picture is not bacterial-style lateral gene transfer, but eukaryotic-style endosymbiosis.  This is the simplest possible scenario for the origin of eukaryotes: there was a single chimeric event between an archaeal host cell and a bacterial endosymbiont.

 

Demise of the the Tree of Life

To understand the oddness, we go back to the “tree of life” that was Darwin’s inspiration.

Through evolutionary history, species diverged via mutations and split off from one another, so that one species became two, in a branching process.  In this picture, due to Darwin, relatedness is perfectly defined, and every species has a unique path tracing it back to LECA.

Once genome analysis became possible in the 1980s, it was an early project to try to reverse-engineer the tree.  But the result of that project was a huge surprise.  Tracing different genes produced different trees, until it became clear that there was no tree at all, but rather a web of interconnecttions.  Everywhere there were cross-links in the tree.  Every individual species had acquired genes from many different places.

How can we reconcile this with the common fact of our experience that every cell comes from a single parent that divided in two?  (Yes, there is sexual combination, so a cell can have two parents, but in our experience these two parents are always very closely related, in fact they are by definition of the same species.)

And most problematic of all is the genome of LECA, parts of the genome that all eukaryotes share.  Those genes seem to have come from a dizzying array of very different bacteria and archaeons.  How can that be reconciled with the idea that LECA arose in a single, improbable event?  How can there be both a unique LECA and such a diverse genomic ancestry?

Different genes in the same eukaryotic organism do not all share the same ancestor. Around three-quarters of eukaryotic genes that have prokaryotic homologues apparently have bacterial ancestry, whereas the remaining quarter seem to derive from archaea. That’s true of humans, but we are not alone. Yeasts are remarkably similar; so too are fruit flies, sea urchins and cycads. At the level of our genomes, it seems that all eukaryotes are monstrous chimeras. That much is incontestable. What it means is bitterly contested.

It was this diversity of genes from many origins that Margulis cited as strong support for her thesis that merging of different, unrelated species has time and again seeded evolutionary saltations (times of abrupt change).  But Lane has a different idea.  These diverse genes were acquired all at once during a brief period (~2 million years is Lane’s astonishing claim) around the time of LECA.  The reason that they now appear to be associated with diverse kinds of bacteria is that bacterial genomes are easily mutable via the bacterial brand of promiscuous sex, the exchange of plasmids.  The apparent diversity of bacterial sources for eukaryotic genes is an illusion based on the taxonomic groupings (“species”) of bacteria today, which may be very different from their groupings of old because genomes are continually reshuffled across the diversity of different bacterial “species”.

Neither Margulis’s story nor Lane’s adequately addresses the greatest mystery (as Lane himself is first to admit):  why there are no surviving missing links between the prokaryotes and the eukaryotes?

 

The Energy Metabolism and the Origin of Life

Lane’s perspective centers on life’s capacity to capture energy and use it for purposes internal and external.  His singular contribution from the past was to remark how strange and curious is life’s universal energy factory: energy is stored and harnessed as a potential difference across an organic membrane.  So it is with all life’s diverse forms adapted to diverse environments.  It was the central insight of Lane’s 2005 book Power, Sex, Suicide that this may be a hint as to how life formed.  There are geothermal vents underwater, where metal oxides are spewed copiously into the sea, creating an alkaline pocket in an acid ocean.  Here are also mineral structures with micro-pores of cellular dimension.  So two of life’s necessities were freely available as foundation for pre-biotic evolution: compartmentalization (micropores) and energy in an appropriate form (gradient of H+ ion concentration).  Lane summarizes and elaborates this story in the new book.

Eukaryotes arose when mitochondria first appeared as an endosymbiont in LECA’s interior, providing a generous and reliable source of energy in the form of ion gradients, with input from biotic fuel and ambient oxygen.  It is Lane’s ambition to explain the broad outlines of eukaryotic life from this one event—the diversity, the behaviors, and the similarities of all plant and animal life, all derived from the character and circumstances of mitochondria.

