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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Anti-Aging Pills in the News

Last week Len Guarente announced his company will be selling a proprietary formula based on NR, the NADH precursor.  This week, there’s an article about a project at Novartis to make a safe anti-aging pill from rapamycin.  I’m more excited by the latter than the former.

drawing by Maddy Ballard

drawing by Maddy Ballard

 

An MIT Lab offers NADH plus Blueberries

Several readers have asked my comments on the Guarente formula, being sold through Elysium Health.  Len Guarente is a solid, innovative scientist who has contributed a lot to our field and trained several students who went on to make substantial contributions of their own.  He’s also an honest guy, with his heart in the right place.

The formula he plans to sell consists of Nicotinamide Riboside and pterostilbene.  I wrote about NR a in November.  I’m not convinced.  It’s just too easy to extend life span in worms and flies–much more difficult in mice and people.  I have see no data on NR and life span in mice.  The most promising results I have seen show that NR slows progression of Alzheimer’s Disease in mice that are genetically engineered to be susceptible to AD [ref].

Pterostilbene has a chemical structure similar to resveratrol, and it is thought to be one of the beneficial components in blueberries.

Pterostilbene shows the same kind of benefit as NR in the mouse model of Alzheimer’s [ref], but it does not extend life span of outbred mice [ref].

The press release about the Elysium product claims that there is an expected synergy between NADH and pterostilbene.  Len knows a lot more than I do about genetics and biochemistry, and I’m inclined to give him the benefit of the doubt.  But I don’t think that theory about the biochemistry of aging is in any shape that we should rely on it without direct evidence, and I look for that evidence in mammals.

 

Rapamycin from Novartis

There’s an article from Bloomberg today about research at Novartis toward an anti-aging drug based on rapamycin.  Rapamycin has the opposite issues from the Elysium product.  It works great extending life span in rodents, but it is a powerful drug that may have too many side effects to be considered for general use by people who aren’t sick.  It’s also prohibitively expensive for most of us, though it is not as difficult to get as it was a few years ago when the dramatic effect on mice was first announced in Nature.

The reason rapamycin is scary is that its primary use is as a powerful immune suppressant, preventing rejection by people who are receiving organ transplants.  If rapamycin makes the immune system tolerates someone else’s kidney (so the reasoning goes), what else will it tolerate?  Cancer cells?  Invading viruses?  Herpes?  The Bloomberg article hints that rapamycin may be more selective than that, and there is at least one study which seems to show that a drug acting on the Target of Rapamycin (TOR) can enhance the immune response as well as suppressing it.

Novartis is not trying to market rapamycin, but to look for variants that might have the same benefit without the side effects.

The article mentions Mikhail Blagosklonny as a prominent researcher who has enough faith in rapamycin to take it himself. He has written an article making the case that it acts directly on the core of the aging metabolism. It really does slow aging.

“Some people ask me, is it dangerous to take rapamycin?” Blagosklonny says. “It’s more dangerous to not take rapamycin than to overeat, smoke, and drive without belt, taken together.”

For counterpoint, the Bloomberg article quotes Valter Longo,

“Rapamycin works on pathways that are too fundamental to normal cellular function to be used as a drug in healthy people until we have much more safety data,” says Valter Longo, a professor at the University of Southern California who discovered key pathways related to TOR. He points out that periodic fasting also shuts down the same pathways, without the side effects.

This same Bloomberg article mentions a claim by Brian Kennedy that metformin lowers mortality in diabetics so well that it’s actually 15% below mortality rates in age-matched non-diabetics [ref].  This is a remarkable finding, the best we can hope for, since there are no long-term data on effects of metformin for people who are not diabetic. It contradicts several meta-studies [ref, ref] that find no net mortality benefit for metformin.  (I think that the balance of evidence favors metformin, and I take it myself. If you are overweight or leaning to high blood sugar, you might consider it.)

 

The Bottom Line

We are at a stage in the science where there is much promise and little certainty.  How do we decide when to take a chance and what to take a chance on?  All the scientific data are still only half the input; the other half is in each of us as individuals.  There is a reason there is so much scatter in the statistics, and even inconsistency from one study to the next.  We are all unique individuals, both in how our metabolisms respond to drugs, and in what we want out of life.  We may try to choose a strategy for the long haul, but if a treatment helps us feel more energetic or more alive or better balanced in the short run, that is and should be a part of the choice that we make.  I have written about my experience with low-dose deprenyl, which I take for life extension, but which also loosens my inhibitions a bit in a way that I appreciate.

A part of the calculus which is rarely discussed is our stage in life.  The older we are (and the worse our health), the more inclined to take a risk on some treatment that may be our last best hope.  I am 65 and can still hike all day, but I may have run my last marathon.  I attend to the changes in my body from year to year, and I am willing to take some risks to slow down the loss.  My friend, Stan, still works long hours at two psychiatry clinics at 86, and dances on the weekends.  He is more willing than I to take a flier on a new idea.  I hear rumors about 90-year-old tycoons who…but they are only rumors.

I am saddened when a prominent member of the anti-aging community consents to request for treatment with Lupron by his 12-year-old son.  Lupron blocks testosterone and delays puberty.  The boy should know that he will have far better options for a long and healthy life as science continues to progress.  I tell my daughters, in their 20s, to take good care of themselves and plan for a life of 200 years.  In the near future, aging may no longer be the dominant risk to our health and wellbeing. I am more confident that tomorrow’s technology will be there to delay aging for our children than I am in our collective ability to deliver to them intact ecosystems that support human life.


