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 10 days or so.  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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Fertility is Kaput, but Life Goes On

PRLS

 

I study evolution of aging because I think it is a scientific conundrum.  But frequently, people tell me that the evolution of aging is easy to understand.  After the individual is done reproducing, its job is finished, and there is no more evolutionary force to keep it alive.  It can be pushed over with a feather (if natural selection had feathers to push with).

It’s not just naive people who make this statement.  People who should know better sometimes say the same thing.  I have heard this explanation from the mouth of a Nobel laureate in medicine.

The reasoning is correct, of course, but the problem is that it begs the question, how did the loss of fertility evolve? Sure, it’s true that once the individual has lost the capacity to reproduce (and is no longer caring for its offspring) there is no evolutionary reason for it to remain alive.  But why, in the first place, does evolution put up with the loss of fertility?  Why aren’t we all like oak trees that grow larger, stronger and more fertile with every passing year?

The mystery is not that we die after we lose our fertility; the mystery is why natural selection has permitted us to lose our fertility.

Semelparous organisms are those that have evolved to reproduce in one big burst.  All of them, to my knowledge, are also evolved to die promptly after reproduction.  Familiar examples include Pacific salmon, the octopus, many insects and annual plants.  Usually, it is clear that death is internally orchestrated, triggered by hormonal signals, behaviors and anatomical changes.  Mayflies, gnats and cicadas have no mouths or digestive capacity as adults. Octopus mothers stop eating and starve to death.  Salmon poison themselves with steroid hormones. Pansies shrivel up as soon as they “go to seed”, but you can keep them alive all summer as long as you remember to clip off the flowers when they begin to wilt.

Evolutionary biologists thought they had a good understanding of this dynamic, with the exception of human females. Women lose their fertility in their thirties or forties, but can go on to live into their seventies or eighties. What was evolution thinking, in cutting off female fertility?  In classical neo-Darwinian thinking, fitness is maximized by natural selection. There’s no such thing as “enough offspring—ok to stop now,” because if someone else has genes that permit more reproduction, then those genes will be the ones that spread through the next generation and grow to dominate the gene pool. Perhaps there is some physiological limit, and nature has tried and tried to extend female fertility, but it’s just a difficult problem… But that’s just not plausible. Women are born with millions of eggs, but over the course of a lifetime, only a few hundred ripen and descend the fallopian tube where they might be fertilized. The rest die in a process called atresia, akin to programmed cell death. Perhaps the eggs just become damaged over time, and they can no longer develop into a viable foetus. It is true that birth defects increase with a woman’s age, but this hardly seems to be a hard-and-fast physiological limit.

The explanation that was offered until a few years ago was the grandmother hypothesis. Perhaps a woman in her 50s can contribute more to her genetic legacy by helping out rearing her grandchildren. Perhaps infertility frees her from raising new babies of her own, so that she can devote full time to grandmothering, and in this way the number of surviving grandchildren is actually increased over what it would be if she remained fertile for an extra decade or two.

The Grandmother Hypothesis was never so plausible on its face, but it survived by default, having no competition. But a few years ago, some Exeter University researchers did a computation confirming what should have been obvious: If your goal is to have as many children as possible, cutting off your fertility is not a good choice. New children to whom you might be able to give birth if you carry on will all bear your gene, whereas grandchildren have only a 1 in 2 chance of carrying the gene, and you can only indirectly help their survival. Michael Cant and Rufus Johnstone estimated the net cost of menopause with real survival statistics from several primitive human cultures, and it wasn’t even close.

There’s more. Humans are not the only animals to lose their fertility and go on living, as it turns out. Whales and elephants are social mammals, and you might imagine that the grandmother hypothesis applies to them. But birds don’t care for their grandchildren, and several kinds of fowl become infertile long before they die. Fish don’t even care for their children, and post-reproductive life has been discovered in guppies.

Lab worms, C. elegans quite drive the point home as they are hermaphrodites, born with more eggs than sperm. They simply run out of sperm, and stop reproducing after about 4 days, but they can go on to live for 10 days.  This is a striking example of programmed deathbecause sperm is an itty-bitty, stripped-down cell.  Metabolically, the cost of producing sperm is negligible, even for a creature 1/10 mm long.  So running out of sperm while there are still plenty of eggs to be fertilized can only be seen as a purposeful curtailment of fertility.

Measuring life span and fertility in the wild is not so easy, and to date there are only a dozen or so examples. But wherever they look, field biologists are finding post-reproductive life span.

This is indeed a mystery. If natural selection is optimizing something called “fitness” which depends most directly on the number of offspring left by an individual, why is fertility being curtailed?  If there are resources that could be invested in reproduction or traded in for chips that help to keep the body in good repair, then why are so many chips mis-invested in longevity, when fertility would pay a dividend, and longevity, none?

A couple of years ago, Charles Goodnight and I proposed a solution to this conundrum, but it comes at a steep price. We left behind the neo-Darwinian framework in which maximizing fertility is the essence of fitness. We offered an answer in terms of the Demographic Theory of Senescence. This is a theory that says that nature does not maximize individual fitness only, but also concerns herself with stable and robust communities. The key point is that for animals (but not plants), over-consumption and over-population are ever-present, looming threats to the community. It is all too easy to “win” the game of reproducing, using a strategy of beggar-thy-neighbor. Animals in an area share a communal pool of food, and the easy way to reproduce more is to eat more, to gather more biomass and convert it to babies. This strategy offers a very short-lived victory, because once the food species is depleted, it may take many generations to grow back.

I may have more children than you, and get more of my genes into the gene pool of the next generation. But the result is that my children are greedy, like me, and there are more of them, and it doesn’t take long before they outgrow the food supply that was once sufficient to support our community, and everyone starves.

