‘one of the most important aging discoveries ever’

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

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

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

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

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

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

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

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

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

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

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

 

The Future

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

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

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

 

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Is Aging Controlled from the Brain? NPY and ALK5

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

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


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

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

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

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

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

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

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

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

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

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

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

 

Why NPY probably is not the Philosopher’s Stone

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

 

Other Signal Molecules from the Brain

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

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

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

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

 

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Global Consequences of Increased Human Longevity

I am a passionate life extensionist.  I am a passionate conservationist.  I have been living with a contradiction, increasingly stark as my understanding of both these causes, and my commitment to them deepens.


Nearly 20 years ago, I first became convinced by a variety of experimental evidence that aging is programmed into our genes by evolution.  It was five years after that that I had my first inkling how this could be.  This led to a study of evolved population regulation, and I became exquisitely aware of the entanglement of evolution and ecology.

Why would evolution create something as antithetical to the interests of her children (individually) as aging unto death?  A gene for aging is the opposite of a selfish gene.  And yet it is abundantly clear that we have genes* with no other purpose than to kill us.  Suicide genes.

My principal contribution to the field of aging research is the Demographic Theory of Aging, which says that aging evolved for the purpose of population stabilization.  There have been other theories of programmed aging in the past, usually based on the need for population turnover to assure adaptability, ongoing evolution and the ability of a population to change as conditions change.  What I demonstrated (first in a 2006 paper ) is that population dynamics provides a far more potent selective force than this.  Yes, the need to maintain population diversity and to change over time is certainly real .  But (for animals) the need to avoid population overshoot and subsequent crashes to extinction is far more urgent (not so for plants).  All animals depend on an ecosystem, and if they grow faster than their ecosystem, they are doomed.  Not doomed “eventually” in some abstract, far-off morality tale.  They are doomed within a generation or two.

Every animal population must have the latent capacity to grow quite rapidly in a pinch.  You can translate this to mean, roughly, that a population must be able to double in each generation when it is threatened or expanding freely into a new and fertile environment.  Human families in indigenous cultures can produce 6 or 7 babies, 4 of which survive to breed.  Roundworms can lay 300 eggs, 2 of which survive to breed**.  And, of course, microbes reproduce by cloning and double exactly with each generation.

art by Maddy Ballard

art by Maddy Ballard

But the doubling of a population that is already at carrying capacity can spell disaster.  Every blade of grass is eaten, or every rabbit is hunted, or every tree is denuded, and the ecosystem crumbles from the bottom up.

An ecosystem is a food web–predator and prey, the predator’s predator and the prey’s prey, multiply, connected and entangled, in an intricate network of interdependencies.   Stability of the network does not come for free.  There is no “invisible hand” that produces a grand harmony from a thousand selfish actors.  Rather, there is deep and ongoing coevolution.  Natural selection has taught each species cooperation and restraint via a billion years of tough love.  Those species that overreached to trash their own ecosystems brought their ecosystems crashing down, and their rapacious behaviors died with them.

(To this thesis, scientists in diverse fields say, “of course–that’s the essence of natural selection”.  But professional evolutionists have been trained to deny that such processes as this can occur.  Many still insist that evolution can only work to promote selfishness, never cooperation.)

Food web

Ecosystems are resilient.  There is an ability to bounce back after disturbance, from a natural disaster or the loss of a keystone predator.  This, too, is a property honed by natural selection, a strength of the community that has evolved gene-by-gene in its component species.  The unexpected happens, and the ecosystem has to deal with it.  Those ecosystems that can’t recover from an invasion or a decade of bad weather have long ago disappeared from the biosphere.

But recovery of an ecosystem requires time.  Bouncing back after a small disruption may require a dozen years or a dozen dozen.  Bouncing back from a major geologic or climate event requires thousands of years.  And in the history of multicellular life there have been five major extinctions.   Each time, the biosphere required tens of millions of years to recover.

We are now in the midst of the sixth global extinction , and as far as archaeology can tell, the anthropocene extinction is as deep and as rapid as any the earth has seen.

And how did we get here?  I believe the road to the Sixth Extinction was paved with ideology.  I speak not just of the Biblical ideology that says it is our place to “be fruitful and multiply, and fill the earth and subdue it; and have dominion over the fish of the sea and over the birds of the air and over every living thing that moves upon the earth.” [Genesis 1:28]  There is also the dominant version of Darwinian ideology that admits no explicit need for cooperation, but celebrates the creative power of selfishness.  Worst, perhaps, is the capitalist ideology that assigns no value to anything that cannot be translated into dollars , and that demands perpetual growth in order to support a return on investments.

 

Does Life Extension Contribute to Overpopulation?

Well yes, of course it does.  Human history since the advent of agriculture has been a quest to tame the environment, to substitute predictable domestication for nature’s wild ride.  We have done this to avoid death and the risk of death.

But only since 1840 has there been any  significant advance in human life expectancy .   Our animal nature has responded reliably, compensating with a lower birth rate that not even fundamentalist religious ideologies have been able to hold back.  But between lowered death rates and lowered birth rates there has been a gap of 30-40 years, leading to a dramatic growth in the human population.   Aldous Huxley recognized this pattern as early as 1956. “What we’ve done is ‘death control’ without balancing this with birth control at the other end….”

The gap between falling death rates and falling birth rates produces a population surge.

Currently, Africa is the last continent where technology is finally moving in to increase life expectancy, and the African birth rate is coming down, but not fast enough to avoid devastating population increases. Over the next 30 years, the population of Africa is expected to double from 1.1 billion to 2.4 billion, a larger absolute increase than the rest of the world put together.

Life span in 1840 was about 40 years in the world-leading European countries. In 2015 it was 83 in Japan and Scandinavia, the present world leaders.  And indeed, the increase has been quite steady and gradual, so that “one year for every four” is an accurate characterization.  For the first 120 years, increased life span was a story of early deaths prevented.  Before about 1970, all this progress in life expectancy was achieved by preventing people from dying young, benefits reaped from antibiotics, hygiene, and workplace safety. But since then, a remarkable thing has happened: the maximum human life span has risen, and continues to rise at an accelerating pace (as recounted by Oeppen and Vaupel). What is more, people in their seventies and eighties are healthier today than ever before. Although there are dramatically more seniors in the population, the proportion of the population in assisted living and other dependent care situations is not rising. This is just what we wanted–we are staying active and healthy longer, retiring later, delaying the ravages of old age and “compressing morbidity” of late life into a shorter endgame.