It means, astonishingly, that mitochondrial variation alone can explain the evolution of multicellular organisms that have anisogamy (sperm and eggs), uniparental inheritance, and a germline, in which female germ cells are sequestered early in development—which together form the basis for all sexual differences between males and females. In other words, the inheritance of mitochondria can account for most of the real physical differences between the two sexes.

Lane even takes a stab at explaining the life cycle, including aging.  I applaud his vision and ambition in stepping back to look at the big picture and addressing the Great Questions.  To what extent are his answers convincing?  I’ll continue next week with some ways in which Lane’s perspective offers fresh new understanding, and some equally Great Questions that he does not address.

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Large New Survey Tracks Telomere Length and Mortality

Last week, a Danish study was published that tracked 65,000 people over a median of 7 years.  The bottom line was that telomere length robustly predicts longevity, even after factoring out the effect of age, smoking, exercise, blood cholesterol, BMI, and alcohol consumption.  This adds immensely to our knowledge of telomere length and its predictive power.  For perspective, the original [2003] study by Cawthon detected the relationship between telomere length and mortality based on fewer than 200 subjects.

The new data set is large enough to show trends over all of the health-related lifestyle variables.  Smoking, inactivity, weight (body mass index), and alcohol consumption all correlated negatively with telomere length.  So it should not be surprising that blood pressure and LDL choloesterol also correlated negatively with telomere length, and it is then a foregone conclusion that mortality must correlate negatively with telomere length.  This demonstrates without a doubt that unhealthy behaviors lead to shorter telomeres, as Epel and Blackburn have been telling us for a decade.  (They have emphasized the converse: that healthy life choices lead to longer, healthier life through the medium of longer telomeres [Ref, Ref, Ref, Ref]).

The bottom line of the new, large study is the extra predictive power of telomere length, even after all these other lifestyle and indicator variables are factored out.  Correcting for smoking, correcting for age, correcting for weight and cholesterol and exercise habits, there is still a powerful negative correlation between telomere length and mortality.  The shorter your telomeres, the greater your chance of dying.  The 10% of people with the shortest telomeres were dying at 1.4 the rate of the 10% with the longest telomeres, a result that was overwhelmingly statistically apparent (p<2×10-15).

Are Short Telomeres a Cause of Aging or Just a Marker of Aging?

There are many traits associated with aging that are mere markers.  For example, grey hair is associated with aging, but you don’t expect that coloring your hair will lead to longer life span.  Even if you found a treatment that restored your hair color by rejuvenating the pigment in your follicles, you wouldn’t expect to live longer as a result.

On the other hand, inflammation increases with age, and we know that it is not just a marker but a cause.  Reducing inflammation leads to longer life.

So are short telomeres like hair color or like inflammation?  Can we reasonably expect that lengthening telomeres will lengthen life?

Many lab scientists (and some gerontologists) think that it can’t be so easy to combat aging.  Theory says that if telomerase could increase life span, then evolution would have granted us more telomerase.  After all, the hTERT gene is already there in every cell, the metabolic cost of producing it is inconsequential.  Telomerase is free, and it can be released with the turn of a metabolic switch.

The theory continues: we know that diseases, lacerations, stresses all require more cell replication to repair them.  This must leave telomeres shorter than they would be otherwise. Smoking and inflammation are also known to shorten telomeres.  So (by this reasoning) people with shorter telomeres are expected to have shorter life expectancy because the shorter telomeres are telling a story that the person has suffered more stress.  Short telomeres are only a symptom of aging, and not a cause.

This new Danish study puts this theory to rest.  At last there is enough data that corrections can be made for smoking, obesity, exercise, and all major life style variables that could conceivably be have an impact on mortality comparable to the large effect we find associated with telomere length.

The correction is done using a statistical method called ANOVA, which can partition the causes of mortality into statistical bins and say how much is due to smoking, how much is due to blood cholesterol, how much is due to age, and how much is due to telomere shortening.