The classical wisdom is that this is a form of “group selection”, and it’s bound to be slow and inefficient compared to “individual selection”. But as Michael Gilpin first demonstrated 40 years ago, population overshoot can be the basis of a swift and lethal form of group selection. With judicious use of computer modeling and careful mathematical logic, he demonstrated that, in this case, it is easy to understand how group selection tempers individual selection.

The radical conclusion of Gilpin is that, in animals, reproduction can never be maximized without destroying the population. This undermines the assumption at the foundation of classical neo-Darwinism, and introduces a new, more communal picture of how evolution works.

It was in the context of this picture that Charles and I were able to demonstrate the evolutionary benefit of post-reproductive life span. Sustainability is a target of natural selection.  The goal is to stabilize populations in good times and bad, to avoid population overshoot that leads to collapse and extinction.  The mechanism of natural selection couldn’t be clearer: communities that are not sustainable collapse to extinction.

How does post-reproductive life span help?  An infertile, older population acts as a kind of buffer during times when the population might otherwise be expanding too fast. When there is plenty of food, the post-reproductive segment eats some of it, but they do not add to population growth in the next generation. Then, when times become more difficult and food is scarce, the older, weaker segment of the population is the first to die off, and this is no real loss to the population’s reproductive potential.

Remember, all this works in animals but not plants. In fact, post-reproductive lifespan is not found in plants, and indeed most plants appear to follow the expectations of neo-Darwinian theory far more closely than animals; which is to say that plants do appear to be maximizing their reproduction, while animals do not.

This demographic perspective may or may not be the solution to the conundrum of post-reproductive life span.  Clearly it doesn’t explain everything–for example, why do pansies die promptly after they go to seed?  But at present the Demographic Theory has few competitors, and we think it is a good beginning, and should be a fruitful basis for exploring a new understanding of evolution’s basic machinery.

More details of the Demographic Theory of Aging in my blog post from last year. Here is a link to the journal article by Mitteldorf and Goodnight.

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Tomorrow’s Anti-Aging Therapy, Available Today

For people who have a few hundred thousand dollars to spend and are willing to take on the risks of an “early adopter” and travel to South America, options are now becoming available that were inconceivable just a few years ago. A new company is leapfrogging over the time-consuming process of testing and regulatory approval, and offering the best-established and most promising experimental anti-aging technologies in the near future. This is a new vision for combining research with treatment, for treating diseases that have no proven therapies, and for aging itself.

(This column begins with a couple of pages of background.  If you want to cut to the chase, scroll down to BioViva.)


You only have to read Time Magazine to notice that this is the year anti-aging medicine is coming of age.  Promising life extension technologies are being debuted, with potential for preventing many diseases at once, adding decades to the human life span, and restoring youthful function to an aging body. These include telomerase therapies, stem cell therapies, epigenetic reprogramming, removal of senescent cells, plasma transfer, and hormonal therapies inspired by gene expression changes between young and old.

Inevitably, this has brought a surge in the number of companies eager to jump the gun and offer treatments to consumers based on early lab research, before the technology has proved  safe and effective in humans.  In an age of wildcat capitalism, we are well-advised to approach all claims with a skeptical eye, and assume that hucksterism is rampant.  Anyone who considers signing on with a new company that is offering a promising but unproven anti-aging technology had best start with a foundation of second opinions and broad considerations of risk and rewards.

But I stop short of saying, “stay away”.  The field is too important, with too much at stake for us individually and as a human community, to sit on the sidelines, to wait for the research to be sorted out.  Political control of medical research has protected us imperfectly, and has held back life-saving treatments, sometimes for decades.  The system serves pharmaceutical profits more effectively than the public of medical consumers.  Too often, the treatments that are approved are not those that offer the best risk/reward ratio, but those that are patentable and owned by someone who can afford to invest hundreds of millions of dollars in scientific advocacy.

The standard path to regulatory approval respects individual human life, and is “conservative” in the Hippocratic sense of “first do no harm”.  But it is far from the most effective way to move science forward, and probably is not the most efficient way to save the most lives, even in the short run.  Many libertarians, anti-aging enthusiasts and ordinary citizens who find themselves with a condition for which there is currently no effective medical treatment want the freedom to participate in experimental medicine, and experimental medicine certainly wants to try to help them and to learn from successes and failures.

For people who see their options for an active and creative life being closed by age-related disabilities, for people who are willing to take personal risks to help move the science forward, for people who are bold and adventure-seeking, the choice to try experimental anti-aging technologies can be a rational decision.

 

The Promise of Telomerase Therapies

In my opinion, the best-validated and most promising of the experimental therapies is the direct delivery of telomerase through gene therapy.  This is a technology pioneered in mice by Maria Blasco’s lab in Madrid, with stunning results.  In a ground-breaking 2012 paper by Blasco’s student Bruno Bernardes de Jesus, ordinary lab mice were given gene therapy with an “extra” telomerase gene spread to their cells by a genetically-engineered virus.  the mice lived 13-24% longer, and the experimenters reported “remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging.”

Some strategies work better in mice than in humans, but there is theoretical reason to believe that this technique should work (even) better in humans than in mice.  Untreated mice already have plenty of telomerase, and the telomeres of lab mice are at least 3 times as long as humans’, with shorter life spans in which to lose their telomeres.  Before the above experiment, it was reasonable to think that telomere length was a primary aging clock in humans, but not in mice.  Mice can live up to six generations after their telomerase gene has been knocked out (no telomerase at all), whereas people exhaust their telomere endowment in a single generation.

