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.”



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—
Among the clouds, a peek-a-boo of sun.
Mere thought of self can be the death of fun —
My consciousness, more fractured than it seems.

While newly born, 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

Caloric Restriction, Hormesis, and what they teach us about Evolution

If aging is driven by damage, then damage must accelerate aging. If hormesis induces damage and slows down aging, then aging is not driven by damage. So a straightforward explanation is that aging is not caused by accumulation of molecular damage.” —Mikhail Blagosklonny

Last week, I wrote about hormesis*, which is the strange tendency of living things to languish when conditions are ideal, and thrive best when life is tougher.  Lab animals are found to live longer when they are underfed, exposed to toxins or radiation or pathogens or temperatures that are uncomfortably high or low.  I will follow up in this column with more about Caloric Restriction, which is the clearest example of hormesis.  Then I mean to expand and clarify the statement about the implications of hormesis for evolution, and for our understanding of aging.

Hormesis is where my study of aging began, though I did not yet know the word.  In 1996, I learned for the first time that many animals live longer when they are underfed, and their life span continues to increase with decreasing calorie intake, right up to the treshold of starvation.  I drew the logical conclusion: It does not make sense that animals would be able to do something when they are starving that they are unable to do when they have enough to eat.  If animals have shortened life spans when they have all the food they need, it means that their genes are not evolved for maximum life span.  Aging must be“voluntary”, in the sense of a genetic program, crafted by natural selection.  Quite simply: if animal metabolisms were “trying” to live as long as possible, then certainly “as long as possible” would be shorter when they have plenty of food, and when they don’t have to fight off various diseaes or repair damage from radiation or injuries, or expend energy in running.

This is the realization that convinced me I had a mission and a message in the field of evolutionary biology of aging.  18 years ago, it was a guess based on a single piece of information, but much that I have learned in intensive study since that time has confirmed the proposition that aging is programmed into our genes.  There are many other forms of hormesis, sampled in last week’s column.  Additional proof comes from the fact that the genetic basis for aging is very old.  Genes that regulate life span are closely related in species as diverse as worms and mice and even yeast cells, though they represent branches of an evolutionary tree that diverged more than half a billion years ago.  Of course, there are many genes that we share with these early life forms, but all of them are involved in core life processes of the cell, like replication and transcription and energy production.  We can only conclude that nature has treated aging like a core life process.

And as more is learned about the physiological mechanisms of aging, it appears that some are quite avoidable, and others look like deliberate self-destruction.  For example, late in life the genes that code for protective enzymes such as ubiquinone and glutathione are dialed down, while signals that spark inflammation are dialed up to the point where inflammation becomes a major risk factor for cancer, heart disease, and Alzheimer’s


Caloric Restriction Experiments

The connection between less food and longer life predates modern scientific study.  Hippocrates hints at it.  In 15th Century Venice, Luigi Cornaro wrote a volume titled Discorsi della vita sobria (Discourses On the Temperate Life) about his personal experiments with caloric restriction, supplemented by half a litre of wine daily.  Cornaro lived to 102. Benjamin Franklin wrote in Poor Richard’s Almanac, “To lengthen thy life, lessen thy meals.” (1733).

In the depression of the 1930s, the issue of widespread malnutrition was discussed in America.  How would it affect people’s health and longevity if they did not have enough to eat? Clive McCay was a young researcher at Cornell when he received a grant to study the relationship between delayed growth and life span in rats.

McCay wasn’t thinking in terms of hormesis, and evolution was far from his thought process.  In fact, his framework was rooted in the (discredited) rate of living theory.  He thought that perhaps growth, development and aging are all synchronized on a common clock, so that if he could delay growth and maturation, then perhaps aging would be delayed as well.  In fact, the way that McCay controlled his rats’ diet was to give them just enough to eat to keep them from dying, without allowing them to gain weight.  His experiments with underfeeding produced dramatic results, but they were not recognized as being important, and there was little follow-up for almost half a century.