 

Visomitin Eye Drops — a Personal Follow-up

Last year, I wrote about a product developed by Vladimir Skulachev, veteran biochemist at Moscow State University, that targets Coenzyme Q to the mitochondria.  It is available as eye drops, which in lab studies have brought horses and dogs back from the brink of blindness. (A closely-related molecule is available in pill form and as a cosmetic from Mito-Q, New Zealand.)

I have been taking Visomitin eye drops for a year and a half, and had an eye exam at the start of this period, and again this week.  Results of the two eye exams were just about the same. Perhaps the beginnings of yellowing of the lens, an early stage of cataracts.  I am fortunate to have eyes that focus well at mid-range (slightly myopic), so I still am comfortable without glasses most of the time.  But over this year, I noticed that there are more times when I reach for reading glasses.

If any readers have personal experiences to share with Visomitin, with Metformin or with Rapamycin, I hope you will comment below.

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Do we really need epidemiology to tell us to get off our duffs?

The meme we hear in the news is that sedentary time, time spent sitting, is bad for us. I started out researching this week’s blog on inactivity, and ended up thinking about how to keep aspirations high and stay engaged with community.

Last week, the largest meta-analysis to date of inactivity was reported in the popular science press [for example]. The message is that even for people who exercise vigorously for part of each day, sitting still for long periods during the rest of the day poses an independent health risk. I found that evidence for this interpretation is weak. There is stronger evidence for the harm caused by sedentary behavior at the other end of the spectrum, for people who get little or no exercise.

I’ve been thinking about what that means, how “inactivity” is measured, and what we can do to avoid it.  I’m leaning toward the conclusion that getting up and moving frequently is good for us as part of a general program to avoid tunnel vision, to improve well-being and creativity even though the “independent mortality risk” is likely to be lost in the noise.

For people who don’t exercise at all, David Alter and colleagues at U of Toronto found a significant 46% additional mortality risk from too much time spent sitting.  But combining the statistical power of 41 separate studies, they found only an insignificant 16% added mortality risk for those with a vigorous exercise program.  In context 16% is not a lot–and here it was not statistically distinguishable from zero.  The failure of statistical significance in this case is not for lack of numbers, but because the different studies produced inconsistent results.

The reason 16% must be regarded as small is that all the different studies attempted to extract information about sedentary behavior from a diverse group of people who differed in many other ways. The statistical tool for separating out different causal factors is called “multivariate regression,” and it works reliably with 2 or 3 variables, but beyond this number, the statistical power is overwhelmed by the exponentially growing number of ways in which the different variables can interact.

Here’s what I mean (applied to the present case): All the studies here compiled were seeking information about time spent sitting, and how it might contribute to risk of mortality and disease. But the people being interviewed differed in many other ways as well, ways which had far more powerful effects on mortality risk than the time spent sitting. So for the study to produce meaningful results, it must disentangle such things as diet, obesity, exercise, family and social support, depression, and psychological passivity.

The researchers aren’t so dumb, so each of the studies that are included in this meta-analysis controls for just 2 or 3 other variables.  But these variables differ from one study to the next, making it hard for Alter and his team to draw meaningful generalizations.

Almost all these studies rely on self-reporting, which is notoriously inaccurate.  People are reluctant to admit how passive they are, and they are likely to be dishonest with themselves, let alone an anonymous researcher. The “good” response was supposed to be when people report less than 8 hours of sitting in a day. But what does this mean in a culture where our “society is engineered, physically and socially, to be sitting-centric.” [quote ref] Are these people who have jobs as sales clerks where they are on their feet all day, as opposed to desk jobs? Or are they just failing to mentally aggregate the time spent in a car, at a desk, at the kitchen table, and in front of the TV?

Translating the results into behavior change recommendations is also problematic.  The most obvious and frequently-recommended remedy is to get up from sitting, say once or twice in an hour, for some activity that gets the blood flowing.  But exactly none of the studies compared people who do this with people who sit through without getting up.  The questionnaires only asked about total time spent sitting.  We must take it on faith that briefly interrupting the sedentary period has benefits out of proportion to the time invested.

Though this is an article of faith (or theory – which is but another name for faith), I’m inclined to extend my faith in this direction.  In my own experience, while I’m reading or writing, I’m either pleasantly engaged in what I’m doing, or I’m in a stupor.  Either way, getting up to do something vigorous for a few minutes doesn’t seem at all appealing. But when I make the effort, it almost always invigorates me.  I come back, not just more alert, but often with a fresh idea or a change in my reference frame.

So I recommend taking 1 minute out of each hour for vigorous exercise, though I admit to finding this difficult myself. Getting up to think and walk is also something I can recommend from personal experience. The treadmill desk is something with which I have only vicarious experience.

 

Physical Passivity and Mental Passivity

About a third of the studies asked not about “time spent sitting” but about “time watching TV”.  In fact, TV has proven to be a robust predictor of mortality, with a clearer signal than the current emphasis on “sitting”.  Among the many studies in Alter’s meta-analysis, some of the largest effects came from those designed to study TV time, not sitting time.

Is there a difference between sitting behind a desk writing poetry, and sitting in front of a TV watching a program you don’t particularly like?  Emotional factors in mortality risk are huge, and depression is right up there.  Those who feel helpless and hopeless have far higher mortality risk than those who feel empowered, useful, and pro-active in their daily lives.

Watching TV brings on a dead state of mind for many people in our culture, who are numb while being passively entertained.  The relative risk for TV watching is far higher than the general risk of “sedentary behavior.” [ref].  Is mental passivity even worse than physical passivity?