I’ve written in the past about telomere length as one of the body’s primary aging clocks.  Very little telomerase is expressed in human adults.  As our stem cells divide during a lifetime, telomeres get progressively shorter with age.  Some results include the most important symptoms of aging:

  • fewer functioning stem cells to replenish the stock of blood and skin cells
  • more senescent cell, each sending out distress signals that promote the body’s hyper-inflamed state
  • decline of the immune system, as new white blood cells form more slowly
  • a cascade effect, as cells with short telomeres senesce and then trigger senescence in neighboring cells
  • higher cancer rates, as the chromosomes in cells with short telomeres become unstable, and the immune system sentinels that nip cancer in the bud go AWOL.

Yes—higher cancer rates result when telomeres get short.  There is a theory that our bodies withhold telomerase in order to prevent cancer, but it is an idea with no experimental support.  Fear of cancer has held back telomerase therapy, and this is a red herring, based on misunderstanding of evolutionary biology.  All evidence suggests that telomerase therapies will lower cancer risk.

 

BioViva

BioViva is a new company offering experimental medical services outside US borders.  Their team includes

  • a lab that provides genetically modified viruses with a gene payload, made to order.  (This has now become a reliable and predictable technology.)
  • A doctor who has experience with experimental gene therapy, and who had the courage to experiment on himself five years ago, with good outcome thus far.
  • Sites in Colombia and Mexico where doctors will administer therapies for which there is not yet FDA approval.
  • Most important, a Scientific Advisory Board that includes two of the most prominent, senior biochemists who developed the science of telomerase in the 1990s and before.  They are Bill Andrews and Michael Fossel.

What they offer is gene therapy with hTERT and a proprietary myostatin inhibitor “in the same family with GDF-11,” according to CEO Elizabeth Parrish.

Parrish stresses that AAV gene therapy is a mature technology and has already passed FDA tests for safety.  “AAV has become increasingly common as a vector for use in human clinical trials; as of [2008], 38 protocols have been approved by the Recombinant DNA Advisory Committee and the Food and Drug Administration (FDA).” [ref] The uncertainties are no longer about safety, but about whether the virus will be destroyed by the body’s immune system before their payload can be delivered.  The rejuvenation benefit is likely to be systemic, and will have ripple consequences that we can only learn with human subjects.

In a surprise marketing move, Parrish has offered a guarantee for Patient #1 only.  If results for the first patient are disappointing, and Bioviva learns to avoid pitfallss and do a better job over the next 2 years, Patient #1 will be re-treated without cost, using the updated technology.

 

How Gene Therapy Works with AAV

AAV stands for Adeno-Associated Viruses, and there are several types in use.  This virus makes its living by

  • slipping its payload of DNA into a human cell (shedding its protein shell at the cell wall)
  • finding its way to the cell nucleus
  • copying itself into a specific place on Chromosome 19,
  • from where it manufactures copies of its own DNA, and also of the proteins that it needs to replicate, to penetrate other cells.

In therapeutic applications, the AAV DNA strand is modified to include a payload of therapeutic DNA, and to eliminate the genes coding for proteins that AAV needs in order to reproduce.  In this form, the modified virus can infect a cell, but once inside it cannot reproduce, infect more cells, reproduce there, and spread, causing disease.  It becomes a one-trick pony.  Each individual virus can infect one cell only, and then it has shot its wad.  No way this infection can “go viral”.

AAV therapy has been studied for over 25 years, and there is some reason to expect that the payload gene can remain active for a long time.  So this is a permanent change in the DNA of some cells in the body, though it is not a permanent infection.  Though AAVs are common in the environment, 80% of us have a naive immune response, so the treatment can be effective.  (For the other 20%, temporary immune suppression may be necessary.)  Repeat treatments are sometimes possible.  Here is a good semi-technical introduction to the subject.

Adeno-associated viruses, from the parvovirus family, are small viruses with a genome of single stranded DNA. These viruses can insert genetic material at a specific site on chromosome 19 with near 100% certainty. There are a few disadvantages to using AAV, including the small amount of DNA it can carry (low capacity) and the difficulty in producing it. This type of virus is being used, however, because it is non-pathogenic (most people carry this harmless virus). In contrast to adenoviruses, most people treated with AAV will not build an immune response to remove the virus and the cells that have been successfully treated with it.

Different AAV viruses can be customized to infect different cell types, and of course the place where the virus is injected is the most likely place for the virus to take root.  Viruses used in previous generations of gene therapy tended to disrupt the body’s own DNA by inserting at sites that are essential, and cancer rates were raised by some early forms of gene therapy.  AAV is favored because its target site seems to be safe, and its insertion harmless.

 

 

Therapies with hTERT and Myostatin Inhibitor

hTERT is only half the telomerase molecule, but it is the half that is in short supply, and hence the bottleneck for production of telomerase.  Of course, the DNA in our every cell contains the hTERT gene, but it is covered up and remains un-expressed almost all the time.  The new copy on Chromosome 19 is active, and in tests in cell cultures and live mice, telomeres have been lengthened.

I believe that telomerase is the closest thing we have at present to a cure for aging.  Bill Andrews and others have a long-term goal of developing drugs that will signal the body to activate its own telomerase gene, but these seem to be a few years off.  For now, adding an extra gene for hTERT may be the most promising generalized anti-aging intervention.  An important issue is that a large viral dose may be needed to saturate the body’s stem cells with the gene payload.  This is because a small minority of cells with the shortest telomeres is the source of some of the body’s biggest problems.  We’ll learn about the body’s response—if we are lucky, a rejuvenated immune system will itself eliminate the residual senescent cells without the need to lengthen telomeres in every senescent cell.

