Since this is a blog and not a more formal article, I get to tell a personal story this week. This will be a view of the evolution of my views on evolution.

I’ve always been scared of death. I’ve jealously tried to preserve my youth, but the way in which I’ve understood aging has been remade, and thus my anti-aging practice has turned on its head…twice.

Anti-aging and anti-cancer, Stage One

Before 1983, I was Mr Natural. I didn’t distinguish between diseases of age and diseases of youth. I believed that the biggest threat to my health was the modern life style. My body is doing its best to thrive, I thought, and the best way I can help it is by simulating the environment in which it was evolved to work best. Humans were evolved in a time when work was hard, but there was no constant din of cars and construction, no fragmenting of the attention by advertising and seductive multi-media, no pesticides, preservatives or pollutants. Diets of early humans was more plant-based before animals were cultivated. My anti-aging practice consisted in endurance exercise, a vegetarian diet, and avoidance of industrial chemicals.

I was especially eager to avoid cancer. I believed that cancer was caused by chance events, whose probability was promoted by carcinogens. The body is not evolved to handle industrial poisons. These chemicals can randomly mutate our DNA. Most such mutations are merely dysfunctional. But there is an odd chance, if we are very unlucky, that the mutation will be just of the wrong type, and a cell will be transformed into a selfish monster that grows and divides and reproduces without check. Cancer was the enemy, and since the cause of cancer was an unlucky mutation, the best thing I could do was to avoid mutagens. And the sun. Did I tell you that my uncle, a schoolteacher in the winter and a fisherman in the summer, died of skin cancer when he was 49?

I avoided food additives, air pollution, dental x-rays and the sun. Such were my practices and my beliefs Then, in 1983, I read a cover story in Science Magazine by Bruce Ames.

Natural carcinogens and the genesis of Stage Two

Bruce Ames is a very smart biochemist at UC Berkeley. His invention of the Ames Test  launched him into prominence back in the 1970s. The Ames Test revolutionized the way FDA identified carcinogens in food additives. Before the Ames test, the standard procedure was to feed large amounts of the chemical to hundreds of rabbits over several years, and to count how many of them developed cancer. It was expensive, labor-intensive, and slow. The Ames test* allowed for a pre-screening in a matter of hours, in a convenient lab test. FDA procedures were transformed and streamlined. The world’s rabbits got together in 1973 and voted Ames a Human of the Year award.

It was 1983 when Ames came out with an article that changed the way we thought about pesticides in food. Ames noted that many plants, including food plants, had evolved their own pesticides as a defense against insect predators. These natural chemicals could be far more carcinogenic than the man-made chemicals that we avoid like the plague, and yet they are completely un-regulated by FDA. FDA does not test nor regulate the toxicity of natural foods.

This article revealed to me that some of the foods I had considered most healthful contained carcinogens far more potent than the man-made chemicals I had been avoiding. Here are some of them. (This table is extracted from an article I wrote  in the 1990s, a time capsule of my attitudes at the time.)

Ames devised a scale of danger he called HERP, for Human Exposure / Rodent Potency, based on dividing the amount of the substance that people are likely to consume by the amount that is found to cause cancer in lab rats.

For several years, I stopped eating beets and celery and basil and black pepper and potatoes.   Such were my practices and my beliefs Then, in 1996, I read a Scientific American article by Richard Weindruch that turned my attitudes around yet again.

Hormesis, and Stage 3 in my thinking

This article told me for the first time that many animal species had been found to live longest when they were on the brink of starvation. “Many species” implied that it was no accident, but an evolved feature of sufficently general import that it is all over the biosphere. It dawned on me for the first time that Nature (and her alter-ego “evolution”) had betrayed me.

Our bodies are programmed to die. It’s in our genes. We destroy ourselves from the inside out. This is an evolutionary conundrum, of course, because, on its face, aging is the opposite of fitness. I’ve devoted much study to this paradox, and written about it, for example, here.

There’s another, more practical conclusion from the fact that we are evolved explicitly to get old and die. It followed that no “natural diet” could address the issue of aging. All my attention to giving the body the foods which it was evolved best to work with was misguided, because aging is not a failure of the body. The body knows just what it wants to do, and what it wants to do is gradually, inexorably to self-destruct. My mission changed from supporting the body and its evolutionary program to manipulating the evolutionary program, tricking the body into living longer.