Rising life expectancy over 160 years (from Oeppen & Vaupel)

Rising life expectancy over 160 years (from Oeppen & Vaupel)

 

Gratifying for the individual–treacherous for the collective

World population at 7.3 billion is about ten times what it was in 1800.  A tenfold increase over 200 years is a good run, but it’s not unusual in the context of the biosphere’s history.  Far from it.  Bacterial populations routinely expand by a factor of a million.  Insect populations can boom and crash.  There are many examples even of large animal populations that have grown far faster than Man.

But other population increases have been local, while the rise of mankind has been all over the planet.  We are now a global population, adapted to living in deserts and jungles, snow-capped mountains and forests and fields.  We mow them all down, or burn them, or pave them over.  Man has put many other predators out of business, from mastodons and sabre-tooth tigers to moas to a slew of toads and salamanders in the present age.  We inhabit every corner of the earth and have wrought just as much devastation on the seas–perhaps more.  Technology has enabled us to dominate such a wide range of other species, and it has made human beings a uniquely devastating competitor.

killing-dolphins

 

Will we Destroy all Life on Earth?

Don’t give yourself airs.

Eradicate Gaia? Life is bigger and more robust than anything we are able to disrupt. No, the threat is not to Gaia but to ourselves. Life will eventually roar back, more diverse, more wondrously inventive than ever. But recovery from a mass extinction requires, typically, a few tens of millions of years. That’s nothing for Gaia, but for our grandchildren, 30 million years may try their patience.

There is life in boiling hot sulfur pits and life on the pitch black ocean floor, thriving under pressure that would crush a SCUBA tank, and life embedded in dry rock, equally deep under the land, living on who-knows-what. There are spores that were trapped in salt deposits 250 million years ago, recovered by scientists and brought back to life in the laboratory. To eliminate all life on earth is far beyond humanity’s destructive power for the foreseeable future.

But can we imperil the ecosystem that sustains human life? Quite possibly we can.

We may imagine the worst case scenario is that we destroy all of nature, lose all biodiversity and turn the earth into a vast farm to feed 20 or 30 billion humans.  But it’s a good bet that this kind of world cannot be, and it is certain that we don’t know how to create it.  Ecosystems are complicated and interdependent.  From bees to bacteria, our farms and our pastures and livestock all sit atop ecosystems that we do not  fully  understand.  Already, we are washing into the sea each decade topsoil that took 1,000 years to create .  Farmers rent hives of pollinating bees, and the beekeepers are keeping them alive with increasing difficulty .  For nitrogen-fixing bacteria, we have substituted saltpeter that we mine from the ground until there is no more of it left to mine.

Still life with steamshovel

Still life with steamshovel

Factory farming and antibiotics are two of mankind’s most successful and heavy-handed biological interventions.  Each has worked spectacularly well for a few decades, and we have perhaps a few decades more before each will as spectacularly fail.  We have that much time to create more sustainable replacements.

No, a world of monoculture to feed humans is not a viable world.  We are animals.  From an ecosystem we derived, and, for the foreseeable future, on a natural ecosystem we will continue to depend.  We are not nearly smart enough to build an artificial ecosystem to support human monoculture.  In all likelihood, the end of natural ecology would be the end of humanity.

Poets bemoan the loss of our spiritual connection to nature.  Meanwhile, ecologists warn us that we are starving more than our spirits.  We can’t engineer our way out of this.  We don’t know how.  We can’t understand or model ecosystems, so we have no idea how to move them in a given direction, even if humanity had the collective will to do so.  If we destroy the ecosystem we have, we will have to wait for nature to take her course, and the wait is likely to be tens of millions of years.

 

Libertarian ethic

Many of my colleagues in the life extension community lean to libertarianism, and in some ways I am with them.  I am frightened by our disappearing Bill of Rights, corporate takeover of the Free Press, exceptions to habeas corpus, wholesale domestic surveillance–and all this in service to perpetual war which most Americans want no part of.

But overpopulation and ecological collapse are problems that cannot be addressed individually.  China realized decades ago that we cannot allow each family to decide how many children they wish to have.  Still less can we condone men who impregnate women and walk away; and worst are the institutions that seek to preserve the morals of other people’s children by denying them knowledge of basic reproductive biology.

Gathered to see the Pope

Gathered to see the Pope

We will have to find ways to come together.  The good news is that polls show consistently that people are aware of the threat and willing to put aside their own (short-term) economic interest to address it.  (This despite concerted efforts to downplay the issue in the media.)  The bad news is that present political structures will not address the problem.  Our existing political order is, in fact, a big part of the problem.  Politics is dominated by capitalist megacorporations that have their own agenda, and preserving the ecological foundation of human life is not part of it.  Subversion of democracy by capitalism may have taken root in America and West Europe, but it is now a global blight.

We must work around government, the corporate media, the megacorporations and the whole capitalist economy.  We must come together to consolidate and act on an existing consensus for

  • A rapid transition to renewable energy
  • Policies to encourage smaller families
  • Limits to fishing, among other measures to protect the oceans
  • Protections for natural habitats on land

I invite your thoughts and ideas about how to do this.


The more dramatic images in this column were taken from the book Overdevelopment, Overpopulation, Overshoot , published this year and available free online or for purchase in hard copy.


* Aging genes or the equivalent, combinations and epigenetic networks that work to ensure that our bodies weaken and ultimately self-destruct over time.

** Since they are hermaphrodites, each worm can breed without a partner, and so needs only 2 surviving offspring rather than 4 to double its population.

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We Know Nothing about Longevity Drug Interactions

Years ago, I worked for an energy conservation priest whose motto was, “anything worth doing is worth doing poorly.”  We were training unemployed young people to install fuel-efficient furnaces in the homes of people who couldn’t afford heat.  My boss’s point was that the new furnaces were so much more efficient than the old that even if they were installed sloppily they would save enough fuel to turn a profit.  

If you focus on the big picture and get it right, the details don’t matter so much.

In tests with mice, a dozen or so different treatments have been found to lead to modest life extension.  The most urgent need at present is to begin studying how these treatments work in combination.  But there are too many combinations, and tests with mice are expensive.  That’s why it makes sense to do a quick-and-dirty job testing all combinations at once.

(This is a research proposal, the germ of an academic publication that I have been working on in recent months, and plan to submit to a journal and to the NIA next year.  I am experimenting with the idea of publishing it first as a blog.)


I take about a dozen different pills for longevity.  There is some evidence behind each of them, but what we really don’t know is how they interact.  It would be nice to think that their benefits simply add, so that if one pill produces a 10% average increase in life span, then 10 pills increase life span 100%.

Fat chance.

Some of them are ineffectual, of course.  But for the ones that offer a benefit, most of the benefits are probably redundant.  (When different treatments work via the same pathway, we can’t expect that two together work any better than either one of them separately.)  A few may mutually interfere.  But there also may be a few magic combinations that synergize positively.   If they work via pathways that are substantially independent, we might hope that the life extension from the two together might be equal or even greater than the sum of the benefits separately.