The myostatin strategy grows from (of all things) body-enhancement strategies for muscle-builders.  Myostatin is a member of the TGF-β family, is also called GDF-8*, and is a gene that inhibits muscle growth.  So if myostatin can be tied up, there is less inhibition and more muscle growth.  In the last several years, creatine has become a popular supplement for body-builders, and it works directly at the level of the gene, by inhibiting expression of myostatin=GDF-8.  Later in life, expression of the myostatin gene increases, and it is thought, logically enough, that this is a cause of the loss of muscle mass (sarcopoenia) that is almost universal with aging (though it is mitigated by exercise).  Bioviva offers gene therapy for a myostatin inhibitor (the specific gene is not disclosed), and it has been tried by one of the team members, experimenting on himself 5 years ago, with good results in a younger man.  Here is an article that offers a balanced view of reasons to believe this might or might not work for age-related sarcopoenia.

Perhaps more important, the same gene has been found to clear blocked arteries, with expected reduction of the risk for heart disease and stroke.  There is rodent data and good theoretical reason to expect this will work, and there has been one heart patient who has received the AAV/myostatin treatment it with excellent results.  Blocking myostatin is also expected to reduce the progression of insulin resistance that is a driver of many age-related diseases.

 

Alzheimer’s Disease

There is a well-supported theory of AD that it has its roots in the microglial cells of the brain.  These are not nerve cells, but they act as a kind of immune system for the brain, protecting it from inflammation and cleaning up plaques.  Their secretions promote growth and repair.  Unlike nerve cells, microglia are continually replicating, and so they lose telomere length over time.  On the theory that restoring telomeres in the microglia will reverse dementia, Bioviva is offering gene therapy with hTERT in the brain as treatment for AD.  Direct evidence that this might work comes from a 2011 experiment from the de Pinho lab at Harvard Med School, in which brains atrophied in mice deprived of telomerase, and the brains actually regrew when telomerase was provided.

 

The Bottom Line

Experimental treatments are, by definition, at the wrong end of the learning curve.  But there is so much to be gained, and the people involved are such experts, that I am deeply hopeful about Bioviva’s work, and the prospect of a fast track to meaningful anti-aging therapies.

____________________

* Myostatin is GDF-8, not to be confused with GDF-11, which has also been recently in the news.  Both are in the TGF-ß family.  GDF-8 inhibits muscle cell growth, while GDF-11 inhibits nerve cell growth.  Curiously, Bioviva’s anti-aging strategy is to suppress GDF-8 but last year’s headline-making paper from Harvard found benefits in  promoting GDF-11.

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Kill Senescent Cells Before They Kill You

Several readers have asked me to comment on the press release and preprint that came out of the Mayo Clinic this week.  Researchers searched for ways to eliminate cells in the body that have become senescent and destructive.  Their tests in cell cultures and in genetically-modified mice turned up two substances, one natural and cheap, the other patented and dear.  I think theirs is a promising approach, and will soon offer substantial life extension in humans with minimal side-effects, but my guess is that the particular cocktail they have found will be left in the dust.

Here’s the Theory

Our stem cells divide through a lifetime, renewing our muscles, blood vessels, and especially skin and blood cells that turn over rapidly.  But in the process, chromosomes in those stem cells lose their telomeres.  When its chromosomes have telomeres that are too short, a cell becomes “senescent.”  Senescent cells are not just sluggish and moribund, they actually poison the nearby tissue (creating more senescent cells) and poison the body with chemical signals (cytokines) that fan the flames of inflam-aging.  This is called SASP, for “senescent-associated secretory phenotype”.  A tiny number of senescent cells can do a great deal of damage.

Would we be better off without senescent cells?  It was the insight of the Mayo Clinic’s Jan van Deursen to ask this question with an experiment four years ago.  He genetically modified mice in such a way that senescent cells had a bomb and a trigger attached.  By feeding the mice a molecule that matched the trigger, he could cause the senescent cells to self-destruct, leaving normal cells intact.  He did a controlled experiment, comparing the same genetically-modified mice, with and without pulling the trigger.  The result was eye-popping life extension in the mice that had their senescent cells removed.  20 to 25% increase in life span from a single treatment, fairly late in life [ref].

Just a decade ago, such discoveries would remain languishing in the lab for a maddeningly-long time.  But it is a sign of the times that venture capital and even Big Pharma are investing in longevity science.  Van Deursen’s discovery was quickly seized by half a dozen different labs around the world (including a for-profit spinoff by van Deursen himself).  What they are looking for is a drug that will attack the 0.01% of senescent cells while leaving 99.99% of non-senescent cells unharmed.

 

The Research Strategy

The research group at Mayo/Scripps started with gene expression profiles for senescent cells, comparing them to profiles for non-senescent cells.  This was used to identify targets for the drug.  Van Deursen had used p16 to identify senescent cells.  P16 is a gene that keeps senescent cells alive when they really should be eliminating themselves.  The Mayo/Scripps team identified several other drug targets, but did not use p16.  They used RNA interference to silence these genes, one at a time, to help identify effective strategies for differentially targeting the senescers.  Then they screened 46 compounds to see which would best attack the targets they had identified.

The result was two drugs: quercetin seemed to work best for endothelial cells (in arteries), and dasatinib was best for fat stem cells.  Quercetin is cheap and found in many herbs and berries; dasanatib is a patented chemotherapy agent, sold for a scandalously high price by Bristol Myers Squib.  The team tested the combination Q+D for short-term health effects in mice, and found encouraging results.

Q + D

Quercetin is a common flavonoid, polycyclic, found in black currents, cilanthro, red onion, watercress, cranberries, and smaller amounts in many fruits and herbs.  It is an anti-oxidant, but you know I’m not much impressed by that. Though it is natural, it is a mutagen, which means it breaks DNA. Substances like this would never be approved by the FDA, if they had to be approved by the FDA, but they don’t because they escape regulation as GRAS — “generally recognized as safe”.  This is not to damn the stuff–many toxins have a beneficial effect in small doses.  This is hormesis, a paradoxical but common and well-documented fact of longevity science.