The program is not for a fixed life span, but a flexible life span dependent on circumstances. When life is hard and plenty of people are dying of starvation or disease, there is not so much need for aging to keep the death rate up. So aging takes a (partial) vacation when hardship is detected. This is the phenomenon of hormesis, and the reason that food restriction and physical exercise are among the best things we can do to prolong our lives, despite the fact that one denies the body resources and the other wastes resources and generates toxic by-products.

I no longer think that cancer is caused by a single deadly mutation in a rogue cell. I think that such mutations are happening all the time, and in a young person with a healthy immune system, the cancerous cells are quickly attacked and eliminated. I think that cancer is a disease associated with failure of the immune system and, of course, such failure becomes much more common with age. I’m less concerned about chemical carcinogens, natural and artificial, and more concerned about maintaining a healthy immune system.

I’m less concerned with toxic chemicals, natural and artificial. I’m less concerned with dental x-rays and sunburns. There is some evidence that low doses of toxic chemicals and even of radiation** can actually increase life expectancy. Here’s a review on hormesis.

I’m more concerned with challenging myself physically, and a little obsessed with the hard work of pushing to my limits. I try to challenge myself mentally as well, entertaining new ideas that seem preposterous, and trying to evaluate the evidence afresh; learning new skills an putting myself into uncomfortable social situations, because I think it helps to keep me alive in multiple ways.

And I focus on the ways that the body is destroying itself directly, and measures I might take to interfere with that process. For the present, that means an anti-inflammatory diet and a crude attempt to rebalance the body’s hormones at a more youthful level***. For the near future, I think the best strategy will be to oppose telomere shortening, which is the body’s most accessible aging clock.

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* Bacteria were bred to be unable to produce their own histidine, so that they required histidine in their diet in order to grow. For the Ames test, the bacteria are cultured in a medium without histidine, then the test chemical is added. If the chemical is mutagenic, then many of the bacteria will mutate and a few will, by chance, re-aquire their ability to manufacture histidine. If the bacteria won’t grow in the medium that’s a negative result – the substance hasn’t mutated them. If they do grow, then that’s a positive. The substance causes mutations, and there’s a strong likelihood it causes cancer as well.

**Every time I say this, it sticks in my throat because it’s just too damn convenient for the nuclear power industry. IMHO, the nuclear power industry is a plague on humanity for reasons that are not mitigated one iota by hormesis. The problems with nuclear power are the danger of more Chernobyls and Fukushimas, and the legacy of toxic waste that our great, great grandchildren will have to safeguard for 10,000 years. Did I mention that without public subsides (Price-Anderson!), the cost of nuclear power would be off the charts?

***But stay away from growth hormone.

 For basic information about healthy living for a long life,
see the author’s permanent page at AgingAdvice.org.

Eating less helps you live longer, but eating less is hard.  One line of experiment suggests that eating less of just one protein component, methionine, is sufficient to extend life span, perhaps as effectively as though less calories were being consumed.  It’s an intriguing idea, though the research is fraught with contradictions, and to separate methionine from other protein components is not easy or cheap.

It was first reported in 1993 that rats subjected to a diet restricted in methionine (MR) enjoyed comparable life spans to rats that were on caloric restriction (CR).  In the first experiments, methionine was reduced to ⅕ its normal level in the diet, and growth of the rats was severely stunted.

What is methionine?

Proteins are the workhorse chemicals of the body, macromolecules consisting of folded chains of sometimes tens of thousands of amino acid molecules strung together.  There are 20 amino acids to choose from*, and the particular sequence of amino acids in the chain determines how the protein will fold up (“tertiary structure”), and thus what shape it will have, and how it will function in the body.

When we eat protein, it is “someone else’s” long chain protein molecules that we ingest.  The particular form that the protein takes was useful to the plant or animal that we’ve eaten, but not to us, so our digestion breaks down the protein into the component amino acids, and then rebuilds the protein chains we need from these “recycled” pieces.  Of the 20 amino acids, our bodies rely exclusively on the foods we eat to get 8 of them, the “eight essential amino acids” made famous by Frances Moore Lappé 40 years ago.  The other 12 we can manufacture for ourselves.