Most of the life extension drugs that we have target a single pathway: they work through the insulin metabolism.  The remainder work to suppress inflammation, or re-energize mitochondria, or lengthen telomeres, or reduce TOR signaling.

 

Tests in Mice and Rats

There are many ways to extend life span in worms and even in flies.  Some of these have also been tested in rodents, and they don’t pass muster.  I have argued that we should concentrate on mammals.  Even though they are much slower and more expensive, longevity studies in mammals are a far better guide to what might work in humans.  When a drug is found that extends life span in mice, there is a good chance it will also work for people (though percentage increase of our 80-year life spans is likely to be smaller than the corresponding percentage in the 2-year life span of a mouse).

Caloric restriction and exercise work consistently to increase average life span in mice.  Several genetic modifications are known to work, too.  The drug and supplement treatments for which there is best evidence include:

The many drugs that show promise but need further testing include

    • Deprenyl
    • ALK5 inhibitor
    • Epitalon/Epithalamin
    • MitoQ/SkQ
    • Beta Lapachone (Pao d’Arco)
    • Spermidine
    • Berberine
    • Dinh lang (Policias fruticosum)
    • Pterostilbene
    • Gynostemma pentaphyllum (jiao gulan)
    • N-Acetyl Cysteine (NAC)
    • Ashwagandha
    • Turmeric/curcumin
    • C60
    • Oxytocin (not oral)
    • J147
    • NR and NAD precursors

(Most of these were discussed briefly in a column I posted in September, and in other past columns.)

Almost no work has been done with combinations of longevity treatments.  In 2013, Steve Spindler’s lab published a study based on eight different commercial formulas of vitamins and supplements.  Their data were beautiful–and the survival curves for each of the eight fell exactly along the survival curve of the control group.  I have heard that the NIA’s Interventions Testing Program (ITP) has tested rapamycin in combination with metformin, with successful results (to be published next year).

In a rational world, some of the billions of dollars that go into “me too” drug development and chemotherapy trials by Big Pharma would be diverted to test all of the above compounds, alone and in combination.  But in the branch of the multiverse where you and I live, this will not happen in 2016.  Hence “quick and dirty” (= cheap) alternatives look attractive.

Proposal

The plan is to screen for combinations of drugs that offer dramatic life extension in mice, using the minimum number of mice to test the maximum number of combinations.  Standard practice is to use 30-80 mice for each test in order to get a clean survival curve.  The innovation I am offering is to use just a few mice for each combination of treatments so that more combinations can be tested, albeit less precisely.  How many mice do we really need to be reasonably sure of not missing an outstanding combination of treatments?

I have been modeling the situation with computer-generated data, testing different statistical methods to see which works best, and how many mice are needed in order to be reasonably certain of not missing a great combination.  My definition of a great combination is that it extends life span in excess of 50%.  The test I propose will not be capable of distinguishing “which is better” among the rank-and-file of many treatments and combinations.  However, there will be enough statistical power to identify the really hot performers, which are of most interest to us.

Specifically, I have modeled experiments based on 15 different treatments.  In the most practical and successful of the methods, I combine all different triples among 15 treatments (there are 455 of them, from a well-known statistics formula Combin(15,3)).  I’ve assigned 3 mice to each triplet of combinations for a total of 1365 mice.

I use statistics to tease apart the effects of different treatments and different combinations.  Analysis is based on multivariate regression, but since MVR works best with just 2 or 3 variables at a time, I have been experimenting with the details of an analysis program that looks at 1 to 3 variables at a time, then does a smart search for “nearby” criteria that might do a bit better.

 

The Model

I generate sample data for 1365 mice, based on each mouse having a randomly life span drawn from a bell-shaped curve.  The center of the bell-shaped curve depends on what treatments the mouse is getting.  (This is the “right answer” that the analysis is trying to find.)  The width of the bell-shaped curve is between 20 and 25% of the average, because this is the scatter that the better mouse laboratories find in their life span data.

To generate the means, I assume that each treatment offers some random amount of life extension, also drawn from a bell-shaped curve.  I assume that the treatments interact in pairs and that the interactions are mostly destructive, but some of the treatment pairs interact synergistically.

For example, if a mouse is receiving treatments A, B and C, then I assume its mean predicted life span is the sum of A and B and C separately plus the three interactions (A,B), (B,C) and (A,C).  (To simplify, I have assumed there is no separate term for a purely three-way interaction of (A,B,C).)   This is the mean life span for that one mouse, and that mouse is assigned a life span that is a random number centered on that mean.

Since we are most interested in combinations that yield large benefit, I have adjusted the parameters so there is always at least one triple combination that (on average) has benefit of >50% life span extension.

 

Preliminary results

      • About 40% of the time, I hit the nail on the head and identify the best triple and the best pair.
      • About 85% of the time, the best triple is among the top 3 generated by my analysis
      • About 95% of the time, the best triple is among the top 6 generated by my analysis

 

Tentative conclusion

I think this looks promising.  I am working with Edouard Debonneuil, who will check my calculations and contribute some of his own.  Edouard has more experience than I have both in the practical business of managing a lab experiment and in the practical business of finding funding and sponsors.

I believe that using about 1400 mice in an experiment lasting about 3 years, we should be able to evaluate all combinations of 15 separate life extension treatments, and narrow the field to 6 candidate triples that show offer life extension in excess of 50%, and thus show promise for further testing.

 

…and in the Real World

The program I have outlined could be undertaken for less than the cost of testing the 15 separate treatments using traditional methodology, and I think what we would learn from the combinations protocol could be a great deal more useful.  The total cost might be $1 to $3 million, depending mostly on where the work is done.

The biggest risk is that the high-benefit “magical” synergistic combinations that this program is designed to look for simply don’t exist.  If they do exist and can be found, the public health impact is likely to be enormous.

But in today’s economy, who will fund this work?

National Institute for Aging in Baltimore has the Interventions Testing Program (ITP), funded at $4.7 million.  Because they have high overhead and because they fund elite institutions with American salaries and because they repeat each experiment in triplicate, they can test only 1 to 2 compounds a year.  There is no activity from pharmaceutical companies, except for the few compounds that can be patented.  Some private foundations and crowd-funding groups have stepped forward to try to fill the void.  The Glenn Foundation has cut back.  The SENS Foundation is spread pretty thin.  I’ve recently connected with the Major Mouse Testing Program (MMTP) of the International Longevity Alliance.

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Anti-Aging Medicine: Two Paths Diverge

…and sorry I was I could not travel both.