But in the case of quercetin, it has been tried in longevity tests with mammals, and the results are not promising.  In 1982, the first published study showed no life extension, and perhaps a slight shortening of life span in male mice. Stephen Spindler, our reality check for life extension claims, found that quercetin had zero effect on mouse life span in a 2013 study.

Dasatinib is a chemotherapy agent, sold by Bristol-Myers Squibb as Sprycel at thousands of dollars per dose for treatment of leukemia.   Dasaitinib has been tested for toxicity but never for life extension.

 

To put this in perspective…

The gold standard for a life extension drug is that it works to extend life span in rodents.  That’s because it’s too easy to extend life span in simpler lab models like worms and flies, but tests in humans overtax our patience.  Even for mice, the test requires three years and hundreds of thousands of dollars, so researchers are motivated to screen different compounds with tests that can be done in a petri dish, or with short-term studies of physiological changes in live mice.  This is exactly what the Mayo/Scripps team did, and it should have yielded good candidates for life extension drugs.  But the result was a “good candidate” that had already been tried, and didn’t do so well.

The reason that short-term benefits to the metabolism are not a good indicator of what might increase longevity is that body chemistry is complicated.  Life span is tightly regulated, with a mind of its own.  Some substances have short-term benefits, and the body over-compensates with a shorter life span.  Anti-oxidants are a good example.  Other substances do short-term damage, and again the body over-compensates and the result is a longer life span.  Look at the way paraquat affects life span in worms!

 

The Bottom Line

I’m betting that the search for strategies that differentially kill senescent cells will soon lead to better drugs than quercetin or dasatinib.

 

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“What Looks Like Cooperation is Really Selfishness”

Three years late, Scientific American is reacting to a paper on evolution of cooperation  [2012] with a hint that something is rotten in the state of Denmark.  This is what my wife used to call an FGIO, a faint glimpse into the obvious.  The paper was by interlopers from physics, mathematically adept senior luminaries.  The message of their mathematics was that if you put together a group of selfish individuals what evolves is (I’m sure you’ll be shocked to hear this) a selfish community.  A non-communal community.  The authors use the colorful word “extortion” to describe the dysfunctional social relations.

The reason this is important is that the standard evolutionary theory of cooperation says that global cooperation can emerge from behaviors that are individually selfish.  It can’t.

(We may be tempted to dismiss the whole topic as esoteric or peripheral, but in fact it pokes a hole in a framework of evolutionary thinking that has become sclerotic, and is overdue for rethinking from the ground up.  At stake is the way that we think about evolution, and by extension, the way we understand purposes and mechanisms in all of biology.  Aging is one particular case in point.)

 

Diverse forms of Altruism in Nature

Human soldiers offer up their lives all too readily in wars of questionable legitimacy.  Amoebas stop competing among themselves and form a “fruiting body” that behaves like a single organism.  Worker bees spend their entire lives serving a colony whose only reproduction is by a queen bee that may not even be a blood relation to the worker.  And yeast cells will commit suicide to digest themselves as food for their cousins when they detect that the local region has run out of food.  Fish of two different species work together to hunt more effectively.

When we look at the biosphere, the ubiquity of grand alliances is striking.  Everywhere, we see extreme examples of individuals sacrificing their lives and their legacy for the good of the community.  Not infrequently, the sacrifice is complete, in that the individual leaves no offspring at all; and yet the benefit to the group seems modest and indirect. What theory could account for the mismatch between individual cost and communal benefit?

In stark contrast to this broad observation, we have the dominant version of evolutionary theory that purports to explain how all this came about.  This is the “selfish gene” model.  The great majority of papers published in evolution today are still framed within this model.  This mode of thinking has infected and distorted scientific understanding of aging, which is why I became interested in the problem originally, and why this subject belongs in an aging blog.

Of course, adherents of the dominant school feel responsible to provide some account of cooperation, but they look at the world with tunnel vision.  There are just two narrow windows through which the broad spectrum of cooperative phenomena are permitted to be viewed.  One is kin selection: a gene that causes altruistic behavior in its bearer may survive if the altruism is directed toward close relatives who are likely to have copies of the same gene.  Second is Tit for Tat reciprocal altruism.  Higher animals that recognize each other as individuals may learn who they can trust, and on the basis of a network of pairings, broad cooperation can spread through a group.  It is reciprocal altruism that has been called into question by the 2012 paper referenced above, by William Press and Freeman Dyson.

 

Hamilton’s Contributions

I find it curious that both these windows were opened by William D Hamilton, early in his career, before Hamilton became a convert to group selection.  He died untimely of malaria after a trip to Africa observing and collectins specimens in 2000.

Kin selection is understood in terms of Hamilton’s Rule, which says C < rB.  In order for an altruistic behavior to evolve, the cost to the altruist (C) must be less than the benefit to the recipient (B) multiplied by their mutual relatedness (r). Relatedness r is ½ between siblings or for parent and child, and it goes rapidly down from there.  “I wouldn’t jump into the river to save my brother,” quipped J.B.S. Haldane, “but I’d lay down my life for two brothers or eight cousins.”

Reciprocal altruism is understood in terms of the “Tit for Tat” strategy, made famous in a paper by Hamilton with Robert Axelrod in 1981.  Based on a simulated tournament implemented with the crude computer facilities available at the time, Hamilton and Axelrod concluded that the most successful selfish strategy could be a basis for global cooperation.  This was validation of the “invisible hand” that Adam Smith had described two centuries earlier.  Emergent order in a system where everyone was only looking after himself.  Emergent cooperation in a system where everyone is behaving in a manner wisely selfish.