Methionine is one of these eight essential amino acids, and one of just two that include the element sulfur.

 Costs and Benefits

Various rodents fed on a low-methionine diet have been observed to live longer.  In some of these experiments, food intake was strictly controlled to assure that the MR animals and the controls received the same total calories. [ref]

 Oxidative damage from the mitochondria is a hallmark of aging, and this has been noted to decrease reliably with methionine restriction.  [ref]  The authors of this article “conclude that methionine is the only dietary factor responsible for the decrease in mitochondrial ROS production and oxidative stress, and likely for part of the longevity extension effect, occurring in CR.”  In other words, the only reason that caloric restriction extends life span is that the body gets less methionine in the process. This may be an extreme, if tenable position.  I don’t believe that an experiment has yet been done in which rodents are fed a diet that is both high in methionine and low in calories.

Methionine restriction lowers cancer rates, and has been proposed as a cancer treatment, logically enough since it limits cell growth.

The Start Codon

Here’s a clue about why methionine is special.  The instructions for making proteins is coded into DNA, via the genetic code, which specifies words of 3 DNA letters, each corresponding to one of the 20 amino acids.  The genetic code also contains “punctuation”, instructions to start and stop.  The “start codon” is also the word for methionine.  Every chain of amino acids that the body constructs begins with methionine.

No methionine – no protein synthesis.  A shortage of methionine means that the body is inhibited in making every kind of protein.  I remarked a few months back that more genes are expressed (more proteins synthesized) as the body grows older.  Perhaps methionine restriction is putting a brake on this production of extra proteins that are not produced when we’re young, and that contribute to aging.

 Paradoxes

SAMe is a supplement I take.  The “Me” in SAMe is for “methionine”, which is part of the chemical formula.  SAMe promotes methylation of DNA, which decreases gene expression, which (theoretically) extends life by a similar mechanism to methionine restriction.  Go figure. 

Methionine is a necessary ingredient for the body to synthesize glutathione, “the mother of all anti-oxidants“ and a longevity factor.  And yet, less methionine has been associated with more glutathione.

Toward a Practical Diet 

We can’t live entirely without methionine – the body would not be able to make any proteins at all.  Restricting methionine is likely to have impacts on growth, health, and wellbeing that are as yet unstudied in humans.  “rats fed a diet without methionine developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks.”  (Wikipediia) In one experiment where methionine was severely restricted but not eliminated entirely, ⅕ of the mice died, and the other ⅘ went on to live longer than control mice.

A separate issue is how to accomplish methionine restriction in practice.  Proteins that we eat consist of chains of amino acids with all 20 mixed in.  Even if you chew your food very carefully, you can’t just spit out the methionine and swallow the other 19.  So methionine restriction in practice involves eating foods that are low in methionine.  Though all protein has methionine, some protein sources are much lower in methionine than others.  I compiled the following table from data available at USDA Nutirtion refrence site.

You can see that all animal sources (including milk and especially eggs) are high in methionine.  So an MR diet is a vegan diet, not just any vegan diet, but a subset of vegan protein sources.  There appear to be no general rules.  For example, almonds are a good source of low-methionine protein, but Brazil nuts are terrible.  Lentils are first-rate, soy beans not so good, and wheat germ is poison.

The table also makes clear that even a strict vegan diet (free of Brazil nuts) would only reduce methionine intake by about 1/2.  Extrapolating from the rodent experiments, we may need to reduce by ~ 3/4 before crossing a threshold where benefits kick in.

(Note incidentally that CR is not like this.  There is no threshold for caloric restriction.  Eating less increases life span quite smoothly.  You get a little benefit from eating a little less, and a lot of benefit from eating a lot less.)

A long shot idea

Glycine is the simplest of the 20 amino acids.  (It is literally just an amine group linked to an acid group, NH₂CH₂COOH.)   It was reported at an experimental biology conference two years ago that increasing glycine has similar effects to decreasing methionine in the diet, showing life extension and some of the same metabolic benefits in rats.  To my knowledge, this has not yet been written up in a peer-reviewed journal.  I’ve written to the author, and will add a comment below this post if I hear anything.