The modern re-discovery of Caloric Restriction (CR) came when Roy Walford served as “house doc” in the Biosphere II experiment in Arizona, 1991-93.

Biosphere 2

This was to be a hermetically-sealed environment in which a team of bionauts grew all their own food, recycled all their water and even used photosynthesis to supply their oxygen.  But farm productivity was way below expectations, so the crew didn’t have enough to eat.  Walford noticed that underfeeding the bionauts had dramatic health benefits, though it made them irrascible.

Over the years, experiments have been done with yeast cells, worms, fruit flies and other inspect species, arachnids, crustaceans, fish, various rodents, dogs, horses, and rhesus monkeys [Ref].  A project at Washington University has followed the health histories of people who practice CR [Ref], though mortality comparisons may not be available for a long while. Shorter-lived animals tend to show greater proportional life extension, but health and longevity benefits were discerned even in the monkeys, with a life span of 25 years [Ref1, Ref2].

McCay’s guess about a biological clock and delay of development turned out, at best, to be only partially correct.  CR works even if begun in adult animals.  Life extension is not as great as when begun earlier, but qualitatively the effect is the same.

CR increases both mean and maximum lifespan.  It’s much easier to increase average life expectancy by preventing early death than by truly delaying aging.  The signature of slowed aging is often taken to be the impact on the last survivors, because that is where it can be observed most sensitively.  Sometimes the difference is illustrated with survival curves that look like these two:











Results of caloric restriction experiments typically look like the graph on the right, which is regarded as the “real McCay”.

Short-lived and simpler animals tend to show (proportionately) a better response to CR than long-lived animals.  Lab worms fully-fed live only 10 days, but if starved early in life, they go into a suspended state called dauer, which is something between hybernation and a spore.  Dauers are extra tough and resistant to heat, cold, dehydration, and other things that normally would kill a worm, and they can survive up to four months without food.  A dauer is alive just enough to detect food and water in its environment, and when it does, it picks up life and growth from where it left off

Lab mice normally live two years, and with a severely restricted calorie intake they can survive for three.  Dogs typically live an extra 2 years on CR.  The longer the life span, the less the proportional gain.  Some reporting in the popular press would lead you to think that the long-term experiments in Rhesus monkeys found little or no gain in longevity, but I’ve viewed the results as positive, though there were plenty of interesting complications.

CR in humans has attracted many enthusiasts.  It’s a very individual practice.  Some people have been overweight most of their lives, and are trying to get their weight under control; others are very skinny, and disciplining themselves to be yet thinner.  There are major differences between people who take lots of supplements and people who go “natural” or “paleo”.  The greatest diversity is around exercise: Some people on CR are also doing high-intensity exercise programs.  Exercise independently increases life expectancy, and has health benefits in the present.  Exercise is the most robust and long-lasting anti-depressant known to psychological science.  (Personally, I tend to swim with this school.)  There are others who avoid exercise, because exercise burns calories, and this inevitably leads to more eating.  They are tracking calories rather than weight.  People in this school often base their thinking on the fact that exercise increases only mean life expectancy but not maximum life expectancy (see above two graphs), so it does “not truly slow aging”.  My response to this is to re-phrase the issue: Yes, there are a lucky 2% of people who will live a long time whether they exercise or not, but there are 50% of people who delude themselves into thinking that they are in that 2%.  Read stories and get a sense of the culture at CRSociety.org.

Of course, there are many other people who have decided that the discomfort and discipline of either calorie restriction or exercise are too high a price for the (substantial) improvement in health or the (modest) increase in life expectancy.

An important implication of the CR experiments is that life span is extended not through some physiological action, but through the effect on signaling.  This carries a powerful message for evolutionary understanding.  Aging is not simple accumulation of damage, because the damage can be delayed by mere chemical signals, or instructions to the living metabolism.  Here’s a sample of some of the studies that demonstrate this.