In epidemiology and longevity studies, we have paid more attention to physilogical than to psychological variables, but psychology is at least as important. What is more, the physical and the mental are often difficult to disentangle, and there are other reasons to pay attention to the state of our wellbeing and empowerment and general satisfaction with life, even if there weren’t huge longevity benefits.

Depression is a huge risk factor for mortality–larger than obesity and sedentary life style combined.  Depression raises the risk of mortality by a factor of 3.1 for men, 1.7 for women [ref, ref].  For comparison, obesity (BMI>35) increases mortality by a factor 1.3 [ref]. Lack of exercise is associated with a similar risk factor of 1.3 in men and 1.4 in women [ref].

What is depression? I invite your comments on the subject.  I am convinced that depression is more a cultural than a psychological disease.  There are some countries in which depression is virtually unknown.  I think of depression as a lack of affect, a helplessness and detachment, a feeling that nothing I can do matters.  I imagine that the state of the American economy and politics contribute to feelings of isolation, disempowerment and hopelessness.

There is “clinical”, incapacitating depression that has afflicted people close to me.  Less extreme, there is walking through life like a zombie, afraid to feel and to act, unmotivated to change, unsure that anything that we do matters.  I have been there.  Closer to “normal” on the continuum, there is a general damping of the sense of wonder and zest for life that are our birthright.  Leaving this birthright behind, or at least putting it aside, seems to be a pre-condition for normal participation in work and social activities, (especially for white folks).  A video from The Onion helps me laugh about it.

From sedentary to television, from television to depression, from depression to powerlessness–these connections are my own, and I can’t claim the authority of science.  But I think they’re legitimate parts of the discussion if we’re looking for solutions that offer us more fulfilling lives on the way to health and longevity.  I welcome your perspectives in the comment section.

 

It doesn’t matter if I’m feeling blah,
just so long as I’m not clinically depressed

Many of us in Western capitalist cultures not only have vague feelings of powerlessness, but we tend to feel powerless about our powerlessness.  We don’t want to think about it because there would seem to be nothing we can do about it. We don’t want to be stigmatized as a whiner, let alone as a psychiatric patient.

But the excesses of capitalism and the humdrum lives into which we are forced by economic conditions have profound effects on our wellbeing and also our longevity.  In other words, it’s not just that clinical depression has a huge effect on your health; the “subclinical” version that is so familiar to most of us is also harmful.  This is an understudied effect, because sublinical depression is the norm–what do you measure it against?  This week, another study from U of Toronto gave us a hint at how the subject can be approached.

Researchers have linked positive emotions–especially the awe we feel when touched by the beauty of nature, art and spirituality–with lower levels of pro-inflammatory cytokines, which are proteins that signal the immune system to work harder.

“Our findings demonstrate that positive emotions are associated with the markers of good health,” said Jennifer Stellar, a postdoctoral researcher at the University of Toronto and lead author of the study, which she conducted while at UC Berkeley. [Science Daily]

Interpolating between studies of depression and studies of inspired joy, I think there’s probably a continuum of psychological effect on health and longevity.

Elissa Epel shows us that feeling stuck in circumstances beyond our control accelerates aging of our telomeres, while meditation elongates telomeres.

I offer this in the spirit of an invitation, not an accusation: How many times have you experienced awe and wonder this week?  Why is it uncomfortable to even think about this question?  Why do we shrink from a perspective on life that may be expansively beautiful, but which interferes with our ability to play our familiar roles?

Can you be a better friend to yourself?

 

The Bottom Line

Your exercise program may be the most important factor for your mental health.

Get up and move because it interrupts your routine and encourages creativity, because it helps you feel empowered and connected.

Get your legs up in the air.  Renew the blood flow to your brain, and turn your habitual perspective on its head.

It’s reasonable to expect more from life than relief from depression and suffering.  Dare to reach for inspired joy.  Your life is an experiment.

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MYC: Bad and Good, but More Bad than Good

MYC is the name of a gene that promotes cancer.  We’ve known this since the 1970s.  Trouble is, MYC is also necessary for growth, so we can’t eliminate it, and we’ve been very careful about targeting targeting MYC for inhibition, except in the extreme case of cancer patients.  That’s why we didn’t learn until last week that mice with half as much MYC live longer and seem healthier in every way.

The standard theory of why we age is called “Antagonistic Pleiotropy”, a fancy way of saying that nature has been forced to compromise.  Natural selection rewards long life, it is true, but also rewards rapid growth and high fertility.  It is genes like MYC that force nature into a kind of devil’s bargain, accepting a cancer risk (and a shorter life) as a necessary concomitant of growth and fertility.

This idea was a gift of George Williams [1957], last week’s featured celeb here at Aging Matters, and for more than 50 years it has been so well-established that scientists presume–not just evolutionary scientists, but also clinicians and medical researchers presume that nature has done her best by us, and we oughtn’t to tamper with the mix of genes that Nature has bequeathed us.

Inserting or deleting a gene has become so routine in thousands of research labs around the world that it is only surprising it has taken so long before researchers at Brown University prepared mice with one parental copy of the MYC gene missing, and the second intact.  Last week they reported that the mice lived longer, were less susceptible to cancer, were more active, had healthier blood lipid profiles, and their immune function remained stronger, longer.  Heart muscles stayed more pliable, and cholesterol buildups occurred later.  The mice died of the same cancers as normal lab mice, but later.  (Mice missing both copies of MYC are not viable.)