  • Aging is an accumulation of damage.  If we want to return the body to a more youthful state, we’re going to have to repair that damage.
  • The body never forgets how to be young.  Given the appropriate signaling environment, the body will restore itself to a youthful state.

The future of medicine is the future of anti-aging medicine.  I don’t think anyone seriously disputes this.  Infectious diseases are a minuscule problem compared to a century ago, and with hygiene, good public health practices, and responsible restraint in applying antibiotics, we may hope to avoid a return to the days when tuberculosis and syphilis were pandemic.  We are fast learning to treat congenital disorders, and safe gene therapies are already being tested.

This leaves diseases of old age as the next frontier.  To slow the progress of aging, there is no doubt that signaling approaches work in animals, and will work (probably with less efficacy) in humans.  Caloric restriction (CR), exercise and other forms of hormesis are the best approaches we know at present.  Pills (e.g. metformin, berberine) may offer some of the benefits of CR without the hunger, and an “exercise pill” has been proposed.

The next step is to actually reverse aging, to restore the body to a more youthful state.  Among those of us who advocate research in the technology of age reversal, there are two prevailing paradigms.  I am with the school that says the same signaling approach can be extended to trick the body into thinking it is younger than it is, and the body will renew its cells and replace damaged biomolecules on cue.  The other school says that once the toothpaste is out of the tube, it’s not going back in.  We will have to engineer prosthetics, use bioengineering and regenerative medicine to replace body parts that have worn out.

Theory

“Everything degrades over time–it’s basic physics”

This is just wrong, but it’s so prevalent (among gerontologists and the great unwashed masses alike) that I’ll refute it yet again:  There is no physical necessity for aging.  Analogies to wearing out and to chemical corrosion are flawed and misguided.  The body may accumulate more damage than it repairs; but it may also repair more damage than it accumulates.  The choice is made by the metabolism (as programmed by evolution), not by physics.

  • The Second Law of Thermodynamics is specifically about closed systems, meaning systems that don’t interact with the outside world.  But living beings are evolved to take in order from food or sunlight and dump entropy back into the environment.  All of life is an end run around the Second Law.
  • Still, some people say the “end run” has to come to an end some time.  How can repair be “perfect”?  Well, it doesn’t have to be perfect. There is nothing perfect about a 20-year-old body, and it is the body’s metabolic choice whether to build itself ever stronger, more resilient and less vulnerable to disease, or allow it to decay, or (in between) to maintain a constant level of youthful robustness indefinitely.
  • …and indeed, some animals and many plants do go on getting stronger and larger, with lower and lower mortality risk, year after year after year.  This is called negative senescence, a fancy word for aging backwards.  Most trees do it, as well as lobsters, clams, some turtles, and possibly sharks and whales.
  • If physics demanded that living organisms always degrade then growth and development would be impossible.

Evolutionary biologists almost all appreciate this—aging is a problem for evolution, not for physics.  Though many of the symptoms of old age may look like accumulated damage, there is no necessity for the damage to accumulate; the body is making a choice to repair the damage only partially, as opposed to rebuilding better-than-new, which is perfectly possible, both physically and biologically.

More detail is in my blog post from 2014.  Here is an academic paper on the subject.

“If the body could rejuvenate itself, it would already have done so.”

This is also a common view, and harder to dispel.  I think it is just as wrong as the one above, but full disclosure compells me to admit that I’m still in a minority on this question.

Since the 1960s, Nature has become an object of reverence, especially among the secular quarter in Western culture, people who are skeptical of religious dogmas.  The myth is that evolution has worked for millions of years to perfect the individual, and that human intervention is more likely than not to trip over the law of unintended consequences.  Biochemistry is not only highly optimized, it is also highly intricate and every biochemical plays multiple roles.  

Like most myths, this one carries some truth.  A lot of Western medicine treats symptoms, not causes, and has questionable value in the long run.  Human attempts to “manage” nature have been fraught with rude surprises.  And a natural diet of vegetables and fruits is a much better starting place for healthy nutrition than is a diet of processed food.

But “natural medicine” can never reverse aging.  The problem is that we are not just evolved to be strong and fertile individual competitors, but we are also evolved to be part of a stable ecosystem.  Aging was bequeathed to us by evolution, not for our sake as individuals, but as a way to stabilize ecosystems.  Individuals need to die on a schedule that is internally determined because if we left the matter of death to the world outside, then starvation would be the principal cause of death, and starvation tends to take everyone down at the same time.  This is called “extinction”.  The population can’t afford to eat whatever is available and die only when the food runs out, because then everyone would die at once.  The population would swing wildly up and down.  Evolution has taken pains to protect our species from extinction, just as surely as she has taken pains to make us individually tough and resilient and fertile.

When it comes to aging, we can’t assume that “we tinker with evolution’s product at our peril, because evolution has already done her best to make us live as long as possible.”  In fact, the body’s repair mechanisms slow down as we get older (just as we need them most).  The immune system goes haywire, failing to attack pathogens but turning on the self (arthritis, diabetes).  Healthy nerve and muscle cells commit suicide (Loss of nerve cells is part of Alzheimer’s Disease; loss of muscle is called sarcropenia, a universal wasting disease.)  

As we get older, the balance of signals in our blood changes in some ways that are random and some that are predetermined.  All the predetermined changes are detrimental; signals in the blood raise the level of inflammation, which is the most significant root cause of all the diseases of old age.

The idea that aging was programmed into us for the sake of the ecosystem isn’t just an abstract theory; the theory was devised to explain the reality that the aging body both shuts down repair mechanisms and turns on active self-destruction, in a way that looks quite deliberate.  All the principal mechanisms of aging have been preserved over the vast stretch of evolutionary time. 

 

Examples of the Rebuilding Approach

Prosthetic limbs, artificial knees and hips are nothing new, but they do keep getting better.  Computer technology promises artificial limbs that can interface with existing nerves so that amputees can learn to control them.  When lenses in the eyes become clouded by cataracts, surgery to replace the lens with plastic have become routine.  Artificial eyes are now conceivable, and there are crude working models.  Mechanical hearts would be most useful, but the technology has been the subject of an intensive bioengineering program since 1969, while mortality rates remain stubbornly high.

Tissue engineers are working on techniques to grow organs on scaffolds.  Tracheas and bladders have already been implanted successfully in humans.  

Despite impressive technological advances, the challenge facing this approach is formidable.  Things that go wrong as we age include clogged arteries, inelastic skin, and weak, degraded muscles.  These parts are not easily replaced.  Brain aging presents the ultimate challenge.  No one wants a prosthetic brain.  (Maybe I’m wrong about this.)