  • From Cynthia Kenyon’s UCSF lab, it was reported that merely sensing (“smelling”) food without actually ingesting the calories was sufficient to cancel some of the life extension from food restriction in worms.
  • The same lab discovered one of the genes (DAF16) that served as point man for the CR response.  They were able to genetically engineer worms that had the  DAF16 gene only in their muscle cells, or only in their nerve cells, or only in their digestive cells.  From experiments with these mosaic worms, they were able to show that it was the nervous system that dictates the life span.
  • In experiments with rodents, every-other-day feeding extends life span, even though the animals eat so much on the in-between days that they get almost the same number of calories as fully-fed animals.


Theoretical Understanding of CR – what they got right, and what they missed

The first (and now standard) explanation to relate the CR adaptation to evolution was by veteran mouse geneticists at Jackson Labs in Bar Habor, where different genetic strains of lab mice are bred for labs the world over.  (This was 1989!  For the first half century in the history of CR research, no one had thought to connect this major adaptive response to evolution.)

Harrison and Archer theorized that the CR response originated as an adaptation to famine.  During a famine, it would not pay an animal to reproduce, because its offspring would probably starve.  Better to conserve resources and try to live out the famine.  In fact, those animals that managed to survive past the famine would have an opportunity to deliver their offspring into a world where food was once more plentiful and competition for that food was thinned by starvation.  Their genes would seed a renewed population with enhanced opportunity for success.

In my view, this is exactly right.  But they did not take the next step to explore the crucial (and controversial) question:  What enables animals that are starved to live longer?  This vague idea of “conserving resources by not reproducing” helps explain why females don’t reproduce when they’re starved, but perhaps that doesn’t need much explaining.  The point is that

  • males still do have most of their fertility when they are calorically restricted, and
  • females that don’t reproduce don’t live longer.  (They may live shorter.)

This shows that the life extension is not caused by restraining reproduction.  There are two independent signals, one that shuts off fertility and one that turns on longevity.  Here’s my paper on the subject.


Once again, the message is that aging is controlled by signaling, and the signaling for aging rate is separable from the signals that control reproduction.  The idea of “conserving resources” is a red herring, because aging is not caused by scarcity of resources.


Why have so many smart biologists missed this message?

Most biologists have been led astray by evolutionary theory.  This happens both directly (because they understand the deep conflict between the ideas of evolved aging and the Selfish Gene) or indirectly (because they are immersed in a cultue that reveres nature, and they believe nature has made each individual just as strong and as durable as possible).

Darwin’s vision of natural selection says that the name of the game is to prevail in evolutionary competition, to survive and to leave more offspring than your compatriots.  Aging destroys your competitiveness and cuts off your fertility.  Aging is the opposite of fitness, and the idea that aging could be “adaptive” is absurd on its face, a non-starter.

But that’s what nature is telling us, so we’d better find a way to re-fashion our theories to accommodate reality.

As I mentioned last week, Harrison and Archer’s theory about CR actually points us to the place where evolutionary theory needs to be corrected.  Animals are not just adapted to be prime individual competitors, but also to be members of a stable ecosystem.  Ecosystem collapse is a very real danger.  It can happen in a single generation, and presumably that is exactly what has happened many, many times in the deep past.  As a result of natural selection among ecosystems, we have today a world of relative stability and homeostasis.  I have explained in a previous columns my Demographic Theory of Aging, and I have academic articles on the subject [2008] and [2012].

The bottom line is that starvation in nature is ubiquitous, and it is especially dangerous to the community.  Starvation tends to happen to happen to everyone or no one.  (If I can’t find anything to eat, then chances are that you can’t either.)  Natural selection has responded by designing individuals to die on an individual schedule, so they don’t all die at once.  Even better, natural selection has arranged to relax the schedule when starvation is afoot, because at times when many are dying of starvation, the last thing the community needs is for more to die of old age.

* I am grateful to readers who pointed me to two factual errors that made such good stories.