“What looks like cooperation is really selfishness” is a theme that pervades the evolutionary literature, in guises both direct and quite subtle.  It was the basis of the sociobiology movement a generation ago, and it thrives today in fields as diverse as evolutionary ecology and the medical biology of aging.

 

Origin of the Current Crisis

This way of thinking took it on the chin in 2012 when Dyson and Press published their paper, demonstrating a form of selfishness that Axelrod and Hamilton had not considered.  Their diabolical strategy took evolutionary learning into account, and gradually trained opponents over time to be submissive, using a purely mathematical form of “extortion”.

This is but the latest scream in the chorus of voices telling us that the “selfish gene” version of evolutionary theory doesn’t work.  The strength of cooperative groups is that they win out in competition against other cooperative groups.  The idea that the power of a cooperative group is just a lucky side-effect of selfish behavior self-organizing never was credible, and finally it may be biting the dust.  The truth is that the “selfish gene” version of evolution has outlived its usefulness. It is long past due for an overhaul.  Evolution does not work “one gene at a time”.  Cooperative relationships have evolved not by accident, but because cooperative groups are very successful competitors, and they can spread and take over areas where individuals are unorganized and selfish.

 

What does Selfish Gene Theory Leave Out?

Now that we see the truth, we can go back and ask about the Selfish Gene theory, what is the reasoning that supports it, and what is the flaw in that reasoning?

There are two lines of reasoning relied on by Selfish Gene adherents:

  1. All mutations originally appear in just one individual.  If a mutation for altruism appeared in one individual surrounded by selfish behavior everywhere, that individual would be left in the dust. Everyone around her would accept her generosity, thank you very much, and then use the advantage she had given them to out-compete her and leave her behind.  Genes for altruism could never spread in a selfish community.
  2. Conversely, in a community where everyone was cooperating, if a gene for selfishness arose in one individual, she would be able to benefit from the help given by all the others around her without herself bearing any of the cost of helping others.  Her star would rise, her progeny would prosper, and her selfish gene would spread through the community, poisoning it from the inside out.

This is a compelling perspective, and not obviously wrong.  However, it does not describe the world that we see.  It predicts that cooperation should be rare in nature, when in fact we find cooperation wherever we look, and not just among close kin.

So we know that the argument for the Selfish Gene must have a catch somewhere…what can the problem be?

In my theoretical work, I have offered a general answer to this question that I derived from the work of Michael Gilpin in the 1970s.  It goes like this:

All animals depend on an ecosystem.  There is a common reservoir of food in the form of living plants or animals on the next trophic level down.  The community of animals dependent on the same food stock is tied together in their fate by a need to conserve that resource.  It is all too easy to eat everything in sight, to deplete the food species and to use all that extra food energy to reproduce like crazy.  But the collective consequence of this behavior is rapid disaster.  Once the food species is gone, it takes a long time to grow back.  The next generation will starve, and the ecosystem will take a long time to recover, if it ever does.

There is a powerful tendency for population dynamics to fluctuate wildly, leading to extinction.  The extinction is rapid, and can occur in a single generation.  Therefore, it constitutes a very potent force of natural selection, one that can easily counterbalance selection for pure selfishness, and defeat the Selfish Gene.

So when Selfish Gene adherents think about a gene for selfishness taking over a community, what they’re leaving out is that the community would likely be destroyed in the process–the community would die out before the selfish gene could become dominant.  This is true of the easiest and most powerful form of selfishness, which is overconsumption.  And computer simulations show that once this most powerful form of selfishness is tamed, it ties communities together in a way that makes it easier for other forms of cooperation to evolve.

This is the mother of all cooperation, the glue that binds communities and makes selfishness a dead end.  Selection for population homeostasis opens a door that permits all other forms of cooperation to evolve.

 

The Bottom Line

Let me conclude with this bold statement of my radical new thesis:  If it looks like cooperation, it probably is.

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Ideology is Holding Back Aging Research

We can all agree that priorities in research for a longer, healthier human life span are far from rational.  Among the distorting influences are

  • Leap-frogging ahead to medical research in a field where the basic science is not yet fully understood.
  • Inertia from a research infrastructure that has been built on the wrong priorities.  Both people applying for grants and people evaluating those applications are stuck in an old paradigm.
  • Investment capital seeks profits in short-term, low risk projects
  • Misunderstanding of the basic nature of aging—a misunderstanding which also has capitalist roots.

Last month, an article in Nature Biotech surveyed the firms that are involved in longevity research, their resources and their strategies.


Until recently, research in aging medicine has been Balkanized into study of atherosclerosis, cancer, Alzheimer’s disease, Parkinson’s, and various smaller projects to study the diseases that affect older people.  The idea that we might be able to address all these diseases in one fell swoop if we can alter the fundamental biology of aging is not new, but it has been slow to take hold, and even now, research priorities remain lopsided.  Basic research in the biology of aging is absurdly under-funded, when compared to budgets for research on particular diseases.  The National Cancer Inst alone has a $5 billion budget, and Big Pharma is investing billions of their own in new chemotherapy agents that may or may not be marginally more effective than the old.  Meanwhile, the basic science of aging is studied on a budget estimated to be less than $1 billion.  Within that budget for the pure science of aging, I would propose that there are also substantially distorted priorities.

An article in Nature Biotech last month surveyed the private biotech investments in anti-aging technology.  We should all pause to celebrate the fact that this field finally has credibility, and is attracting substantial funding.  But, in my view, the funding is largely misdirected, and a few projects that I think would be good bets for a major leap in life extension have yet to be funded at all.

Researchers on aging are slowly pivoting from treating aging as a disease or indication to considering it a collection of age-related diseases.

This is the good news.  There is an enormous streamlining available when we turn from treating diseases separately to treating the root cause of aging.  But there is still a lot of ideology that says, “it can’t be that easy.”  This is the bad news.