Aubrey de Grey and his SENS Foundation have prominently championed the repair-and-replace approach to geriatric medicine.  The current research program of the SENS Foundation (from their web site) includes

      • Engineering new mitochondrial genes
      • Fighting cancer by shutting down the cancer cell’s ability to maintain telomeres
      • Convincing the body’s immune system to attack amyloid plaques
      • De-fanging or eliminating senescent cells
      • Enhancing lipofuscin clearance
      • Engineering a new thymus
      • Epimutations in single aging cells
      • Finding amyloid in the heart
      • Quantifying extracellular crosslinks
      • Rejuvenating risk/benefit analysis
      • Rejuvenating the microenvironment
      • Repopulating the Gut
      • Scaling up glucosepane research

Four of the thirteen may be regarded as signaling approaches; the rest are conceived as building understanding and a technology of control at the molecular level that SENS hopes will ultimately be the basis for engineering aging out of the human metabolism.

 

Examples of the Signaling Approach

 

A growing number of anti-aging researchers are betting on the idea that we don’t need to repair everything that goes wrong with aging because the body can repair itself, if only we can rejuvenate the signaling environment.

FOXN1 rejuvenates the thymus

The slow disappearance (“involution”) of the thymus over a lifetime has been implicated in the age-related decline of the immune system.  The rebuilding approach seeks to replace the aged thymus with tissue engineering [ref, ref]; in contrast, the signaling approach seeks to stimulate the body to regrow the thymus on its own.  Of course, this is the easier approach, if it works.  Greg Fahy has reported success with growth hormone.  Several labs have recently reported hopeful signs that a signal protein called FOXN1 might be a specific trigger for regrowth of the thymus [ref, ref].

 

J147

Last week, a press release from David Schubert’s group in the Salk Laboratories in La Jolla made headlines for J147, a compound they have focused on more intently.  The world was introduced to J147 with a 2011 article in the high-profile journal PLOS One, which didn’t receive as much attention as it deserved.  There is a new article in the subsidy journal Aging that is getting more attention that it deserves.

The most notable thing about J147 is that it is a promising result from a new methodology for drug development.  Schubert’s lab began with curcumin, the active neuroprotective and anti-inflammatory component of turmeric.  Chemists synthesized and isolated hundreds of chemical cousins of curcumin, which were screened in cell cultures for neuroprotective activity at lower and lower doses.  

In the end, the molecule J147 doesn’t look much like curcumin.

J147

Curcumin

Both molecules have two aromatic rings.  The curcumin molecule is mirror symmetric, which J147 is not.  And J147 contains fluorine, which no natural biomolecules do.  (Among popular drugs Prozac and Lipitor contain fluorine.)

The best ones were tested in rodents.  J147 improved memory in young mice and old.  In a mouse strain genetically engineered to be vulnerable something close to human Alzheimer’s disease, daily doses of J147 were able to delay onset of memory loss.  Even after the mice suffered memory loss, J147 was able to reverse it [ref from 2013]

The reason the new paper made more of a splash than the old was that it was framed in terms of general anti-aging benefits, rather than neuroprotection or memory improvement.  The new paper reports that mice on a lifelong regimen of J147 show generalized abatement of markers of aging as they grow older.  The work is promising, but it was all done with SAMP8 mice, genetically engineered to contract a version of Alzheimer’s disease, which usually kills them before they are a year old.  J147 has not yet been assayed for life extending potential in normal mice.  

J147 is presently available in tiny quantities for a prodigious price.

 

ALK5 Inhibitors

Mike and Irina Conboy working at UCBerkeley have identified ALK5 as a pro-aging signal, and report success in rejuvenating tissues and whole mice with a molecule engineered to block the ALK5 pathway.  Their recent paper may be viewed as a manifesto for the signaling approach to anti-aging medicine.  It begins:

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

This sentence is dense with meaning that is worth deconstructing.

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches,

The traditional view is that cells suffer damage with age.  Stem cells know they are old because of shorter telomeres.  They accumulate lipofuscin, and their DNA mutates over time.  Of course, aged stem cells cannot be as effective as young stem cells.  But the claim here is that the cells themselves are fine.  They are responding to signal molecules in the blood that tell them to lay down on the job.

elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus,

The bad actor is fingered and, what is more, its source is traced to the hippocampus—a region of the brain known for neuroendocrine signaling, and implicated in other time-cyclic processes.

analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age.

The Conboys had previously found that TGF-β signaling was responsible for inhibiting muscle growth in aged mice.

The article goes on to describe the receptor for TGF-β, one step downstream, that is responsible for the negative consequences of TGF-β signaling.  The receptor is called ALK5, and there are known molecules that can clog ALK5, blocking the signal pathway that has inhibited new growth in old bodies. “Very interestingly, both neurogenesis [new nerve cells] and myogenesis [new muscle tissue] were significantly enhanced in the aged mice treated with ALK5 inhibitor, compared to the animals receiving control buffer.”

ALK5 inhibitors are also available from lab supply houses, even more dear than J147.  But, to be fair, the molecule is more difficult to synthesize and the dosage is probably smaller.  (In fact, we have only theory to guide us for human dosages, since both these molecules have yet to be tested in humans.)

 

The Bottom Line

In the beginning, anti-aging medicine was thought to be fanciful, if not impossible.  How could human engineering improve on processes that Nature has been perfecting for a billion years?  Then a science of regenerative medicine began very slowly chipping away at that conventional wisdom, and a glimmer of hope pointed to promise of fixing the body directly with engineering, at least in the long run.  

But a funny thing happened along the way.  There are indications in many areas that the body knows perfectly well how to rejuvenate itself, and we need only learn to speak the body’s (biochemical) language in order to say, “Have at it!”  A few people like me are pointing out that this contradicts everything we thought we knew about evolutionary biology, and that the “selfish gene” is in need of an overhaul.   But bench scientists are choosing to sidestep this theoretical debate and simply to do the practical thing.  They are pursuing a signaling approach because  it works.

 

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Does donating blood extend your life expectancy?

Last week I came upon a 1998 study finding that the risk of heart attack was 18 times lower in people who donate blood, compared to a matched sample of people who don’t.  I ran out to my local Red Cross Blood Drive, and then came home for some follow-up reading.  The consensus from a handful of studies on blood donation seems to be far less dramatic, but still worth considering.


Hippocrates thought that women purged blood every month to release their toxic humors, and that men might benefit from an artificially-induced version of menstruation.  From ancient times until the 19th centuries, bloodletting was a common medical procedure.  Leeches were  prescribed for a wide range of ailments.  