  • Paraquat is not the same as Agent Orange, which became infamous in the Vietnamese war.  Both are defoliant poisons, and strong oxidants, but they are chemically quite different.
  • Survivors of Hiroshima and Nagasaki did not have lower cancer rates later in life.  They had elevated cancer rates, as you would expect.  Some epidemiologists claim to see a signature of hormesis in the data of those whose radiation exposure was quite small.

…thanks for keep me honest.  I think the thrust of the narrative is intact.

What Doesn’t Kill Me Makes Me Stronger

Most people over 50 have some kind of joint and back pain.  We think that when we gain weight, there is more pressure in every step, more strain on the joints, and it makes our arthritis worse.  But the truth is stranger than this.  In fact, exercise helps to prevent and to relieve arthritis [Ref1Ref2, Ref3Ref4].  (The only exception is extreme, punishing exercise, like the elbow of a major league pitcher or the knees of a lineman in pro football.)  Walking around with a 40-pound backpack has the opposite effect of carrying an extra 40 pounds of belly fat.  The reason that weight gain exacerbates arthritis is that every fat cell is a hormone factory, pumping out inflammatory signals.  Together these signals (called cytokines) tell the blood cells to turn up the heat on the inflammatory attack that is eating away at the cartilage in our joints.

Was mich nicht umbringt, macht mich stärker.
— Friedrich Nietzsche

Maybe the fact that overeating is bad for our longevity is so familiar to you that you no longer think it’s strange.  But believe me, it’s strange.  It’s strange that the harder you work your body the longer it lasts.  And it’s strange that life span in lab animals can be modestly extended not by protecting and coddling them, but just the opposite–by challenging them with one hardship or another.  A list of things that have been found to increase life span include

  • low-dose radiation
  • toxins
  • pathogens and infections
  • heat, and
  • cold
  • hypoxia (oxygen starvation)

Paraquat is a powerful herbicide, and highly toxic to humans.  It is the opposite of an anti-oxidant.  When paraquat was sprayed from the air to destroy marijuana fields in Chiapas, Mexico, 16 people died.

In the McGill University laboratory of Siegfried Hekimi, life span of roundworms is extended remarkably by adding paraquat to the medium in which they swim.  Tiny doses of paraquat have little effect, and high doses kill the worms, but if the dose is adjusted just right, the worms live 70% longer.

When challenged, the body adapts by becoming stronger–this much is no surprise.  What makes us stand up and take note and rethink how we’re put together is that the body “over-adapts”.  It becomes so much stronger that we actually are healthier and live longer in the presence of challenges and toxins and hardships than when we are coddled in an ideal, unstressed environment

The name for this general phenomenon is hormesis, and it was first described in the 19th Century.  But the word “hormesis” dates only from 1943, and it is only in the last two decades that the idea has received some scientific respect.  There are three reasons the scientific community has resisted the concept:

  • Association with the problematic science of homeopathy.  In the early 20th Century, people who promoted homeopathic medicine were prominent supporters of the concepts of hormesis.
  • Polluters and chemical manufacturers seized on the idea to argue, opportunistically, that pollution is actually a boon to public health!  In fact, owners of nuclear power plants argue that leakage of radiation is not a problem as long as it is below a threshold dose*.
  • The true strangeness emphasized above.  Hormesis implies that the body is unable to be fully healthy if it has all the food it needs, and is deprived of poisons and stressors.


Examples of Hormesis

  • The most dramatic and obvious examples of hormesis are that less food and more exercise both lead to extended life span.
  • Chloroform is a trace contaminant in toothpaste.  Manufacturers tested the safety of their product by feeding toothpaste to dogs with and without the chloroform.  They were surprised to find that the mortality rate was lower for the dogs that got chloroform [Ref].
  • Repeated, mild burns slow the age-related damage to human skin cells [Ref].  Worms that are exposed to heat shock also live longer [Ref].
  • In an Australian study, people exposed to more sunlight had less long-term UV damage to their DNA [Ref].
  • Rats that were bathed in cold water 4 hours per day lived longer and had lower cancer rates than rats that stayed warm [Ref].
  • Mice exposed to 25 or 50 times the normal background level of gamma radiation lived 20% longer than mice that received only the ordinary background [Ref].
  • Fruit flies exposed to disease enjoyed greater fertility and longer life [Ref].