Results from the study:

  • Impact of telomere length on mortality, raw data:   3.38 (meaning that the 10% of people with the shortest telomeres were dying at a rate 3.38 as high as the 10% with the longest telomeres)
  • Same calculation, corrected for age:  1.54
  • Same calculation, corrected for age and all other hazard variables:  1.40

Conclusion: This demonstrates that age is the biggest factor in mortality, and telomere length has a strong effect, independent of age.  All the health variables together are a small factor compared to age and telomere length.

Short telomeres are not just a marker but a major cause of mortality.

Evolution has turned telomerase off such that short telomeres substantially affect our life span.  Turning telomerase on would not have cost anything, but that is not what evolution has done.

So the theory is wrong that says evolution has already made our life spans as long as possible.  Evolution has arranged for us to age and die “on purpose”.  Withholding telomerase is part of an evolved death program.

What does this say about the Cancer Hypothesis?

Suppose you believed that telomere length has been optimized by natural selection for a compromise between cancer prevention (short telomeres) and adequate capacity for tissue renewal (long telomeres).   Then you would predict that, since the length is at an optimal level, there is a smooth, flat top in the mortality curve.  People with slightly longer telomeres will have greater death rates from cancer, but lower from other causes; and people with shorter telomere length will have slightly greater death rates from other causes, but lower from cancer; and the sum (all-cause mortality) should be comparable for the two groups.

That would be the prediction.  But what the Danish group found instead (consistent with other studies in the last 10 years, but now unassailable because of the large sample) is that all-cause mortality decreases with telomere length.

We can only conclude that telomere length is not optimized for maximal life span.

 

Caveats

The prediction is vindicated to the extent that telomere length is not as strongly associated with cancer mortality as it is with cardiovascular mortality.  (Cawthon, too, found this in his tiny data set.)  This shows that the theory is correct to the extent that short telomeres seem to offer some “protection” against cancer.  But this “protection” is relative only to mortality from other sources.  The net result of short telomeres is to increase cancer risk—just not as much of an increase as for heart disease. It is a safe bet that the reason for this increase is that short telomeres lead to more senescent cells (more inflammation) and less effective T-cells (less effective monitoring against early stages of cancer).  Hence, the net result is that longer telomeres offer cancer protection that more than compensate the increased risk.

The one finding in the article that could most easily be mistaken for vindication of the cancer hypothesis is that there are three genetic markers of telomere length that were also tracked in these 65,000 subjects, and these markers are also correlated with higher cancer risk.  The three genetic markers correlate with higher cancer risk and also with longer telomeres.

The way in which this result is reported is biased, a bit misleadingly, toward the standard cancer hypothesis.  The authors write,

“We found that genetically short telomeres were associated with low cancer mortality but not low cardiovascular mortality, death from other causes, or all-cause mortality.  This implies that genetically long telomeres are associated with higher cancer mortality.”

The misleading thing is the use of the words “genetically short telomeres”.  You might read this and think it was referring to telomere length that the subjects were born with.  But in fact, this was not measured.  Without being able to go back in time, we have no way to know what was the subjects’ telomere length at birth.  The fine print in the article tells us what they mean by “genetically long telomeres” is the variant of these three genetic polymorphisms that is statistically associated with longer telomeres late in life.

(A bit of background: a SNP is a “single-nucleotide polymorphism”.  This refers to the smallest possible genetic difference.  Our DNA is made of units labeled A, C, T and G, and the vast majority of your DNA is absolutely identical to mine and every other human beings’ DNA.  What makes us unique is these small differences, and the lowest-level, smallest differences are these SNPs.  A SNP is a place in the DNA where some people have an A while others have a C, for example, amidst a sea of letters before and after that are identical.

There are three SNPs in the region around the telomerase gene that presumably help to determine when and how much telomerase is transcribed.  Some people make more and others less, based on these tiny differences.  What the new study shows is that the version of these three SNPS associated with longer telomeres is also associated with higher cancer rates.)

This result is expected, and could hardly be otherwise.  If the standard selfish-gene version of evolutionary theory works anywhere at all, it must work for the tinest variations.  Indeed, that is where the theory logically must apply, and that is the only place it has been tested.