Bottom line

The number of experiments that have been done with methionine restriction is tiny compared to caloric restriction.  There is no data at all, that I am aware of, for humans on a methionine-restricted diet.  It’s an intriguing idea, and I’m guessing that more study of methionine restriction will yield interesting insights into aging.  I don’t think we know enough  yet to consider adopting MR as an aid to long-term health, especially since severe restriction is likely to have side-effects, and mild restriction is is likely to be ineffective. 

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*not to be confused with the nucleic acids that make up DNA.  There are only 4 of those.

A new report this week about signals from hypothalamus reminds us that some of the biggest influences on longevity are mediated through the nervous system.  To this extent, the decision about how long to live comes from a calculation made in the brain.  The new research suggests a hormone known as GnRH as a relatively simple signal by which aging might be slowed, and another signal called NF-kappa-B promotes aging and might be blocked to slow aging.    

In genetic experiments with worms in the 1990s, DAF-2 was one of the first genes discovered that curtails life span.  Delete the DAF-2 gene, and the worm lives longer.  But by what mechanism?  No one had the least idea.  Gary Ruvkun’s lab at Harvard found a way to ask a fundamental question , using genetic manipulations that were just becoming available at the time.

Normally, of course, every cell in the body has exactly the same DNA.  But Ruvkun was able to prepare “mosaic” worms with different genes in different areas of the body.  Lab worms are simple creatures with just three kinds of tissue comprising most of their 959 cells.  So he had three kinds of worms, with

• DAF-2 genes only in the intestinal and digestive cells
• DAF-2 genes only in the muscle cells
• DAF-2 genes only in the nerve cells

What he learned (2000) was that it was only through the nerve cells that DAF-2 shortens life span.

This was the first indication that maybe there are nerve networks that calculate life span, based on many sensory inputs, internal and external.  Maybe the length of our lives is decided in our neurons.  That’s an over-statement to be sure, but what has become clear is that the nervous system has a substantial role in dictating life span, and this is true in mammals as well as worms.

The biggest factor affecting life span from the outside is availability of food. Of course, it’s a conundrum for the traditional view of aging (based on accumulated damage): why is the body able to protect itself from damage better when it is starving?  Biologists have looked and looked for metabolic effects, and traced the biochemistry through the metabolism of the blood-sugar regulating hormone insulin, and the fat cells that signal to ignite self-destructive inflammation. So we are able to understand how, but not why the metabolism is not able to protect itself from these effects when food is plentiful..

But it’s not about “able” so much as “willing”.  The body is programmed to die on schedule when the population has what it needs to be fruitful and multiply, but to hold off the genetic source of death at the individual level when famine is more of a threat than overpopulation.  As if to underscore that this is a choice, rather than a direct consequence of biochemistry, life extension through caloric restriction is found to be mediated through the nervous system.  The UCSF laboratory of Cynthia Kenyon has reported (1999) that destroying the worm’s tiny chemical sensor, the smeller/taster that detects the presence of food, can extend the worm’s life span even as though it were starving even though it has plenty to eat. 

Soon it was discovered that, in mammals, too, the signals that mediate the effect of food in shortening life span are also coordinated through the central nervous system.  In response to eating, the body secretes insulin to make sure that blood sugar doesn’t get dangerously high.  But in addition to this short-term effect, the insulin signaling has a long-term effect that hastens the aging process.  Holzenberger (2004) first suggested that the hypothalamus is the switchboard in the brain from which endocrine signals are sent that shorten life span in response to food.  In a 2009 review, Susan Broughton and Linda Partridge summarized the case against the CNS as culprit in translating the body’s insulin signals into a pro-aging message.  It’s complicated, they add, because the nerves themselves seem to benefit from insulin signaling, so that insulin might protect the aging CNS, even as the CNS does the dirty work of generating the signals that age the rest of the body.  They express hope that the protective benefit of insulin can be separated from the pro-aging signal.  The knockout experiment (excuse the pun) was performed in 2007 in the Harvard lab of Morris White.   A gene that receives insulin signals was knocked out not in the whole mouse but just in the brain (by now mosaic experiments are routine).  The result was mice that are obese and diabetic and insulin-resistant but still their life spans were extended, compared to controls.  Despite being published in Science, this experiment has not received attention commensurate with its promise, perhaps because its methods were so technical.