Don Luckey devoted the last decades of his professional life to documenting the health benefits of radiation exposure, and faced the skeptics to argue that we should all be getting more whole-body radiation exposure than we get from cosmic rays and low background of radioactive elements in the earth [Ref]. The US National Research Council disagrees [Ref].

Edward Calabrese researches the epidemiology of environmental toxins at U Mass.  For 25 years, he reported findings in terms of standard linear models:  If 1 part per million is bad, then we expect half a part per million to be half as bad.  But with accumulating evidence, there came a point where he had to break ranks, and he has been a prominent advocate of the hormetic viewpoint ever since.

From a comprehensive search of the literature, the hormesis phenomenon was found to occur over a wide range of chemicals, taxonomic groups, and endpoints…hormesis is a reproducible and generalizable biological phenomenon, and is a fundamental component of many, if not most, dose-response relationship [Ref].

The Hygiene Hypothesis says that widespread use of disinfectants has reduced childhood exposure to bacteria to an unhealthy extent, and that increased incidence of asthma, irritable bowel syndrome, Crohn’s disease, and various auto-immune disorders has been the result.

Hormesis also has an unusual place in cinematic history. During the 1950s, reports on the capacity of ionizing radiation to stimulate growth inspired the genre of so-called ‘‘nuclear monster’’ movies, which included Godzilla (1954) and Attack of the 50 Foot Woman (1958). Typical of this genre was Them! (1954), in which ants exposed to radiation from atomic bomb tests grow to gigantic proportions and terrorize residents of New Mexico. [Ref]


How to make biological sense of hormesis

The reason that hormesis seems so strange to us is that we like to think that we are evolved to be as strong and as healthy as it has been possible for nature to make us.  It doesn’t make sense for us as individuals to hold back on strength and longevity just because we don’t happen to be starved or poisoned at the moment.  But if we think collectively instead of individually, it all starts to make sense…

My principal contribution to evolutionary theory has been the Demographic Theory of Senescence, which starts from the premise that population overshoot is a danger to most animal species.  If animals eat all the food that is available to them and reproduce as fast is they are physically capable, then the environment will be denuded, the next generation will starve, and the species will face extinction.  All animal species are evolved to avoid this.  [Academic references 2012 and 2006]

Another way to describe this same situation is to say that the main causes of death in nature are all clumped together.  When food becomes scarce, everyone starves at once.  When there is an epidemic, everyone gets sick together.  When there are storms or cataclysms or environmental poisons, they affect an entire population at once.

Aging is nature’s way of leveling out the death rate, assuring that we don’t all die at the same time.  Aging puts our deaths on an individual schedule so we can die at different times; other causes of death tend to kill everyone or no one.

Since aging has evolved to complement the environmental death rate, we expect that when the environment is most hostile, there is little or no need for additional deaths from aging.  So aging takes a vacation during starvation or other times of hardship.  Conversely, when life is easy and stress-free, no one is being killed from external causes, aging is out in full force, helping to thin the population and avoid population overshoot.

So the Demographic Theory provides a natural context for understanding hormesis.  In fact, the Demographic Theory is the only theory of aging in which hormesis is actually a prediction.

(Mikhail Blagosklonny agrees, but stops short of saying that aging is programmed.  Peter Parsons disagrees.)


Implications for Personal Care and Longevity

Well, eat less and exercise more–that’s a good start.  If I were just looking at the data, I’d have to say that introducing a source of gamma radioactivity in the home, 25 times above background might be justified.  But the idea makes me queasy.  We don’t know how to do it well.  Might it be beneficial at some ages and a risk factor at other ages?  People who live in houses with naturally high radon levels have elevated risk of lung cancer [Ref].