I have written extensively (in this blog here and here) that this same standard population genetic theory, the selfish gene, does not explain the big picture in evolution.  By the big picture I mean sex, aging, cooperation, speciation, evolvability, the structure of the genome.  But I would have to be radical indeed to deny that standard selfish gene theory can explain the small picture.  For the record: I think that selfish gene theory offers a good account of SNPs.

Withholding telomerase, allowing cells and whole animals to senesce, is a “big picture” adaptation, built deeply into the structure of the genome.  One small part of this picture is ruled by just three SNPs, and this small part appears to be guided by a tradeoff between cancer and other forms of mortality.

What else can be concluded from this huge new data sample?

This is far and away the world’s largest record of individual telomere lengths.  Here is their scatter plot of telomere length vs age:

Telomere length vs age, new data

Telomere length vs age, new data

This is amazingly detailed compared to what had previously been available.  Here’s an example of what we had been working with before the Danish study:

Old data, telomere length vs age

The first thing we notice is how many more data points there are in the new study.  The second thing is that the scales are so different.  In the older samle, between ages 20 and 80, telomere length decreases from 7,500 to 6,000 base.  In the newer sample, telomere length decreases from 5,000 to 4,000 over a similar age range.  This must reflect a difference in methodology for measuring average telomere length.  Both studies characterize their target variable as the average telomere length for chromosomes in white blood cells from a blood sample.  (Curiously, red blood cells have no cell nucleus, no chromosomes, no DNA.  They are meant to do one thing only, to live a short time, and then be replaced.).

Both the new and old plots show a substantial scatter around the trend line.  Standard deviation looks to be almost 1,000 bp, and there are especially many outliers thousands of bp to the north of the trendline.  Although the downward trend is obvious with so many data points, it is also clear that it is not strong enough to account for the powerful mortality trend with age.  For example, eyeballing from the plot, I would guess that ¼ of 60-year-olds have the telomere length of the median 90-year-old.  But we know that the mortality risk of a 60-year-old is 17 times lower than for a 90-year-old (if Americans and Danes are similar), and if ¼ of all 60-year-olds fared as poorly as the average 90-year-old, then the difference between 60 and 90 could not be any larger than a factor of 4.  This kind of reasoning reminds us that age is a larger factor in mortality risk, and independent of telomere length.

This suggests a strategy for seeking in the new data an answer to an important question for life extension science:  How great are the potential benefits of telomerase activation?  In the next few years, we expect telomere-lengthening treatments to be available, so that telomere length is no longer a factor in mortality.  How many years can we expect this to add?

We might look for an answer in the factor 1.54 quoted above.  People with the shortest telomeres have 1.54 times the mortality risk of people with the longest telomeres.  Referring to the same life table I cited above, that factor of 1.54 represents five years of aging.  From middle age onward, mortality is rising exponentially with a slope of about 0.038 per year.

Log of the probability of death as a function of age

Log of the probability of death as a function of age

Only 5 years?  From one perspective, 5 years is a huge benefit–about what we might get if there were a universal cure for cancer.  But 5 years is a disappointing prospect for people (I am one) who have said that telomerase therapies are the most promising near-term technology for life extension.  The calculation may be misleading for a number of reasons.  For example, it may be that the average leukocyte telomere length is the most convenient thing to measure, but not the most salient.  It may be that the shortest telomeres are more important than the average, and telomeres in stem cells are more important than telomeres in leukocytes.  It may be that telomerase itself has benefits above and beyond the lengthening of telomeres [ref, ref].  Or it may be, as Mike Fossel has emphasized, that absolute telomere length is not as important as relative telomere length, separately calibrated not just for each species but each individual.  For readers who know more than I about the biology of telomeres, I invite your comments.

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Telomerase does Not Cause Cancer

I am one of a growing minority of life extension scientists who believe that telomerase may be our most promising, near-term path to a major boost in the human life span.  Notably, almost all the scientists who specialize in telomere biology have come to this opinion (e.g., Andrews, Blasco, de Pinho, Fossel, Harley, West, Wright).  But research investment in this strategy has been limited and the main obstacle has been fear of cancer.  Back in 1990, a young Carol Greider was the first to float the idea that the reason that man and most other mammals have evolved with short telomeres is to help protect against cancer.   Independently in 1991, senior geneticist Ruth Sager proposed the same hypothesis with more detail, citing circumstantial evidence.  Inference of evolutionary purpose is of necessity indirect.