Bloodletting was thought to be beneficial in healing nearly every disease, from acne and asthma, to cancer and smallpox. Even the loss of blood from a wound was treated by…removing more blood! Bloodletting the already-wounded was thought to reduce inflammation (which is why it was employed prior to surgery as well). Bloodletting wasn’t limited to curing disease either, but was also used as a preventive measure to avoid getting sick. [source]

Modern medical wisdom dismisses these ancient, barbaric practices as fraud, mountebankery and snake oil.  But like most medical practices that stood the test of time (if not epemiology), this one held a core of truth.

Don’t let your barber do this.

For centuries, the local barber not only offered close shaves and sharp haircuts, but also provided medical services including bloodletting. In fact, the iconic barbershop pole with its two brass balls and red and white stripes is a vestige of the days when barbers would slit customers’ arms to relieve their ailments.

 

Epidemiology of Blood Donation

The raw statistics are quite promising.  Here is a study that found occasionally donating blood (every three years) is associated with a 50% drop in cardiovascular disease in men.  This study finds a 40% reduction in cardiovascular risk, after adjusting for other differences between donor and non-donor groups. These [ref1, ref2] looked at short-term benefits for blood lipid profiles studies following blood donation.  These two studies [ref1, ref2] found a slightly lower risk of cancer in blood donors.  In a large study of US blood donors, this study found a 30% lower rate for all-cause mortality.  This large Italian study found a modest decrease in overall mortality among blood donors.

These were balanced with other studies that found slightly higher cardiovascular risk among frequent blood donors, and several [review] that uncovered no benefit.  

 

The Healthy Donor Effect

It is an obvious point that unhealthy people don’t respond to blood drives.  How much of the statistical association with lower health risks is merely self-selection, and how much is causal?  Here is a current study claiming that the unadjusted benefit is 18%, and the residual benefit after accounting for the “healthy donor effect” amounts to 7%.  These percentages represent reduction in mortality rate for each additional annual blood donation.  Based on this unimpeachable source, I have decided to give blood exactly 14.3 times each year, thereby reducing my risk of dying to zero.

 

Iron

I’m old enough to remember Jack Barry on the B&W TV, the merits of Geritol for “tired blood” — a description of anemia that was intended to suggest that low iron was the primary culprit in an epidemic of chronic fatigue.

Jack Barry on the quiz show, “Twenty-One”

Geritol was advertised as an iron supplement.  Today’s epidemiology recognizes that anemia is far less common that the opposite, and that too much iron is a risk factor for heart disease, cancer, and Alzheimer’s.  (Geritol is still sold today, but its formula has less iron  

Modern thinking is that, yes, anemia might limit stamina or even cause fatigue, but people who eat meat and who don’t carry a gene for hemochromatosis are unlikely to be iron-deficient.  When iron is in short supply, the body can readily increase its absorption.  But the body cannot easily remove excess iron, thus excess iron accumulates in the liver.  In fact, too much iron is about four times more common than too little iron in a sample of people over 50 [ref].  The consequences of too little iron are short-term, but the too much iron is a risk factor for chronic disease.

The best-established health risk from too much iron is elevated incidence of diabetes [ref1,  ref2, ref3, ref4].  Insulin resistance, in turn, is associated with higher risk of all the diseases of old age.  But several studies have found only a weak relationship between excess iron and cancer or mortality risk [ref1, ref2].

 

Hormesis

Instinct tells me that lower iron is not the only benefit, or even the main benefit from blood donation.  First, the body can quickly recover iron lost to blood donation by dialing up the absorption from dietary sources.  The effect on the body’s iron stores is likely to be short-term.  Second, the evidence for association between high iron and high disease risk is actually weaker than the evidence for benefit from blood donation.  So my guess is that this is a hormetic effect.  Blood donation is like exercise or a low-calorie diet or low-dose toxins or radiation: it signals to the body that there is danger, which turns on protective mechanisms that go into high gear and overcompensate.  (There is an evolutionary explanation for the overcompensation.)

Social and emotional factors have a dominant influence on longevity.  It is often overlooked, but connectedness with others, sense of satisfaction and fulfillment, healthy loving relationships are all powerfully correlated with health and life expectancy.  Giving blood may be an indicator of pro-social attitudes that prefigure longevity, or it may be an active pursuit of a pro-social behavior that promotes longevity through psychological pathways.

My experience

For several years, Valter Longo has been expounding a theory that an extended fast can reset the immune system.  The data on blood donation suggested to me that something similar was happening, and that there might be synergistic benefit from combining a fast with blood donation. I have been doing Longo’s 5-day Fasting-Mimicking Diet every 4-6 weeks, and it happened that I was FMD-ing when I first read about the benefits of blood donation last week.

I found a Red Cross blood drive on the last day of my FMD within 5 miles of my house.  I chose discretion over valor, and drove out there rather than deploying the bicycle which is my habitual mode of transit.  It had been several years since I have given blood, but I could hardly be surprised that there was 40 minutes of paperwork the Red Cross asked me to read and sign.  Reasons for exclusion include not just infectious diseases but travel  to many regions of the world, intravenous drug use (ever), homosexual activity (ever), cancer (ever), several congenital diseases….I started to feel nervous that they would ask whether I had been on a semi-fast for 5 days, or discover that I hadn’t had a meal in almost 22 hours.  They didn’t ask anything of the sort, and I was able to answer all the questions truthfully.  When I had trouble raising the thermometer above 96 degrees and my blood pressure read out at 85/60, they asked if this was usual for me.  I offered the excuse that ”I am a marathon runner”, which is a stretch.  

Red Cross is strict about the rules, but they really do want our blood.  So I slipped through, stretched out on the table and offered up my left arm.  The procedure itself took only 15 minutes, and went off without a problem.  No light-headedness or weakness–I got up afterward and walked out, hungry and more than ready to re-feed myself after 5 days of minimalist fare.  I might have bicycled after all.

 

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From Roscoff, with Rotifers

Roscoff is a picture-perfect coastal town in Brittany.  I have just returned from the first Monod Conference on the Comparative Biology of Aging.

Looking toward shore from the quay. My hotel is in the middle, just right of the cathedral.

Looking toward shore from the quay. My hotel is in the middle, just right of the cathedral.

The conference was opened by a theoretical lecture by Tom Kirkwood, father of the popular disposable soma theory of aging.  He admonished us that evolution is a mathematical science that yields specific and quantitative information about what aging can and cannot be.  These provide a powerful mathematical underpinning for the understanding of aging.