Most interventions that extend life span in mice work by dialing up the stress response system.  This is the mechanism of hormesis, a beneficial over-compensation to stress.  Caloric restriction is the most common and most consistent way to activate this pathway.  So it is interesting to note that the mice with reduced MYC did not have increased stress response, nor did they eat less than normal mice.  This suggests that the life extension benefit of reduced MYC might be able to synergize with caloric restriction to offer additive benefit.

Many anti-aging measures have tradeoffs. Mice given rapamycin, for instance, have increased cardiovascular disease risk and reduced immune function. In contrast, mice with reduced MYC showed no obvious health problems and were able to reproduce normally. [ref]

Life span was extended 20% for females, 10% for males.  This, too, is unusual, in that, where there is a difference, other interventions commonly extend male life span more readily than female.

MYC is a “transcription factor”, which means it acts by turning other genes on and off.  In fact, MYC is one of the most powerful, broad-action transcription factors, with effects on the activities of thousands of other genes.  One hint about the mechanism of action is that reduced MYC leads to less active ribosomes, the organelles in which proteins are transcribed.  MYC+/- animals have less of every kind of protein, and it is no longer surprising that this leads to extended life span.

MYC has been identified in the past as an intermediary that is necessary to help turn on telomerase activity in response to caloric restriction and mimetics (drugs that act like CR).  The Brown team was encouraged to report that mice with half their MYC missing did not lack for telomerase.

 

What can be done for people who are unfortunate to have been born already with two copies of the MYC gene?

That MYC is overexpressed in cancer cells has been known a long time.  Much of the work on MYC and how to turn it off has been done in the course of a search for effective  cancer treatments.  Peter Vogt’s lab at Scripps Inst in La Jolla has led this charge.  They have searched through thousands of small molecules, looking for chemicals that “turn off” MYC or interfere with its actions.  Here is a paper that catalogs dozens of small molecules that have been studied for their ability to either stop MYC from being transcribed or inhibit the MYC protein from acting.  I was amused to note that the standard notion of a “small” molecule extends to include a great deal of complexity.  The standard for “small” is scaled by protein macromolecules that are fold from thousands of chained amino acids.

MYC-inhibitors

But the abundance of candidate molecules isn’t necessarily good news.  It means that researchers have followed a well-worn path and pursued many candidate drugs, all with limited success for one reason or another.

It is rare to discover death genes, pure and simple–genes that have no other purpose than to kill us.  Such genes are known (or suspected) in worms [ref] but not humans.  But the list of genes that have been co-opted for programmed death is substantial.  I have reported some here last year: TOR, NFk-B, IGF-1, wnt etc.  These genes are over-expressed, especially in old age, with consequences that are purely detrimental.  They make attractive targets for anti-aging therapy.

In other words, death on a schedule is programmed into our genes, but not with specific “time bomb” genes.  Rather, the program works by co-opting genes that have other uses early in life, but that are deployed for the purpose of self-destruction late in life. The classic example is inflammation, which is an important mechanism of defense, but which is loosed upon healthy cells, causing cancer and dementia late in life.

So MYC is one of those genes without which we can’t live and grow, but late in life it slips its leash and causes great damage.  It might serve us well to keep MYC under tighter control, if we can find a practical means to do so.

 


 

I am grateful for this and many ideas to Reason over at FightAging! web site and newsletter.  Week after week, he does a superb job of collecting and summarizing news and research in the field of anti-aging medicine. His viewpoint is a bit more mainstream than my own.* Readers of this page may be interested in subscribing.

In addition to MYC, this week’s newsletter also includes

———-

* Where he sees damage that the body suffers despite its best efforts to resist, I see epigenetically progammed self-destruction.

 

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Programmed Death, H. pylori, and the Legacy of George Williams

Last month, an NYU Med School doc published an article saying that our gut bacteria might be evolved to promote our digestion when we’re young, but kill us when we’re old.  This sounds like evolutionarily programmed death–just the kind of thesis that I have been promoting for 18 years.  The article was picked up by Scientific American, Psychology Today, Science News, and Eurekalart of the AAAS.  Why am I not cheering?


In 1966, a smart, confident young biologist named George Willliams wrote a book that changed the culture and methods of evolutionary biology.  Up until that time, evolutionary biology had been primarily a qualitative, observational science, in the tradition of Darwin.  (There is not a single equation in any of Darwin’s books.)  Practitioners had absorbed the message that natural selection was about gaining an advantage in survival or reproduction, and this was the lens through which they looked at biological function and behaviors.  When they found a subtle or unexpected advantage of this sort, evolutionary biologists were excited to report a new understanding of a phenomenon which perhaps had not made sense hitherto. This was wishy-washy, 19th Century science.

But on a parallel track, having almost no communication with the field biologists, there were a handful of evolutionary geeks–scientists who were trained in mathematics or physics, and who took up evolution in the same spirit, using methods borrowed from theoretical physics.  In the early 20th Century there were Alfred Lotka and R. A. Fisher and Sewall Wright, and in the mid-century there was J. B. S. Haldane and Theodosius Dobzhansky (just to pronounce his name makes you fitter) and Wright just kept on keeping on, writing and researching until his death at age 98.  These men had developed a quantitative science of evolution called “the new synthesis” or “neo-Darwinism” or “population genetics”, but their numbers were few and they tended to think abstractly, without a deep knowledge of biology in all its messiness, and so their influence on the larger biological community was quite limited.

Williams’s book heralded the merging of these two spheres of evolutionary science.

Williams was a biologist through and through, who earned his degree working with real fish in real habitats.  But at a young age, he had also deeply absorbed the methhods and disciplines of the geeks. With a book boldly titled Adaptation and Natural Selection, he challenged his fellow evolutionists to

  • think quantitatively about evolution, and
  • think about the actual mechanisms by which an adaptation might evolve.