Outside of diet, some of the primary factors that predict life span in humans are social.  People live longer when they are needed, when they have in close family ties, when they have status and importance in their communities.  This seems to be true even after the access to good food, healthy environments, and better medical care are factored out.  And it may be true in other non-human primates.  This doesn’t tell us anything about mechanism, but again it is suggestive of a central role for the brain in regulation of aging.

This brings us to the results published this week in Nature from the lab of Dongsheng Cai at Einstein College of Medicine in New York.  Excess inflammation has been recognized for a long time as a direct mechanism of aging.  Inflammation increases cancer risk, destroys arteries, and plays a role in Alzheimer’s disease (here is my blog post on the subject).

The new study shows that there is also an indirect effect of inflammation that magnifies its pro-aging effect.  Inflammation is detected in the hypothalamus*, and pro-aging signals are sent out as a result.  Since these signals further increase inflammation, this could be one of those self-reinforcing loops that accelerate our demise, and are relatively easy to disrupt via medical intervention.  (Cai spoke of ‘cascading benefits’.)  The mechanism described in Cai’s paper involve two more ingredients from the genetical alphabet soup:  NF-kappa-B is emitted in response to danger, and switches on the gene transcription in a cell in a manner appropriate to emergency response. NF-kappa-B increases with age and promotes higher levels of inflammation — Boooo!  GnRH is a signal that commands the reproductive cycle (M as well as F) and incidentally works to protect the body from aging — Yeaaa!  Inflammation increases NF-kappa-B in the hypothalamus, and this, in turn, reduces the flow of GnRH.

When the researchers added GnRH to the hypothalamuses of old mice, they saw that it promoted adult neurogenesis. When they injected mice with GnRH, the mice showed reduced signs of aging.  (from The Scientist)

The one-line take-home is that blocking NF-kappa-B in the hypothalamus increased the life span of mice by 20% (press release).  And that’s as close as I can come to a simple story with a single magic bullet.

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*The hypothalamus is a tiny organ in the lower midbrain that takes nerve signals (electrical) and transduces them into hormonal signals (chemical) for transmission throughout the body.

Eating less is the best-tested and surest way to a younger body and an increased life span.  But it’s a hard discipline to maintain, and many of us would welcome an easier alternative.  Perhaps we can realize some of the benefits applying a more temporary exercise of willpower, with intermittent fasting.  It’s counter-intuitive, but seems to be true, that health and longevity are better served by clumping up our food consumption (feast and famine) than by spreading food consumption evenly through the day and through the week.  The topic is controversial, and the evidence is not just unclear, it’s contradictory.  The bottom line is that it is worth trying.  Some people who drift away from diets involving consistent discipline find that they can comply on an intermittent schedule.  Experiment with different schedules, because individual response varies widely.

The link between restricted diet and longer life goes back at least to Benjamin Franklin:  “To lengthen thy life, lessen thy meals,” said Poor Richard.  Formal experiments on mice established the benefits of calorie restriction in the 1930s.  But calorie restriction remained a backwater of research, unknown to most biologists, let alone the public.  Beginning in 1946, intermittent fasting was introduced as an alternative lab regimen that required less measuring and monitoring.  These early experiments suggested great promise for cancer prevention and life extension by restricting access to food on various schedules.  This was exploratory work, and the experimenters were not keeping proper controls, or varying just one factor at a time, so it’s hard for us now to fit those results into the base of later experiments.

In the 1980s, caloric restriction was already well-established as a robust way to extend life span, and alternate-day feeding and fasting was re-discovered.   In the best outcome, rats lived 83% longer when fed every other day.  Looking back from today, we would want to ask:  how much of that benefit came from lower consumption overall, and how much from the schedule and periods of fasting?  Did they eat much less overall?  Or did they gorge themselves on the in-between days and make up for lost time?  Though no records were kept of the animals’ food consumption, the results seemed to be too good to be due to reduced calories alone.  The schedule seemed to be at least a contributing factor in the success of the diet.