The next morning, Annette Baudisch told us that in reality, nature has produced every combination of aging strategy that you can imagine, and some that you probably never imagined.  The kind of aging that humans know is gradual and accelerating, leading to death on a timetable that is predictable within about 10-15%.  But this brand of aging is a small minority in nature.  There are salmon and octopuses and annual plants that reproduce in a burst and then die suddenly.  There are beetles and jellyfish that are able to “age backward”, reverting to a larval state under stress, then beginning life again with a fresh start.  Baudisch coined the term “negative senescence” for a phenomenon that is not the same thing as this:  most trees and some turtles and lobsters just grow ever larger and more fertile over decades or even centuries.  There are giant lobsters that grow to 40 pounds, and there are clams you can hold in the palm of your hand that have over 500 annual growth rings.  Each of these animals and plants grows progressively less likely to die with each passing year, year after year–hence “negative senescence”.

Charming and perfectly diplomatic, Baudisch overtly praises Kirkwood and the contributions he has made to the evolutionary science of aging; but in truth, she has produced more counter-examples to Kirkwood’s pronouncements than all of us combined. 

I was less diplomatic, and in my presentation, I ranted about the many blatant contridictions to Kirkwood’s “precise, mathematical theory”, and in big red Powerpoint letters counseled the assembled scientists, “Don’t let the mathematicians tell you how to interpret your data.”  The mathematical theory for evolution of aging is based on an early 20th Century paradigm of R. A. Fisher, in which gene frequency changes gradually while the population level and the ecology remain ever stable.  We now know that ecologies change hand-in-hand with gene frequencies, on the same time scale.  Furthermore, there are a dozen mechanisms of evolution that were unknown to Fisher, of which the simplistic equations of classical evolutionary theory takes no account:

  • Ecological interactions
  • Horizontal gene transfer
  • Epigenetic inheritance
  • Population cycles
  • Weather cycles
  • Evolvability
  • Social interactions
  • Learned behaviors
  • Phenotypic plasticity
  • Assortive mating
  • Famines
  • Epidemics

In every other subdiscipline of the bio-sciences, experiment is king, and theory is kept in its place.  This, of course, is exactly the way science should be, and especially biology, which is so complicated that theory has only a limited role.  But somehow evolutionists have carved out an exception for themselves, and when they make mathematical pronouncements that manifestly have nothing to do with the natural world, they are nevertheless taken seriously.

(Part of the problem is the illusion created by experiments in laboratory evolution.  Here the theory works beautifully.  But only in predicting outcomes of breeding, where the experimenter dictates the definition of “fitness”.  We have no way of measuring “fitness” in nature, and have every reason to  believe that it is essentially complicated, multifaceted, and completely dependent on ecological context.  I introduced an aphorism that I hope will catch on:  Nothing in evolution makes sense except in the light of ecology.”*)

* Here I am echoing a great evolutionary thinker of the mid-20th Century, who famously wrote that “Nothing in biology makes sense except in the light of evolution.

 

Worms with Hot Flashes

Researchers in the worm aging laboratory of Meng-Qiu Dong labeled an antioxidant protein with green fluorescent die, and discovered serendipdously that the worms have spots of activity that flash with frequency every few seconds, that you can visualize through a microscope, peaking around day 3 of the worms’ 20-day life span.  Investigation revealed that the mitochondria are producing the flashes, so they’ve been dubbed “mitoflashes”.  Remarkably, the frequency of flashes is correlated with the worms’ date with death two weeks down the road.  Across many different strains, genetic varieties and environmental conditions, the rate of flashes at peak predicts how long the worms are going to live.  Dong had the vision and insight to realize that this implies a longevity plan for the worms that is already in place quite early.  The mitochondria know in advance what the life span is going to be [news article in Nature].  This supports both the perspective of programmed aging, and also the theory that mitochondria act as executioners.

False color picture of young worm, showing mitochondrial hot spots.

 

Sex and the Single Rotifer

Standard evolutionary theories of aging tells us that reproduction and longevity are on a see-saw, so that whenever one goes up, the other must go down.  I don’t believe this, and for years I’ve been collecting exceptions.  My favorite is David Reznick’s guppies.  From the river pools of Trinidad, he identified two varieties of the same species:  one with high fertility and long life span, the other with low fertility and short life span.  It turns out that life span is determined not by individual competition to make as many offspring as fast as possible, but rather by adaptation to the local ecology.  Guppies are the little kids on the block, and where there are prerdators present, their death rate can be so high that selective pressures drive them to mature more quickly, swim faster, lay more eggs, and also age more slowly.  Where there are no predators, they can’t afford to be so prolific.  There isn’t enough food in the small pools to finance a population explosion, and overcrowding risks the spread of fungal and bacterial epidemics

This, of course, is group selection of a kind that mainstream evolutionary theorists still deny, as they have since 1966.  But in recent years, some prominent evolutionists [ref, ref, ref] have defected from the orthodoxy, and have caused a stir with the announcement of what every high school biologist knows in his gut:  that cooperation and competition both have a role to play in evolutionary dynamics, and much of what we see in the biosphere is the result of a tug of war between what is good for the individual and what is good for the community.

In Roscoff, I was privileged to hear Heike Guber, a talented young experimentalist from Max Planck Institute, describe her experiments with rotifers raised in tanks.  Rotifers eat algae and protozoans which they filter from the water.  In different tanks, she supplied various concentrations of food, then followed them through generations to see how they evolved.  The ones with lots of food evolved long life spans and high fertility; those with the slimmer diet evolved short life spans and low fertility.  I was saddened but not surprised to hear that she had trouble getting her results published, simply because they went against the established dogma.

Clearly, what Gruber observed is an outcome that is adaptive for stabilizing the community of rotifers.   But dogma says that evolution always seeks to maximize the reproduction of the individual, no matter what the consequence for the community.  Hence the official skepticism of her results:  if the rotifers harbor this capacity to both to produce more eggs and to live longer, then what could keep that trait from quickly rising to dominance?  (The answer, of course, is group selection; but peer review is often influenced by gatekeepers who deny the reality of group selection.)

 

What is a rotifer?

Rotifers, it turns out, are all around us.  They occupy that size regime (along with mites and nematodes) that so frequently escapes our attention: much larger than single-cell species, but still too small to see.  The oceans, every pond, every stream and many puddles are full of rotifers.  Even mossy patches in a wet forest carry rotifer populations.  Wherever there is water, they thrive; and where water is intermittent, they go into a state of suspended animation, waiting for the next rain. There are 2,200 known species of rotifer, and counting.  The largest are about 2mm long, the smallest are but a speck to the eye.

Rotifers are an important part of the freshwater zooplankton, being a major foodsource and with many species also contributing to the decomposition of soil organic matter.[ref]

photomicrograph from Wikipedia’s article on rotifers

At banquet dinner, Gruber filled me in on the sexual versatilty of rotifers.  When conditions are stable, they just clone themselves.  They lay eggs that are exact copies of the mother.  No sex.