The concept of hormesis has made me relax a lifelong fear of pollution, and I have backed off from Bruce Ames’s program of reduced exposure to natural and artificial toxins. But I’m not ready to do anything pro-active to increase my exposure to toxins or radiation.



* My position on nuclear power is that low-level leaks of radioactivity are the least of its problems.  Nuclear power should be a non-starter because it is uneconomic without huge government subsidies, including the Price-Anderson act which limits liability.  Haven’t we learned anything from Chernobyl, Three Mile Island, and Fukushima?  And don’t get me started on guaranteeing the safe storage of radioactive waste for the next 20,000 years.

Regeneration in Mammals–Ancient Capacity is Not Lost, but Actively Suppressed

It was 1995, and Ellen Heber-Katz ran a busy lab at the Wistar Institute in Philadelphia, at the top of a thriving career in auto-immunity.  Her lab used standard practice to identify individual mice with tiny holes punched in their ears.  In the midst of one experiment, she discovered some un-labeled mice, and she spoke to her post-doc about it.  But Lise Clark said she was sure she had punched their ears.  So Heber-Katz punched their ears herself, and checked back a few weeks later.  She could hardly see the holes she had punched.  Within a few weeks, the ears had healed over, smooth skin, seamless cartilage with nary a scar.  Mice aren’t supposed to be able to do this.

She might have continued the project with an alternate labeling method, but Heber-Katz was more curious than that.  She learned that this particular strain of mouse (MRL mice from Jackson Labs in Bar Harbor) was known for healing over their ear punches.  Other researchers had noticed the “problem” and dealt with the inconvenience, without giving a second thought to the larger implications.

Heber-Katz couldn’t wait to study the phenomenon in depth. But her colleagues counseled against it, urging her not to waste her expertise in the field of autoimmune disease and transplant rejection. They advised her to pursue the disappearing ear holes as “an aside,” like a hobby. But Heber-Katz knew she had stumbled onto something big, and she just had to go after it full force. “I realized, since I didn’t know anything about wound healing, I had better go to a meeting about it,” she says. So she did, and there an expert told her: “Oh no, mouse ear holes absolutely do not close.” So Heber-Katz kept her finding secret. “I was really on cloud nine,” she says.    – Katie Moisse, [Sci Am (2006)]

In early studies with regeneration, she and colleagues found that the hearts of MRL mice heal scarlessly from injury.  When humans suffer heart attacks, heart tissue dies and usually the damage becomes permanent.  Normal mice can’t repair their own hearts either.

Salamanders and zebrafish are among the species that can regenerate limbs and even large portions of vital organs after injury, and the regrown portions of their anatomy are just the same as the original. We mammals cannot do this: we can manage fingernails, occasionally fingertips at a very early age, and portions of the liver, but that is about it. One line of modern regenerative research asks whether it is possible to somehow induce the regenerative biochemistry of salamanders and zebrafish in mammals. Is mammalian incompetence in healing a matter of lost capabilities that originally evolved in a distant shared ancestor species, and thus the necessary biochemistry still exists, but is in some way dormant? [Reason at FightAging.org]

Juan Carlos Belmonte’s Group at the Salk Inst has gotten normal mice to perform the same trick, using a micro-RNA signal to turn normal heart (muscle) cells back into the stem cells from whence they came, so they can make new heart cells. They were able to reactivate

long dormant molecular machinery found in the animals’ cells, a finding that could help pave the way to new therapies for heart disorders in humans. The new results suggest that although adult mammals don’t normally regenerate damaged tissue, they may retain a latent ability as a holdover, like their distant ancestors on the evolutionary tree.
In a [2010 paper in Nature], the researchers described how regeneration occurred in the zebrafish. Rather than stem cells invading injured heart tissue, the cardiac cells themselves were reverting to a precursor-like state (a process called ‘dedifferentiation’), which, in turn, allowed them to proliferate in tissue…

The team decided to focus on microRNAs, in part because these short strings of RNA control the expression of many genes. They performed a comprehensive screen for microRNAs that were changing in their expression levels during the healing of the zebrafish heart and that were also conserved in the mammalian genome.