Some species are adapted to graze continuously, while others have a much greater capacity to store food and digest it slowly.   Even within the same species, different varieties may react very differently to alternate-day diets.  A study by Goodrick (1990) highlighted the different responses of two strains of mice.  Both were put on the same every-other-day regimen.  Both maintained their body weights, with no significant differences from control animals fed ad libitum.  But one strain enjoyed consistent life extension, and the other suffered a slight decrease in life span from EOD feeding.

Experience with people

People have a hard time adapting to no food at all every other day, so the four regimens that have been suggested for humans are

• Concentrating food intake in a portion of each waking day, or eating one meal a day, or fasting every day for 12-16 hours
• Fasting or eating lightly on alternate days
• Fasting one day a week
• Longer fasts of several days, less frequently.

Long-term human studies of EOD fasting and longevity are not available.  (People don’t like to live in cages, or eat the same thing as other subjects for years on end.)  So instead we look for hints in the short-term metabolic response to intermittent fasting.  The metabolic connection of diet to aging is mediated through the insulin metabolism, so it is logical to ask what are the effects on insulin levels, insulin sensitivity, and blood glucose.  EOD fasting shows benefits comparable to CR for some but not all of these.  Higher levels of HDL (“good cholesterol”) have been reported for humans and animals, and there is good support for lowering of cancer risk in animal studies, but no data yet for humans.  In the most pessimistic study, combining calories of 3 meals into one big meal in the evening had a  negative effect on the insulin metabolism.

Protecting the Aging Brain

An intriguing benefit of the EOD regimen seems to be an increase in BDNF (brain-derived neurotropic factor).  This is a hormone that promotes new nerve growth in the brain, and presumably is related to the ability to learn.  BDNF levels decline with age.  There is good evidence that some of the benefits of EOD fasting and of CR generally are not direct effects on the metabolism, but are mediated through the nervous system.  Maybe you have to feel hungry to receive the health benefits.  The BDNF connection supports that idea.

Weight loss – a good indicator

For some people, losing weight is an end in itself, and a primary goal.  But even if your focus is on other benefits (life extension or long-term health), weight loss is a good sign that the diet is working for you.  If you are not losing weight, there still might be benefits from intermittent fasting, but it is harder to know.

For most people, trying to eat less via willpower is counterproductive.  A large majority of people who stay on a diet using discipline find that they regain more weight than they lost after their resolve runs out.  Such statistics, of course, always apply to other people, and each of us knows we can do better.  And some of us are right.

Advice

Experiment with a chosen fasting schedule.  Stick with it at least a month to give yourself time to adapt, and to average over varying life circumstances.  The right diet for you is the one you can live with.  When you find a schedule that is right for you, you will enjoy lightness and alertness; you  won’t feel deprived or resentful; there will be satisfaction in caring for yourself well, and sensing it.

Krista Varady of Univ of Illinois has a research program helping people with every-other-day diets with 7 years of experience.  Varady reports good success using a schedule of alternate day dieting, in which subjects eat one meal on the in-between days, a normal lunch of 400-600 calories depending on body size.  On the eating days, she says subjects average 10% more than their usual diet, but do not pig out regularly, once they get used to the routine.  Some subjects drop out of the program, but for >80% compliance is good.  She says many people are able to stick with this EOD schedule long-term, to lose weight quickly and keep it off.

In summary, intermittent fasting is likely to work, but not for everyone.  Only personal experimentation can tell you if you’re able to accommodate to fasting, if it can fit into the demands of your life, if you tend to overeat before and after.

Personal note:  I’ve found I can live with a complete fast one day a week (usually on Thursday).  I also try to extend my overnight fast at least 12 hours.  I don’t think I eat less overall, because I actually gained a couple of pounds when I started doing this in 1997.  But weekly fasting offers a kind of sabbath that feels right to me, makes me a little less focused, less verbal, less patient but more introspective.