These were much needed disciplines, and Williams had the commanding, incisive writing style to bring his point home to a community that had become accustomed to field biology as a descriptive science.

But these are also difficult disciplines, requiring a fundamental shift in the thought process.  As it happened, Williams’s message in Adaptation was caricatured, and for decades after the publication, it came to be transmitted to students of evolution in the Orwellian form,

“Individual selection, good; Group selection, bad.”

To be sure, Williams was not innocent of this message; nevertheless, his thinking was a lot more cogent and more comprehensive than the sound bytes that came to be transmitted in his name.  The book was written as an appeal for more rigor in Williams’s colleagues.  The part of his argument that survived concerned only group selection, and it went something like this:

Every new trait that appears begins life as a random mutation in one individual.  If the mutation promotes survival or reproduction, it will spread through the population, otherwise it will gradually die out.

Suppose a mutation arises that is bad for the individual’s fitness, but offers a benefit to the community.  (This is the definition of evolutionary altruism.) In theory, this trait might help a group to compete successfully against other groups that did not have the trait.  But its first hurdle must be that it must come to dominate the group.  But every individual who carries the trait is at a disadvantage compared to other individuals in the group.  So the new gene faces an uphill battle in its first step, and it is likely never to get to the next step, where it can show its stuff in group-against-group competition.

Therefore altruistic traits are unlikely to survive natural selection.

(not a quote–this is my paraphrase)

This is a well-reasoned argument, worthy of attention and consideration, but it is not the end of the story.  The argument is rooted in the mechanism of the Selfish Gene Model, which assumes that

  • evolution works one-gene-at-a-time,
  • genes contribute independently to fitness,
  • populations are thoroughly mixed (random mating)
  • genes rise and fall in a population quickly, while the population size (and everything else about the environment) changes slowly

When we write these assumptions out explicitly, it’s clear that sometimes they are true, and sometimes not.  Sometimes the Selfish Gene model does fine, and sometimes a more complex and sophisticated model is called for.

If we take to heart Williams’s deeper message, then when we find traits in nature that look like altruism, we should consider all mechanisms by which it might have evolved, evaluate them quantitatively, and decide on the most plausible evolutionary explanation.

 

If things had developed as they should…

It was right, of course, that the field biologists and the evolution geeks should talk to each other.  They purported to be studying the same subject.  But what should have happened (in my couterfactual history) when the biologists first compared notes with the mathematicians is that the biologists should have had the upper hand.  “Here’s where your theory works–here’s where it doesn’t.  Go back to the drawing board and give us a more complete theory that explains what we see.”  We might have arrived at an understanding of the usefulness of the Selfish Gene, and also its limitations.  Whenever there is a conflict between theory and observation, it is theory that must bend.

But in real life, this is not what happened.  In real life, the mathematicians were smart and brash, and the field biologists were more tentative, nuanced in their understanding, a little embarrassed about the contradictions in their findings, and easily intimidated by formulas.  All too often, the mathematicians simply told the field biologists they were wrong, that they were not seeing what they thought they were seeing, that theory forbids it.

The theory they invoked was the simplistic Selfish Gene theory, because this was a time before computer models, before the ideas of evolutionary ecology had a platform for development.  Theorists did not keep in mind that the Selfish Gene model was just a model, and they insisted that it must explain everything.

The message of George Williams survived mostly in its caricatured form.  The rigor he required proved to be too demanding for biologists, and two generations of evolutionists took the shortcut of affording credence to any explanation that looked to be based on individual benefit, and dismissed any explanation based in group selection.

So this became the era of the Selfish Gene, which is just now winding down, and an appreciation of Williams’s true message is finally spreading through the community.

 

Gut Bacteria and Programmed Death–What does the article say?

We circle back now and consider the article by Martin Blaser, microbiologist at NYU, and Glenn Webb, who does computer modeling of biological populations at Vanderbilt.  The failed revolution of George Williams sets a stage for all that is effective and all that is missing in Blaser & Webb’s analysis.

The age structure of human populations is exceptional among animal species. Unlike with most species, human juvenility is extremely extended, and death is not coincident with the end of the reproductive period. We examine the age structure of early humans with models that reveal an extraordinary balance of human fertility and mortality. We hypothesize that the age structure of early humans was maintained by mechanisms incorporating the programmed death of senescent individuals, including by means of interactions with their indigenous microorganisms. First, before and during reproductive life, there was selection for microbes that preserve host function through regulation of energy homeostasis, promotion of fecundity, and defense against competing high-grade pathogens. Second, we hypothesize that after reproductive life, there was selection for organisms that contribute to host demise. While deleterious to the individual, the presence of such interplay may be salutary for the overall host population in terms of resource utilization, resistance to periodic diminutions in the food supply, and epidemics due to high-grade pathogens.

In particular, they cite H. pylori (famous for its connection to ulcers) as example of a bacterial strain that promotes digestion and good health for young humans, but that can lead to cancer of the stomach or esophagus late in life.  Perhaps this bacteria serves the function of removing from the population older individuals who are no longer fertile, so that they are consuming scarce food, though they are unable to contribute to the reproductive rate that keeps the community viable.

I find the thesis unclear on several different levels.

  • What is evolving here, the genome of the bacteria or of the humans?
  • What is the mechanism by which intestinal bacteria spread through a community?
  • What measure of fitness is applied in the model, and is it the fitness of the bacteria or of the humans?