The idea that lengthening telomeres poses a danger of cancer took a life of its own, based on marginal experimental data and firm grounding in a theory that is fundamentally flawed.  It is now taken for granted in publications, and only token documentation and no reasoning is provided when this view is asserted.  (e.g., “The senescence response is widely recognized as a potent tumor suppressive mechanism.” [ref])  I believe that this concern is misplaced, that activating telomerase will actually reduce net cancer risk, and that the fear of cancer is damping the enthusiasm that telomere science so richly deserves.  I have written a technical article on this subject, and in this and next week’s columns, I’ll take the opportunity to summarize the situation as I see it.

Relationship of Telomerase to Cancer

There are forces at work here in opposite directions:

(Bad #1) Once a cell becomes cancerous, it can only continue to grow if it has telomerase. So giving the cell telomerase removes one barrier to malignancy.
(Bad #2) Secondary to its role in growing telomeres, the telomerase component hTERT also functions as a kind of growth hormone, that can promote malignancy.

(Good #1) The body’s primary defense against cancer is the immune system. As we get older, our blood stem cells slow down because their telomeres are too short. Telomerase rejuvenates the immune system, and helps the body fight cancer before it gets started.
(Good #2) When telomeres in a cell get too short, the cell goes into a “senescent” state, in which it spits out hormones (called “cytokines”) that raise inflammation throughout the body and damage cells nearby. Telomerase protects against this.
(Good #3) When telomeres in a cell get too short, the cell’s chromosomes can become fragmented and unstable, and this can lead to cancer. Telomerase protects against this.

I believe that the three “goods” far outweigh the risk from the two “bads”. In animal experiments this seems to be the case, and I think that the “theoretical” reasons for concern are based on discredited theory. Of course, we won’t know for sure until we have more experience with humans.

The topic is timely, as last week a Danish study appeared in the Journal of the National Cancer Inst, tracking a huge population for the first time, and relating their telomere length to their mortality risk. Because of its size, this study gave a sound foundation to the thesis that longer telomeres portend a longer life.

Background

In the late 1980s, the story of cellular senescence took shape:  The gradual loss of viability that comes from multiple cell replications (the Hayflick Limit) was explained by shortening telomeres.  The process was reset by an enzyme, telomerase, first reported in a paper by Blackburn and Greider, the importance of which the Nobel Prize committee took 25 years to recognize.

Every eukaryotic cell knows how to make telomerase—it’s an ancient and ubiquitous piece of the genome.  (It has to be as old as DNA replication, because without telomerase, DNA can’t be copied for long.)  It was natural to ask the question:  with the remedy so widely and easily available, why should cells ever have to become senescent?  Why isn’t the telomere maintained with application of a little telomerase every time the cell divides?

Withholding telomerase looked like a kind of programmed death, and standard evolutionary theory said that programmed death is impossible.  “More survival, more reproduction” was the standard definition of Darwin’s fitness, and programmed death was just the opposite.  How could programmed death be, in some way, pro-life?

The answer that seemed obvious was:  death of cancer cells = life of the animal.  Maybe cellular senescence was permitted to occur as part of a protection against cancer.  It was known that cancer cells do not senesce; they can go on reproducing forever.  So cancer cells must have learned how to unlock telomerase.  Later, different human cancers were surveyed, and it was confirmed that well over 80% express telomerase.

Normal cells go through many transformations in order to become malignant.  One of these is to unlock telomerase.  Perhaps telomerase is the bottleneck, and the lockdown of telomerase helps to protect us from cells that otherwise might go rogue and turn into cancers.

This explanation was consistent with the standard evolutionary theory, but it was a very human-centric answer.  It was soon learned that cells senesce for want of telomerase in all kinds of animals, including those that don’t get cancer at all.  This might have been an early warning that the simple answer was not the whole story.  Even some protozoa withhold telomerase and suffer cellular senescence (ciliates). The very notion of cancer does not apply to single-celled protozoa.