Last week we talked about a wrong turn taken by 20th Century evolutionary theory.  Foundation for the theory was laid in the 1930s in a model put forward by a towering figure of statistical science, R. A. Fisher.  Fisher’s model was based upon competition among individual genes distributed through members of a breeding population.  He measured success of a gene by the number of copies of that gene in the population, and he equated Darwinian fitness with the rate at which that number would increase from generation to generation.

This is a narrow and one-sided interpretation of Darwin’s original theory, but it is regarded by most researchers in the field today as axiomatic.  Though the “selfish gene” was introduced only thirty years later (by Richard Dawkins), this term perfectly describes Fisher’s model.

There is no provision for cooperation in this model.  In fact, the ubiquitous webs of cooperation that we find in nature are paradoxical and mysterious for 20th-century evolutionary theory.

Fisher was influenced by two things that we might now regard as peripheral distractions, or worse.  First, there were no computers in his day, and he was looking for equations that were simple enough to be solved by hand.  Second, Fisher was a Social Darwinist and a eugenicist, and (perhaps subconsciously) he was creating a scientific system that would support his social beliefs.

Decades after Fisher, there was a worldwide community of evolutionary scientists who were trained and experienced in thinking within his framework, and skilled in solving equations involving the variable (gene frequency) that Fisher had deemed important.  In the 1970s and 80s, the field of Evolutionary Ecology was established, mathematically acknowledging what Darwin had told us all along, that fitness is not an objective characteristic of an individual gene, but a function of the interaction between an organism and its ecosystem.  As the etymology implies, it is about a “fit” between an individual’s traits and the ecological niche in which it lives.  Fitness is relative, and evolutionary processes can only be properly understood in terms of a system of changing individual genes and changing ecosystems.

In the 1970s, the belief became established that ecological change was generally much slower than the change in gene frequency, so that the ecology might usefully be regarded as a fixed background in which gene frequency of a (constant) population could be followed and analyzed.  This was a vindication of Fisher’s model.

Much more recently, ecosystems have been observed changing just as fast or faster than the organisms within them.  But today it is still a minority of evolutionary theorists who believe that ecological change is not generally slower than genetic change, so that the two must properly be regarded as a system more complex and intractable than the one Fisher described. To them, the “selfish gene” is a narrow, incomplete way of looking at evolution, and describes only one piece of the story.

What has this to do with aging?

Within the “selfish gene” paradigm, aging is worse than useless to an individual.  Aging always decreases fitness.  It is inconceivable that there could be “aging genes”, evolved mechanisms of self-destruction on a fixed timetable.

“The way evolution works makes it impossible for us to possess genes that are specifically designed to cause physiological decline with age or to control how long we live.”

stated thus in a 2004 Scientific American article by Leonard Hayflick and Jay Olshansky.

But since 1990, many such genes have been discovered: genes that cause self-destruction, and genes that regulate the timetable of aging based on environmental cues.  Indeed, such genes have been around since the Cambrian Explosion, and have been preserved by natural selection over a vast stretch of evolutionary history.  Modern evolutionary science is in denial about the existence of such families of genes, and evidence for programmed aging has been dismissed piecemeal every time it pops up.  Usually, some loophole is identified through which the phenomenon in question might have been evolved via a process of individual selection, consistent with the standard model.  But when these stories are collected and considered together, a pattern emerges: there is broad, overwhelming evidence for programmed aging in the biosphere.  I have collected and described some of this evidence in a recent book chapter  For example:

• The range of life spans in nature spans a factor of a million.  Some of the same mechanisms of aging are involved on vastly different time scales.  Bats live ten times longer than mice, while burning up a lot more energy and generating more free radicals.  This says that the rate of aging is not controlled by (for example) the natural rate at which proteins become oxidized or sugars cross-linked, but rather that the repair mechanisms for these processes are shut down on a schedule that the body chooses.

• Genes that regulate aging have been conserved for a billion years, since the dawn of eukaryotic life.  All other known genes that have conserved on such a scale relate to core metabolic processes that are absolutely essential to life.  It seems that natural selection has treated aging as a process absolutely essential to life.

• Life span is extended not by helping the body along or shielding it from damage but by challenging the body.  For example (to describe a familiar process in a provocative way), life span is shortened by having enough to eat.  What could it be that the body is capable of doing to protect itself when it is half-starved, but not capable of doing when food energy is plentiful?