To the credit of these authors, they do not categorically dismiss group selection or programmed aging from consideration.  In fact, they claim in the paper’s Introduction to explicitly consider both.  But I’ve had a devil of a time trying to figure out how their model works, let alone how it answers the standard broadsides against group selection and programmed aging.  I find myself agreeing with Williams in his appeal for clarity and rigor.

 

Cui bono?

“Who profits?”  The title of the paper is Host Demise as a Beneficial Function of Indigenous Microbiota in Human Hosts, but whose benefit are they talking about?  Certainly not the individual human who dies or esophageal cancer, nor the gut bacteria that die with him and relinquish their opportunity to be transmitted human-to-human.

The root of the unclarity is that our understanding of the relationship between gut bacteria and the host human is still quite hazy.  There is enormous variability from one person to the next in the type and variety of gut bacteria.  There are benefits to the host human from some combinations, and diseases that come from others.  But it seems that there is no one optimal bacterial community that is right for everyone, but rather that the interactions among an individual’s metabolism, his environment, his diet, and his bacterial community form a complex system.

Do the bacteria in our guts serve at the pleasure of the host (that’s us), or are they opportunistic invaders?  These are major open questions in the field of microbiology. The answer seems to be “neither”, and the ecology of each person’s bacterial community has an integrity and a logic all its own.

Mammals harbour a complex gut microbiome, comprising bacteria that confer immunological, metabolic and neurological benefits. Despite advances in sequence-based microbial profiling and myriad studies defining microbiome composition during health and disease, little is known about the molecular processes used by symbiotic bacteria to stably colonize the gastrointestinal tract…the gut normally contains hundreds of bacterial species… [Ref]

It has been a central thesis of my own work that entire ecosystems evolve together.  The present example is as strong a case as I can imagine.  Each bacterial species much be able to hold its own in the gut ecosystem, and the entire colony must serve the digestive needs of the individual human host, because if the host dies he takes the bacterial colony with him.

There is a great deal of selfishness and a great deal of cooperation involved in this dynamic, in a mixture that cannot easily be disentangled.  Suppose it is in the interest of the human community to eliminate its non-reproducing elders, but if the H pylori kill their host, then they are missing out on the opportunity to continue spreading from this one individual to others, perhaps younger family members who are sharing food.  I look for this issue to be discussed in the paper, and I don’t find it.

Indigenous microbial populations that contribute to the health not only of the individual but also of the host group will be most strongly selected…If indigenous organisms contribute to programmed host death in senescent individuals but not to the death of reproductively active individuals, there may be selection for their maintenance.

Yes, “there may be selection”…but at what level, and by what mechanism?  My guess is that indivdual selection for each bacterial strain and for the human host are all important, and that the communal function of the bacterial colony is also essential, as is the welfare of the human community, and all combinations of interactions among these.

Leslie Matrices

This is simply a linear model for projecting the population age distribution from one year to the next.  If you have this many 1-year-olds this year, then next year, this many of them will die, and the rest will be 2-year-olds.  If you have this many 2-year-olds…, etc.  If you have this many women of child-bearing age in the population, then this is how many newborns you can expect in the coming year…

This is a standard model for calculating population dynamics, (introduced by Patrick Leslie, 1945).  It is the model used by Glenn Webb in the current paper.  But missing from this model is the dynamic of population overshoot, followed by famine.  This is at once the gravest and most ordinary danger to any population, and the one that (in my view) aging was evolved to defend against.  So I worry that Blaser and Webb have left out something important.

 

Loss of Fertility and Loss of Life  
(or reproductive senescence and mortality acceleration)

In many animals (including us) there are two independent aspects of aging:

  • loss of fertility, leading to sterility
  • loss of strength, viability and robustness, leading to death

It is a prediction of classical evolutionary theory that these two should occur at the same time.  Why should an individual go on living after it is no longer able to reproduce?  It can be of no use either to itself or its community.  But in the biosophere, we find this prediction is routinely violated.

Of course, human females undergo menopause, and can live for decades thereafter. For theoretical reasons, post-reproductive life span has been thought to be unique to humans, or perhaps a few other social mammals that take care of their grandchildren.

But field studies show that this isn’t true.  In fact post-reproductive life is widespread in nature–perhaps it is the rule rather than the exception.  C elegans worms don’t take care of their grandchildren, nor do quails or yeast cells; yet all of these have been observed to outlive their fertility.  Add whales, elephants, opossums, parakeets and guppies to the list as well.

How to understand post-reproductive life span is a topic for another week, but Charles Goodnight and I have written about the subject (in journalese) here.

 

Precedents missed

In addition to this, there is another paper I suggest that Blaser and Webb might have benefited from assimilating.

Once fertility has ended, there is a natural selection to kill the non-reproducing individual, because it is consuming food, taking up space in the niche without contributing to sustaining the community.  This idea goes back to Weismann 120 years ago, but in modern times it has been modeled and explained most thoroughly by my colleague, Justin Travis.

 Curiously, there is also a communal reason to keep the post-reproductive members alive for awhile, in a weakened state, assuming that community has excess reproductive capacity.  The post-reproductive segment of the population serves as a buffer to prevent population overshoot and whip-sawing that can lead to extinction.  They consumes food when there is plenty, and thus they help keep the population from growing too fast.  Then, when food is scarce, they are the first to die because they are old and weak.  This is the idea that Goodnight and I modeled and published (2012).

 

The bottom line

For me, the upshot is that I don’t understand enough of how their model works to judge whether they are on to something.  I’m tempted to add that computer modeling of aging is my specialty field, and if I can’t understand their model, for whom are they writing?

In controversial fields like this, where there has been so much confusion and misunderstanding, it behooves us all to be extra careful to follow Williams’s directives: think (and write) in terms of explicit mechanisms of heredity and selection.