The truth is that telomere attrition is an ancient mode of programmed death.  It functions that way in protozoans, and it functions that way in mammals.  Evolutionary theorists are going to have to expand the simplistic, one-gene-at-a-time theory about how natural selection works.

 

What really causes cancer?

It’s true that acquiring telomerase is one necessary step in the progression from a normal cell to a cancer cell.  But this only really matters if it is the rate-limiting step.

In every multi-step process, there are fast and slow steps, and the rate of the process as a whole is controlled entirely by the rate of the slowest step.  Adding telomerase capacity to a cell will only cause the cell to progress toward cancer more rapidly if telomerase was the slowest step, the rate-limiting step.  The best evidence we have is that some other step is rate-limiting, because in practice, adding telomerase does not seem to increase cancer risk.  Already in 1999, a study from the UTexas lab of Woody Wright and Jerry Shay demonstrated that

(What is the rate-limiting step?  My money is on evasion of the immune system.  I believe that of the trillions of cells in our bodies, a few become malignant every day, and that the immune system is constantly looking out for cancers and nipping them in the bud.)

 

Limited evidence for the hypothesis

Some studies in mice have found an increase in cancer incidence when telomerase was overexpressed. Female mice with extra (transgenic) copies of the telomerase gene developed breast tumors, while control mice had cancers in other organs, but not breast [ref].  Transgenic telomerase targeted to thymocytes (stem cells of the thymus) resulted in an increased incidence of T-cell lymphoma [ref].  Similarly, telomerase overexpression in skin stem cells increased the rate of skin cancer [ref].  In a mouse model genetically engineered to be prone to endocrine cancers, disabling telomerase dramatically reduced the frequency of tumor formation [ref].

All authors of the mouse studies note a puzzling aspect of their results: telomerase is already abundantly expressed in mice, and telomeres are never critically short.  According to the standard hypothesis, telomerase rationing should serve the body by halting tumors when they reach a size determined by beginning telomere length.  Any association of telomerase with initiation of cancer must be by a different mechanism, not yet understood.

Lab mice are not among the species whose life spans are limited by telomere attrition, so the evolutionary theory about telomerase rationing ought not to apply to them at all.  These results are interesting, and suggestive that telomerase plays other roles in metabolism, perhaps as a growth promoter; but results in mice cannot be cited as evidence for the standard hypothesis that applies to humans, dogs, horses, etc, (but not to mice).

A surprising line of research has indicated that telomerase has other functions besides maintaining telomeres.  A telomerase component called TERT can act like a growth hormone [ref, ref, ref], and in fact, all the credible pro-cancer activity of telomerase comes from the hormonal activity of TERT, and not from “immortalization” via telomere extension.

 

Cellular senescence is toxic

When human cells become senescent, usually because their telomeres have eroded with too many replications, they do not simply languish and die (like senescent protozoans).  Instead, they become toxic and send powerful signals out into the body that promote inflammation and further increase cell senescence.  This is called SASP, for Senescence-Associated Secretory Phenotype.  Not to mince words, the cells become toxic monsters that have a powerful pro-aging effect.  Van Deusen has shown that life span of mice can be extended 25% just by inducing senescent cells to die [ref].

There is no metabolic logic behind this toxicity, so I think it is probable that it is an evolutionary adaptation, and it must be seen as a pro-death adaptation.  I cite this as evidence that the reason for cell senescence in mammals is the same as the reason for cell senescence in protozoans:  it is an evolved mode of regulated life span.

Once you realize this, it resolves the paradox that led to Greider and Sager’s hypothesis in the first place.  They had been thinking within a limited evolutionary model in which evolution of programmed death has no place.  The inertia of that model continues to be the driving force behind the idea that “there can be no free lunch”, that evolution has already done her best to maximize human life span, and that we tinker with her choices at our peril.  If we are willing to discard that model, then a lot of the “big picture” in evolution starts to fall into place, including adaptations that favor the community at the expense of the individual, and programmed death in particular.