 Their studies uncovered four molecules in particular–MiR-99, MiR-100, Let-7a and Let-7c–that fit their criteria. All were heavily repressed during heart injury in zebrafish and they were also present in rats, mice and humans.

[News Release from the Salk Inst]

In other words, the surprise is that we didn’t lose something in the advance from fish to mammal, rather we acquired a response that suppresses regeneration.  The ability to regenerate remains intact in mammals, but it is switched off.  This raises the possibility that if we want our bodies to be able to regenerate damaged tissue without scarring, we don’t have to acquire a new mechanism or even re-acquire one that has been lost; all we have to do is to fiddle with biochemical switches.  Switching on or off particular genes in particular tissues has become a reliable technology, using any of several techniques (e.g. CRISPR, RNAi, retroviruses).

the team used adeno-associated viruses specific for the heart to target each of those four microRNAs, suppressing their levels experimentally.

Injecting the inhibitors into the hearts of mice that had suffered a heart attack triggered the regeneration of cardiac cells, improving numerous physical and functional aspects of the heart, such as the thickness of its walls and its ability to pump blood. The scarring caused by the heart attack was much reduced with treatment compared to controls, the researchers found. The improvements were still obvious three and six months after treatment – a long time in a mouse’s life.

In the same vein, Heber-Katz’s group has also concluded that the capacity to regenerate has not been lost in mammals, but is actively suppressed.  Four years ago, they had already identified a gene called p21 which is defective in their MRL mice.  They knocked the p21 gene out of normal mice and discovered that those mice could heal their ears similarly to MRL mice.

Animals capable of regenerating multiple tissue types, organs, and appendages after injury are common yet sporadic and include some sponge, hydra, planarian, and salamander (i.e., newt and axolotl) species, but notably such regenerative capacity is rare in mammals. The adult MRL mouse strain is a rare exception to the rule that mammals do not regenerate appendage tissue…Using the ear hole closure phenotype, a genetically mapped and reliable quantitative indicator of regeneration in the MRL mouse, we show that the unrelated Cdkn1atmi/Tyj/J p21-/- mouse (unlike the B6129SF2/J WT control) closes ear holes similar to MRL mice, providing a firm link between cell cycle checkpoint control and tissue regeneration.  [Ref]

Although Heber-Katz’s group was based on genetically engineered mice, there is no reason to expect they could not do the same with normal mice, using one of the three in vivo techniques I mentioned above to shut off the p21 gene temporarily and locally.  I know of no one who is trying this in humans, but it seems to me that this technology is ready, and if I were a heart attack patient, I would eagerly volunteer for early trials.

This story of regeneration not being lost but suppressed fits beautifully with the song that I have sung so often on these pages and elsewhere–that there is no fundamental limit to life span in our metabolisms, but that evolution has programmed a fixed length of life for the purpose of stabilizing ecologies.

One thing that doesn’t fit so well is the story that Heber-Katz has been focusing on the last two years: inflammation is an essential part of the regeneration process [ref, ref, ref].  This could be an example of antagonistic pleiotropy.  Suppressing inflammation is an important anti-aging strategy, and it may have to be pried apart from wound healing in order to make further progress.


Porpoises and other marine mammals

Adult porpoises can repel a large shark, but are frequently injured in the encounter.  It is estimated that 40% of poropoises in the ocean have survived a shark bite, but they don’t carry scars from the event.  Porpoise skin and the blubber layer underneath recover in a matter of days from lacerations up to a foot long.

A Georgetown University pediatrician published this information a few years ago in a dermatology journal.  “Reports of the survival after severe traumatic injury of other marine mammals, such as the southern elephant seal [ref] and the Hawaiian monk seal [ref], suggest that efficient healing of soft-tissue injury might be widespread among marine mammals.”

What do the porpoises have that we don’t have?  I think the proper question is likely to be, by what signals have we suppressed the porpoise’s capacity to heal?