Under stress, mother rotifers lay eggs that can also develop into females.  Females lay eggs that develop exclusively into males in the next generation.  Some of these are males, and they can mate with their own mothers or others of her generation; in this case, the eggs produced will always become female.  

To summarize: the parthenogenic form reproduces more parthenogenicists or females.  Females can reproduce as males with the exact same genome as the female.  Female + male can combine to produce another female, with genes that derive half from each parent.

Gruber also told me that a male rotifer is not so impressive a specimen as a bull or a peacock.  In fact, males are tiny tiny, only about 1/10 the size of the female of the same species.  Males cannot eat or grow.  They live for just one thing, and they don’t live very long.  They latch onto the female body and inject their sperm in any place that happens to be near at hand.  It doesn’t seem to matter; the sperms navigate through the female body, and find their way to the ovaries.     

There are more curiosities and mysteries associated with rotifers.  The bdelloid family of rotifers have no sex at all, and have not known sex for at least tens of millions of years.  Woody Allen asks why they bother to get up in the morning. Evolutionists ask, how do they manage to keep their genomes from succumbing to inexorable accumulation of deleterious mutations. (This is Mueller’s Ratchet).  

And rotifers are usually found in extended colonies.  What do they get from one another?

 

Keynote by Austad

Closing the conference was a keynote address by Steven Austad.  Austad gets along with everybody.  He is widely knowledgable, and famous for his radical common sense.  He described his induction into the field, as a grad student in the 1970s.  The central dogma of his time was that aging could be observed only in protected environments like a zoo, but that animals in nature died of other causes before they could die of old age.  But, working with an island population of opossums as a young student, Austad captured many that were old, some that were clearly very impaired and not long for this world, yet still reproducing.  

 Austad warned us that much of what we have long assumed about the biology of aging is not to be taken literally without exception; and some of it is merely persistence of myth.

 

Life spans of mammals (y axis) vs body mass (x axis) in a log-log plot

He showed us the classic log-log plot of animal size vs lifespan.  In mammals, life span rises slowly, with about the 1/4 power of an animal’s weight, which corresponds to a slope of 0.25 in the log plot.  There are outliers where animals have managed to find strategies to suppress their death rates from predators and disease.  Most birds live longer than comparably-sized mammals, and the most dramatic examples are people and bats.  

I had known that mice are outliers on the downside.  Since mice provide food for a great number of predators, and they freeze to death over the winter; their life spans are below the trend line.  What I learned from Austad is that the exceptions extend to all small rodents.  For rodents less than 8 kg, there is no correlation at all between size and life span.  No one, to my knowledge, has explained this.

The hard thing for me to hear was that, as a way to extend life, caloric restriction is far from perfectly robust and universal.  He reminded me of an experiment a few years ago with 41 diverse strains of out-crossed mice.  The mice were “recombinant inbred” = first generation crosses between different purebred strains.  Under 40% caloric restriction, about a third of these showed life extension, a third showed no significant life extension, and a third actually lived shorter when restricted.  There were more mice with shorter life spans under CR than with longer life spans!

Finally, strain-specific lifespans under CR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of CR exhibits wide variation amenable to genetic analysis. They also show that CR can shorten lifespan in inbred mice…

Strikingly, the majority of strains showed no extension of lifespan under the level of DR used in this study (Figs. 1C, D). Only 5% of the strains for males and 21% of the strains for females showed statistically significant life extension under DR (p values < 0.05)…

Of note, the longest lifespans achieved under DR did not exceed the longest achieved under AL feeding.  [ref]

Differences in life span between CR and full-feed, male (left) and female (right) strains.

Differences in life span between CR and full-feed, male (left) and female (right) strains.

 

Austad himself did a study of CR for mice captured from the wild.  

Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups. [There was] higher mortality in CR animals early in life, but lower mortality late in life.   A subset of animals may have exhibited the standard demographic response to CR in that the longestlived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents

This study demonstrated an increase in maximum life span, but not mean life span under CR.  Many people in life extension are very interested in extension of maximum life span, because, as they say, it demonstrates that the fundamental biology of aging has been affected.  I agree, but note that increase in maximum without mean life span is the nightmare we have here.  It means that the biology of aging has been affected, but not in the same direction for everyone.  There are just as many mice in this study whose life span is shortened by CR as the ones whose life span is lengthened.  This is what I find most troubling.  I once had a graduate advisor who nailed a particular human tendency when we relate ourselves to what we know about others: “Statistics are for everyone else; dumb luck for me.”

As in his past work, Austad offers so much useful good sense in his keynote…And yet he clings to a view that aging is driven by an accumulation of damage, that it can be slowed but never reversed, that there are no genetic mechanisms that have evolved solely for the purpose of assuring a fixed (shorter) life span.  The three points are related but not identical.  Curiously the idea that damage is the root of aging is not the influence of evolutionary theorists, but far older, rooted in ancient concepts of impermanence.  

I have written an academic article [ref] and two blog posts [one, two] in opposition to “wear and tear” theories, and devoted a chapter of my forthcoming book to the subject.  It is the most common misconception in the field that aging in biological organisms is akin to physical wear and chemical entropy, and that it has something to do with the Second Law of Thermodynamics.  

I know it is theoretically possible, and hope that it will prove generally true in practice, that the body knows how to repair all the important kinds of damage that accrue in aging, and is capable of restoring itself to a youthful state, given the appropriate signaling environment.

Austad’s present research is based on the observation that misfolded proteins tend to accumulate in our cells, and are related to dysfunction and disease, most prominently Alzheimer’s.  Long-lived varieties need to keep proteins in the right conformation, with “chaperone” molecules that are particularly effective.  Austad is isolating and transplanting some of these chaperone molecules from his menagerie of 500-year-old clams.

Despite differences in theoretical perspective, I have found the community of aging biologists to be especially personable and gracious.  I have known Austad and Kirkwood in the deep past,  and Baudisch more recently because she belongs to the next generation.  Before I had any reputation or credibility in the field, all of them responded to me personally and respectfully.  The most promising thing to come out of the meeting for me personally is that I told Austad privately of my idea to test hundreds of combinations of life extension treatments, in order to learn how they interact (see my blog from last month).  He told me about an NIA program that evaluates proposals for experiments with mice, deadline later this year.  The program is not terribly oversubscribed because it offers no funding to the winning proposals; however winning proposals will be assigned each to three separate mouse labs around the country that will replicate the experimental design in triplicate.  I’m pumped!

Privately, Austad also told me that a previous winner had proposed combining rapamycin with metformin and the test was successful.  In yet unpublished results from three labs, the combination of metformin and rapamycin extends mouse life span more than the sum of the benefits from the two separate treatments.  

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