And the possibility opens up that lengthening telomeres may indeed be a “free lunch”.

 

Animal experiments in which life span was increased with telomerase

Lab worms would be the last place you’d expect telomere length to effect life extension.  This is because adult worms are endowed with a set of cells that last them through their short lifetimes of 15-20 days.  There is no cell replacement in adult worms, hence no telomere shortening, hence no cellular senescence, nothing for telomerase to do.  So it was quite a surprise in 2004 when a Korean study showed, using not telomerase but a different means of lengthening telomeres, that life span was extended 19%.

Using a cancer-resistant strain of mice in a 2008 study, Maria Blasco’s Madrid laboratory was able to extend life span of mice by 40% by adding an extra copy of the telomerase gene.  Again, this is surprising because it was thought that mice already have plenty of telomerase, and that their telomeres never shortened to a critical level during a lifetime.

An updated study from the same group showed that their care in using cancer-resistant mice was unnecessary.  Introducing an extra telomerase gene increased life span in normal mice as well, and cancer rates did not go up.  Blasco expresses her enthusiasm for the potential of telomerase therapy in this article.  She writes explicitly about the relationship between cancer and telomerase here, in an article that has been a source for my own views.

In a 2011 study from the Harvard laboratory of Ronald dePinho, mice were deprived of their usual abundance of telomerase by knocking out the telomerase gene.  The mice were followed until they experienced dramatic age-associated deterioration, including muscle atrophy, brain atrophy, and cognitive impairment.  Restoring telomerase, they found that both muscle and brain tissues were remarkably rebuilt, not merely preserved.

 

A New Survey of Telomere Length and Mortality

Last week, a Danish study was published that tracked 65,000 people over 15 years.  The bottom line was that telomere length robustly predicts longevity, even after factoring out the effect of age, smoking, exercise, blood cholesterol, BMI, and alcohol consumption. People with the longest telomeres had the lowest cancer rates.  This is a rich new source of statistical inferences, and  I’ll write a full column on the study next week.

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Magnesium

Supplementing with magnesium should be the easiest decision to make, because there are substantial potential benefits and no downside.

Magnesium is a chemical element, a mineral, common enough that the cost is negligible.  The kidneys easily excrete any excess above what you need, so toxicity is not an issue*.  Magnesium is essential for life, with a part to play in the body’s electrochemistry, nerves and muscles.  Hundreds of different hormones contain magnesium.  Mg is found in many foods, especially nuts and greens.  But modern diets tend to be low in Mg, and ⅔ of Americans are getting by with magnesium levels that are sub-optimum.

Wikipedia says: “Inadequate magnesium intake frequently causes muscle spasms, and has been associated with cardiovascular disease, diabetes, high blood pressure, anxiety disorders, migraines, osteoporosis, and cerebral infarction [Ref, Ref].”

The amount of magnesium you need each day is not microscopic.  The USDA recommends 400mg (almost half a gram).  Your body’s total inventory is about 20 or 30 grams (about an ounce).

Magnesium is a chemical sibling to calcium, in the same column of the Periodic Table.  The body’s electrochemistry plays off magnesium vs calcium in the same way that it pairs sodium and potassium.  A nerve fires when sodium replaces potassium.  A muscle contracts when calcium replaces magnesium.

The ratio of magnesium to calcium is tightly regulated, and calcium supplements have been added to so many foods that, whether or not we eat dairy, most of us get more than adequate calcium.  Some but not all calcium supplements include magnesium.  In maintaining your body’s ratio calcium/magnesium, it is better to err on the side of too much magnesium, as too much calcium can lead to calcium deposits in the arteries [ref].  “Magnesium deficiency” is associated with elevated risk of arterial diseases, and that includes most people in the developed world. There is some evidence associating low Mg with the wrong kind of cholesterol in the blood (too much LDL, not enough HDL).

The biggest role for magnesium is in the energy metabolism.  Every cell takes in chemical energy as sugar from the blood, and burns the sugar in its mitochondria to create usable electrochemical energy in the form of ATP.  ATP in its active form is bound to magnesium.