Most readers of this work are already pre-disposed to pre-emptively dismiss the ideas of programmed aging and group selection.  Let’s not give them an excuse to do that.

 

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What is Aging? Most Scientists Still Get it Wrong

Most people misunderstand what aging is.  It’s not just the public who have been deceived — Most scientists and medical researchers who study aging are on the wrong track.

The culprit is the “natural medicine” movement that has dominated thinking about our bodies for the last 50 years.  “Respect the body’s wisdom.  Work with the body to fix what has gone wrong.”  This approach has worked so well with injuries and many diseases that it is understandable that people want to extend it to aging as well.

Diseases of aging have been treated as if they were something that goes wrong, something we have to help the body to fix.  But in fact, the evidence accumulating in recent decades is that aging is not something that goes wrong, and the body is not trying to fix it.  Aging is natural.  It is the body shutting itself down, putting itself out of the way after it has done its job, finished reproduction.

How do we know that aging is an active process of self-destruction, and not just the body “wearing out”?  There are a number of indications, becoming clearer all the time.

  • For one thing, if the body were trying its best to keep in good shape, but can’t help wearing out over time, we would expect that damage to the body makes aging happen faster.  On the contrary, most kinds of external damage actually make us live longer.  The best example is exercise, which generates free radicals like crazy, tears muscles and puts little cracks in our bones.  And yet, people who exercise tend to be healther and live longer than others who don’t.  Starvation is also a way to live longer.  Animals in the lab that are kept on very low calorie diets live much longer than those that have enough to eat.  This is a clear indication that the bodies that get plenty to eat aren’t really trying to live a long time.
     
  • If the body were doing its best to forestall aging, but succumbing eventually to wear-and-tear, we would expect that as we get older the repair functions would be going full-tilt.  But in fact, all our repair and protection systems gradually shut down as we age.  Stem cells, which produce new body tissues, gradually stop working.  And the anti-oxidants that protect us from chemical damage are dialed down in old age, so we don’t have enough of such enzymes as CoQ10, SOD and glutathione.
     
  • Clearest of all: there are actually self-destruction mechanisms that we can see in action.  One of them is inflammation.  When we are young, inflammation protects us from invading microbes, and kills diseased cells; but when we get old, inflammation is dialed up much too high; it kills healthy cells, inflames our arties, leading to heart disease, and inflammation causes cancer as well.  Another mechanism we can see in action is called apoptosis, or cell suicide.  When we are young, only cells that are diseased or defective remove themselves via apoptosis; but when we are old, healthy muscle and nerve cells simply fall on their swords and die, leading to weakness of muscle, weakness of mind and Parkinson’s disease.

This explains why “natural medicine” has been so helpful for infectious diseases, immune function and response to trauma, but in stark contrast natural medicine has failed to make headway against cancer and Alzheimer’s disease, and has made only marginal progress against heart disease and stroke.

For these diseases of old age, we need to abandon the natural approach, and instead simply trick the body into thinking that it is younger.  Then it won’t try to shut itself down.

In fact there are some intriguing indications that this might work.  There are researchers working with this approach and they have produced some dramatic successes just in the last few years:

  • Every chromosome in every cell contains a time-keeper, tacked onto the tail end of the DNA.  This is the “telomere”.  Simply by resetting the telomere clock, scientists have produced dramatic results in lab animals, reversing aging and making animals younger.
  • When the telomere clock signals a critical age, the cell becomes “senescent”.  It goes and strike and refuses to do its job.  Worse yet, it sends signals to nearby cells that cause the other cells to become inflamed and cancerous.   Recently, scientists have had remarkable success making mice live longer simply by removing the small number of senescent cells.
  • As we get older, the hormones circulating in our blood gradually change.  This is the principal way that the body knows how old it is.  There are youth hormones that promote rebuilding and high-efficiency energy output; and there are old-age hormones that turn up inflammation and cell suicide and signal the body to gradually destroy itself.  Scientists have begun to have success by increasing the former and decreasing the latter, resetting the hormone profile of an old animal to match that of a young animal.

These approaches have not yet made front page news, but scientists in the field already recognize their dramatic promise.  If all goes well, we should expect breakthrough treatments that extend life and prevent the debilitating diseases of old age, coming on-line in the next few years.

Disclaimer: This is my own perspective, shared by a handful of world-class aging scientists, but it is not yet mainstream.  In addition to the two views described here–programmed aging and wear-and-tear theories–there is another class of theories favored by mainstream evolutionary scientists, based on compromises that evolution has been forced to make.  These compromises have been made up ad hoc to avoid the inference that aging evolved to benefit the community, not the individual.

There are a great deal of genetic phenomena, as well as hormesis, that can only be explained by programmed theories

 

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Where do We Live?

Most of us who are motivated to extend human lifespan focus on the physical body, and, above all, the brain as the seat of our present awareness, the home of all that makes us gloriously, individually human.

We are conditioned by the standard scientific understanding of brain, mind, and consciousness.  Our personalities and all that makes us who we are are embodied in the circuitry of the brain. Synapses in the brain are the analog of memory gates in a computer, storing long-term memories in a complex but deterministic digital language.  From the brain’s activity, we derive our conscious awareness and sense of self.

In fact, there is an arm of the life extension movement that goes so far as to imagine that people’s thought processes and their creative intelligence will someday be read from the pattern of neural connections in their brains, and re-created in the circuits of a supercomputer.