[Linda] Partridge says “theoretical and practical insights have led to the conclusion that aging is likely to be a highly polygenic trait”. Contributing to aging is a protean list of processes, among them, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.

Partridge’s theory is taken from George Williams’s seminal paper of 1957.  He writes in response to Medawar’s program of isolating the root causes of aging in a small number of physiological processes:

Any such small number of primary physiological factors is a logical impossibility if the assumptions made in the present study are valid. This conclusion banishes the “fountain of youth” to the limbo of scientific impossibilities where other human aspirations, like the perpetual motion machine and Laplace’s “superman” have already been placed by other theoretical considerations. Such conclusions are always disappointing, but they have the desirable consequence of channeling research in directions that are likely to be fruitful.  [Williams, 1957]

But this perfectly reasonable conjecture of Williams was proven to be dead wrong in the 1990s, as single genes were discovered that offered dramatic life extension in worms.  There are now dozens of such genes known, and many of them are genes that need to be disabled, not new genes that need to be added to the genome.  In other words, there are powerful, known pro-aging mechanisms that make promising targets for pharmaceutical intervention.  Throwing a monkey wrench into an existing metabolic pathway is what Big Pharma knows best how to do (e.g., seratonin re-uptake inhibitors, beta blockers, COX2 inhibitors).  What we need is an inhibitor of pro-aging genes.

Rapamycin seems to be the first candidate in this category, and it is being appropriately explored, as reported in this space last week.

Here’s a caveat: The easiest path to life extension is through caloric restriction mimetics.  In other words, trick the body into thinking it has less food than it is really eating.  Some of the early genetic modifications in worms worked in this way.  DAF-2 was an early discovery, doubling life span of worms in Kenyon’s lab when it was partially disabled [1993].  The catch is that lab worms are champions of adjustable life span.  They are exquisitely adapted to be able to survive months at a time with no food at all, but to die within a few days once they have plenty to eat.  Larger animals also live longer when they eat less, but the effect is much smaller.  My guess is that CR potentially adds 5-10 years to human life span–nothing to sneeze at, but not the big, dramatic gains we might hope for in the long run.  If we find a really, really good caloric restriction mimetic, we might hope to capture most of that 5-10 years.

This is the low-hanging fruit being chased by the lion’s share of private investment in anti-aging medicine today.  No doubt, it will be achieved in short order (though it may be decades before we know which strategy works best, because longevity data in humans takes a long time to compile.)

Neglected is the potential for much greater gains that go beyond the potential of CR mimetics.

Let’s go back to Partridge’s “protean list” of complicated processes that have to be addressed:

  1. telomere attrition — This is a primary aging clock, cause of many downstream effects.
  2. epigenetic alterations — Gene expression changes with age.  When we are in our teens, gene expression is modified to halt growth and initiate puberty.  When we get old, a similar process leads to a gene expression profile that gradually destroys the body on an accelerating schedule.
  3. genomic instability — This is DNA damage, and by far the greatest source comes from short telomeres.  Telomeres cap the ends of a chromosome and keep it from unraveling.  When the telomere is too short, the chromosome becomes unstable.  So this may be traceable to #1. => See comment below by Bowles for another mode of genomic instability, this one controlled by epigenetic markers.
  4. loss of proteostasis — This refers to protein mis-folding, which is observed in Alzheimer’s Disease among other diseases of old age.  But proteins are being created and folded and re-cycled all the time.  Part of the reason that mis-folded proteins accumulate with age is simply that the body’s repair mechanisms are slowing down.  Another part is (my guess) that genes that take care of this function are being down-regulated–in other words, we might trace this problem to #2 as primary cause.
  5. deregulated nutrient-sensing — This is loss of response to insulin, related to “metabolic syndrome.”  I believe this happens under epigenetic control.
  6. mitochondrial dysfunction — This is the “free radical theory” or “mitochondrial free radical theory”, still invoked despite all the evidence against it.  It’s true that we have fewer mitochondria as we age, and that the mitochondria process energy less efficiently.  But the activity and the reproduction of mitochondria are under control of the cell nucleus, hence this, too, will prove to be a symptom and not a root cause of aging.
  7. cellular senescence — barely distinguishable from #1, telomere attrition.
  8. stem cell exhaustion — primarily caused by telomere attrition.
  9. altered intercellular communication — hormone signals through the blood are under epigenetic control.

Thus the “protean list” of nine complications derive largely from two ultimate sources: telomere loss and epigenetic reprogramming.  These should be our primary targets for anti-aging research.

* A Cell article this week from Elizabeth Blackburn’s UCSF lab suggests that activating telomerase may have rejuvenating benefits over and above its role in extending telomeres.

Companies investing in anti-aging research

The following table is taken from the same article: 

Table 1 Companies commercializing longevity
Company (year founded, location) Focus Founders (affiliation) Seminal publication
Alkahest (2014) Translating parabiosis, transfusing young blood into Alzheimer’s patients Karoly Nikolich, Tony Wyss- Coray Villeda 2014
Calico (California Life Company, 2013) Research and development into the biology of life span with undisclosed amount of Google funding. Arthur Levinson, Cynthia Kenyon, David Botstein, Hal Barron
CohBar (2009, Pasadena, CA, USA) Develops mitochondria-derived peptides with pleiotropic effects in age-related conditions (diabetes, cardiovascular disease, Alzheimer’s disease) Pinchas Cohen (University of Southern California), Nir Barzilai (Albert Einstein), John Amatruda (formerly with Merck), David Sinclair Muzumdar, 2009
Elysium Health (2014) Consumer health products Leonard Guarente (MIT) Mouchiroud 2013
Human Longevity Inc (2014) Combining human genomics, infor­matics, stem cell advances to solve diseases of aging Craig Venter, Robert Hariri, Peter Diamandis
L-Nutra (2008) Fasting mimicking and enhancing diets Valter Longo (USC) Parrella 2013
Metrobiotech (2008) Compounds that raise NAD+ levels David Sinclair (Harvard) Gomes 2013
Navitor Pharmaceuticals (2014) Selective regulation of M-TORC1, raised $23.5 million in series A round of funding David Sabatini (MIT/ Harvard) Dibble 2013
Proteostasis Therapeutics (2008) Therapeutics that modulate protein folding and homeostasis; preclinical programs in cystic fibrosis, neurode­generative diseases $45M raised Andrew Dillin (UC Berkeley) and Jeffrey Kelly (Scripps Research Institute) Cohen 2009