The muscle protein myosin that is the source of all strength and movement, including heart contractions, has a magnesium atom at its core.

The body can get by with less magnesium, but it doesn’t function as well.  Muscles can cramp and anxiety can be higher when magnesium is scarce.  Calcium metabolism is closely linked to magnesium.  There is some evidence that magnesium deficiency plays a role in osteoporosis.  (Here is a page from Dr Lam on the subject.)

Insulin sensitivity and the sugar metabolism are the most accessible variable in controlling our rate of aging.  More than ¼ of Americans over 65 are formally diagnosed with Type 2 diabetes, and the numbers would be far larger but for the fact that loss of insulin sensitivity is considered part of “normal aging”.  Many studies have documented that higher intake of Mg helps to retain insulin sensitivity with age [for example, ref1, ref2, ref3, review].

Some people who suffer from migraines find that magnesium helps dramatically [example ref].

One study suggested enhanced athletic performance with magnesium supplementation

Life expectancy?

The definitive studies have not been done, but there is suggestive evidence that more magnesium might be associated with longer life.   Here are two studies from Sweden [Ref1, Ref2] that found a connection between magnesium in drinking water and protection from cardiovascular disease.  This is a French study that found lower overall and cardiac mortality rates in people who had higher levels of Mg in the blood.  In this more recent study from Germany, peope with low blood levels of Mg had mortality rates 7 times higher than people with “normal” levels.  (Remember that “normal” is in the minority.)  Here is a Finnish study, however, that failed to find a cardio-protective effect from Mg in the blood.  In this Taiwanese study, the highest levels of Mg in drinking water were found to protect against cancer.

This is important work, and I don’t know why it hasn’t been pursued with more detail.  It these results are correct, there is no cheaper or easier way to better health.

 

Epsom Salt

Epsom salt=magnesium sulfate is cheap enough that you can pour it into your bath.  Absorption through the skin can be all you need, if that is your preferred delivery.  If you eat epsom salt, a bag costing a few dollars will last a year.  The only reason not to eat epsom salt is the taste.

Epsom salt is sometimes used as a laxative at dose of 1-2 tsp.  A daily dose of magnesium is about ¼ tsp.

 

Magnesium and brain aging

There is a separate line of research associating brain aging with lower magnesium in the brain.  This is newer, less well established, and has been promoted by Life Extension Foundation the last few years.  There is an expensive form of magnesium, called magnesium threonate (or MgT), that is more available to the brain.

Supplementing with MgT has been associated with enhanced memory and more effective learning in rats.  In a mouse model of Alzheimer’s Disease, MgT delayed cognitive decline.  There is theoretical support for the effect that invokes the NMDA receptor.   The only human study that I’ve been able to find reported abatement of fear and anxiety with MgT.  Can the memory results be replicated in humans?  I have written to Guosong Liu, now at the medical school of Tsinghua University in Beijing, who originally developed MgT while at MIT. The English version of his academic web site says, “Human clinical trials based on our discoveries are undergoing to translate the knowledge from our research to new therapies for the treatment of neurological disease with decline of memory function and psychiatric disorder such as anxiety and depression.”

The bottom line

If you want to read even more effusive support for magnesium supplements, visit the Center for Magnesium Education and Research.  You can try to have your blood levels tested, but the correlation between blood levels and Mg available in tissues is not so reliable.  The easiest thing to do is add Mg to your supplements.  It’s not going to hurt you, and it may do a great deal of good.

I have recently discovered Examine.com as a source for information about common and uncommon nutritional supplements.  It is encyclopedic in scope, well-indexed, and seems to contain straight, unbiased summaries.  Everything is linked to primary references. Put “magnesium” into their search box and this is what you’ll find. They have digests and cross-indexed sumaries for sale as PDFs, but I appreciate the fact that all their basic research is available on-line at no cost.  Examine.com has already made my work easier.

 

* There is such a thing as magnesium toxicity, hypermagnesemia, but it is limited almost exclusively to people who have kidney disorders and are being medicated with pharmacological doses of magnesium.

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