It is just this model at which David Glanzman and his UCLA laboratory took aim in a paper last month.  He trained snails to respond reflexively to certain chemical cues, then used hormones to block the formation of new neural connections.  The memorized reflexes were gone.  But then, by chemically restoring nerve growth, he was able to bring back the trained behaviors!  So where were the memories stored while the nerves were absent?

Glanzman does not shy from the full implications of this revolutionary finding.  “These results challenge the idea that stable synapses store long-term memories.”

 

Monarchs

Although this is a useful experiment for confronting us squarely with a disparate reality, we actually might have learned earlier that memories can live outside synapses.  We might have realized this if we thought a bit about butterflies.

Near my mother’s house in Pacific Grove, CA is a tree where tens of thousands of Monarch butterflies alight in the fall and sleep through the winter months.  Come spring, they awaken to the warmth and begin their northward diaspora, spreading to reach most of the United States and Southern Canada.  They will die, and their children will feed on milkweed until they are ready to make a cocoon.  The children of their children will live and die next spring, followed by three or four more generations during the summer.  Seven months after their departure, the great great great great grandchildren of those monarchs that left Pacific Grove in the spring will return.  They will fly thousands of miles to find that same tree and congregate there for the next winter’s hibernation.

How do they know where to go?  We say, “science has no answer,”  but this does not acknowledge the depth of the contradiction to accepted science that is embodied in this one phenomenon.  There is no resolution of this mystery that does not profoundly upset our biological models of the brain and its relationship to knowledge, learning and memory.  A minimally revolutionary hypothesis would require that cartographic information can be coded into an epigenetic language, and passed from one generation to the next, for example in the methylation pattern of chromosomes.  Is there really a complete navigational language written in chromatin?  I find it more plausible that this phenomenon is akin to stories of human reincarnation, or to what Elizabeth Mayer calls Extraordinary Knowing, phenomena rooted in a realm of physics that we have yet to discover.

 

Quantum Lessons

Even more subversive to our sense of self-and-other is the science of quantum mechanics.  Schroedinger and Bohr were two of the four originators of the quantum theory in the 1920s.  They described quantum weirdness by saying that there is no objective world out there, but only a space of potentialities that congeals in one aspect or another as we look at it.  Depending on what we look at and what questions we ask, the world takes a corresponding shape.  John Wheeler (Feynman’s teacher) described this as a cosmic game of Twenty Questions, in which the solution to the puzzle does not exist ahead of time, but is gradually shaped by the questions as they are posed.

There are alternative interpretations of quantum mechanics, but they are no less weird.  Fashionable of late is the Many Worlds picture, in which the meaning of the word “many” explodes beyond our ability to conceptualize.  Imagine your own person splitting each second into a googol different universes, that is 10100 separate realities, each of them containing a different version of you, and in the next second, each of those 10100 universes splits into 10100 more universes.

A young Spanish student of quantum physics and metaphysics, Dolors has created a series of videos that help us remember that our concept of an objective physical reality following deterministic mechanical laws went out with 19th Century physics, and is utterly incompatible with the existence of such basic quantum applications as lasers and transistors and superconductivity.

 

 

The Wondrous and Limited Potential of Longevity Science

I counsel my two daughters that they might plan a lifetime of 200 years.  I think it a good bet that we will shortly learn enough about telomerase to add a few decades to human life expectancy, and during those decades there will be time to decode the epigenetics of signaling molecules to stretch a few decades more.

If aging is completely counteracted, the human lifetime would be about 1,000 years.  This is based on the fact that a young person in the prime of life has about a 1/1,000 mortality risk from year to year.  Those deaths are by suicide, by car accidents, drug overdoses, human violence, infectious diseases, etc.  To raise the human life expectancy beyond 1,000 years, we will need to grow collectively and politically, becoming a drastically less violent, more careful, wiser and more environmentally responsible species.

A thousand years is a great expanse of time.  I’m sure we should all feel a sense of wonder and relief contemplating a lifetime of a thousand years.  So much to discover, so much to witness and to learn!  So many skills to acquire and changes to absorb!

But still a blink of the eye on the scale of cosmic history.

 

We are succeeding

at delaying debilitating disease, forestalling bodily decay, extending the prime of life.  But we have not even addressed the fundamental mortality of our physical bodies.  To escape from the finite domain of time requires an expansion into mysticism.  Curiously, science at its bleeding edge, points us in just this direction.

It is clear that we are not our brains.  Our boundaries are fuzzy, some of you extends into me and some of the inanimate is part of the animate.  Maybe the inanimate world itself harbors some nascent consciousness.  To conceive of the world as a creation of mind is at least as valid a picture as the standard view in which mind is an epiphenomenon of computing machines.

But the truth is that we really don’t know and probably can’t conceive who we are, or how we live, or whence derives our precious sense of self.

The most beautiful and most profound emotion we can experience is the sensation of the mystical.  It is the sower of all true science.  He to whom this emotion is a stranger, who can no longer wonder and stand rapt in awe, is as good as dead.  — Albert Einstein (1879 – 1955)

 


An Inquiry into the Texture of Experience
and the Plausibility of Reincarnation

Awareness flashes forth from waking dreams—
A peek-a-boo of sun among the clouds.
Music’s mystery, too, has softs and louds—
My consciousness, more fractured than it seems.

As a child I formed the concept ‘mother’
Abstract from intermittent smells and touch,
And then my precious self, another such
constructed separation from ‘the other’.

My isolation and the dread of death:
not the human fate, but mere illusion.
The goals I set myself in such profusion:
each a meditation on the breath.

If only I might fathom where I’ve been
when, bridging deaths, I wake in different skin!

— JJM 2012 July

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