 

None of these is investigating epigenetic reprogramming, probably because it is too early for commercial investment–no one knows how to do it yet.  The only company based on telomerase activation is Sierra Sciences, which is below the part of the chart I reproduced, companies listed as in financial straits.  The only company with research based on a changing profile of circulating blood factors is the first, Alkahest.

The two wild cards are Craig Venter’s Human Longevity, Inc and Google’s CALICO.  Both are well funded, and neither has offered details about their research programs.  Last year, Venter hired the man who headed Google Translate, signaling a brute force approach, based on theoretical agnosticism: Sequence a million human genomes.  Look for patterns, e.g., what do the genomes of people who don’t get Alzheimer’s Disease have in common.  In my opinion, this is a cumbersome approach, inspired by successes in information processing, rather than knowledge of biology.  As I said, I think aging is controlled by epigenetics, and the largest gains will be made when we learn to re-program the epigenetic profile of an old person to make it look more like a young person.

CALICO, then, is crucial.  Their direction is not yet determined, and will be shaped by Kenyon’s vision and beliefs.  Kenyon has ambition and a wide-open imagination, and she is open to ideas about programmed aging.  We can hope that her extensive experience with worms informs but does not limit her vision.

 

Foundation funding

Historically, Ellison Foundation has been one of the most reliable sources of big bucks for innovative research, with about $400 million in aging-related grants since 1997.  But last year, Ellison pulled out of anti-aging research.  The Life Extension Foundation (LEF.org) has, by its own accounting, funded research totaling $140 million over three decades.  They have been independent of the bureaucratic thinking of the National Institutes, but they have their own biases, favoring natural remedies that can be sold without FDA approval.  SENS Foundation, with an annual budget of $4.5M, has grown from the singular vision of Aubrey de Grey, and has all the ambition and also the limitations of Aubrey’s paradigm.  To their credit, SENS is looking seriously at long-term projects that show potential for major gains in life span.  But, at least from my perspective, they are neglecting the most promising avenues, because Aubrey does not believe it is possible that aging might  be controlled by biochemical signaling.  The “engineering” approach to fixing what goes wrong is a long, hard road.  Peter Thiel has offered the greatest outside support for SENS, and Thiel has also made grants to other anti-aging initiatives.

 

Historical distortion of aging science by evolutionary theory

 In the long run, the greatest damage has been done indirectly, by capitalist ideology that has infiltrated the culture of evolutionary science.  From the beginning, Darwin’s theory was hijacked by “social Darwinism” which twisted the theory to create justification for hereditary class privilege in British society.  “Fitness” was elided with “financial success”.  “Natural selection” became a sanction from Natural Law for income inequality.

In the first half of the 20th Century, Darwin’s theory was re-cast as a modern science, with quantitative measures, equations, and predictions.  The work was spearheaded by R.A. Fisher, who happened to be both a prodigious genius in statistical theory, and also an elitist/eugenicist.  The version of evolutionary theory that was bequeathed to us was further caricatured by Richard Dawkins as the Selfish Gene.  In this version of evolution, the emphasis is on individual competition to the exclusion of cooperation.  There is little room for self-sacrifice, and such obviously communal adaptations as sexual reproduction have become inscrutable mysteries.

This kind of theoretical foundation has made the biological community blind to clear and manifest signs that aging is an epigenetic program, akin to growth and deveopment.  When you are a teenager, genes are turned on that cause secretions of sex hormones, and reproductive function is awakened.  When you are in your 60s and after, another set of hormones is switched on epigenetically, and the body becomes hyper-inflamed, auto-immune, insulin resistant and self-destructive.  Most biologists look at these changes and they figure that the body must know what it is doing, that there must be a redeeming positive benefit for these changes, and it would be dangerous to second-guess the body’s wisdom.  But the truth is that these late-life epigenetic changes have little benefit, and their predominant purpose is to destroy the body on an accelerating time scale.

Most researchers are busy asking themselves what goes wrong.  Neglected is the process plain and clear, where the body is being destroyed by “what goes right”.

It follows that the greatest opportunities for radical anti-aging are to characterize the chemical signals that control aging, and to adjust the signaling environment of an old body to make it more like a young body.

To some extent, this can be accomplished simply by lengthening telomeres, which have a substantial epigenetic reach of their own (TPE).  There are knowledgable advocates in the field who think lengthening telomeres is the most important thing we can do.  It is certainly the most accessible path, and should be a high near-term research priority.

 

My candidate for basic research:
Study the Epigenetic Clock that Controls Development as well as Aging

Biological science today does not know how the onset of puberty is timed.  We know that epigenetic changes are triggered at an appropriate age, and a few key sex hormones initiate the onset of fertility.  What we don’t know is how the body detects that the time has come for this to happen, whether there is an internal clock mechanism, and if so, how it works.  To me, this would be one of the most valuable studies in basic science, and I believe that when the epigenetic/developmental clock is understood, the results will carry over directly to understanding of the aging clock.  And if we can reset the aging clock, it’s a whole new ballgame.

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