• There are two ancient modes of programmed death at the cellular level, namely apoptosis and telomere shortening.  These are the primary modes of aging in protozoans, and both these mechanisms seem to have been preserved and modified over time, so that they are both implicated in human aging today.

Why does it matter whether aging is programmed?

Our concept of what aging is and where it comes from has a profound effect on our approach to anti-aging medicine, and has influenced the course of research on diseases of old age such as cancer, atherosclerosis and Alzheimer’s as well.

If you believe that aging is a process of accumulated damage, then you want to help the body’s natural defenses.  But if you believe in programmed aging, then you want to thwart the body’s natural self-destruction –  jam the signaling that controls self-destruction, or trick the body into a younger gene expression profile.

If you believe that evolution has already optimized the body for the longest possible life span, then improving on Mother Nature is going to be difficult indeed.  Things that go wrong with age must be because evolution has tried and failed to find a solution, and it is up to us to engineer something that is cleverer and more effective than nature was able to find.

But if you believe that evolution has programmed the body to self-destruct on a time schedule, then you look for the clock that sets off the time bomb, you study the body’s signaling language to learn how the assault is triggered.

Here are some of the ways in which the body actively self-destructs.  These are ripe targets for research that will not only lengthen life spans, but also lighten the burden of diseases of old age, lessen suffering, and relieve an overtaxed system of medical care.

• Inflammation turns against healthy cells, destroying joints and arteries and brain cells, as well as increasing cancer risk.

• The immune system shuts down over time, making us more vulnerable to infections and cancer.

• Telomeres shorten with age, and the stem cells we need for healing and regrowth are fewer in number and less active.

• Apoptosis – programmed cell death – destroys healthy tissue, especially muscles and neurons.

Re-channeling just a small portion of medical research funding into these areas holds the possibility for simultaneous and enormous benefits in many aspects of our health.

 For basic information about healthy living for a long life,
see the author’s permanent page at AgingAdvice.org.

Darwin’s legacy, his gift to science is the idea of a creative competition that selects the strong, the robust, the fertile, and thereby ratchets the complexity of life.

But does this contest take place one individual against another?  Or more collectively, species against species?  Do whole ecosystems compete with other ecosystems, or is it “every gene for itself”?

These are questions which it seems Darwin never posed.  Apparently, he did not think of these different modalities of natural selection as antagonistic or mutually exclusive, because at different times, in different books, he described the mode of competition variously, as suited the trait or natural phenomenon that he was seeking to explain.

The “selfish gene” idea in particular did not come from Darwin; in fact, Darwin knew nothing of the mechanism of biological inheritance.  The words “gene” and “genetics” were coined by Gregory Bateson 20 years after his death, and though Gregor Mendel with his pea plants was working out the fundamental laws of heredity contemporaneously with the Origin of Species, yet Darwin never knew of this keystone discovery in his lifetime.

Curious, then, that in the 20th Century, Darwin’s legacy came to be associated with the “selfish gene” picture exclusively.  In the 1970s, this rather narrow picture of evolutionary competition came to dominate evolutionary theory, and still does so today – not without some controversy and vigorous dissent.

The story of how this came to pass is one of the great object lessons in the history of science because, in my view, a great scientific community took a wrong turn, and has wandered in the desert forty years.  Twentieth century evolutionary theory was grown on the foundation of laboratory experiments, and is just now finding its way back to a picture that is grounded, more appropriately, in observations of nature.

But this is a blog about aging.  Why are we diverting into a morality tale about the controversial details of how Darwinian selection operates in nature?  Because aging has turned out to be a glaring exception to the “selfish gene” picture.  Because this wrong turn in evolutionary theory has affected our conception of aging generally – not just medical research and long-term social policy, but standard care for heart disease, cancer, PD and dementia has been affected.

Evolutionary Altruism

In fact, for most features of biology, it doesn’t matter much if we think in terms of the fitness of the individual or the fitness of the community, because they amount to the same thing.  A swift herd of gazelles is no different from a herd of gazelles, each individually evolved to be able to run fast.  In most cases, collective fitness is simply the sum of individual fitness.  It is only in those areas where the good of the individual and the good of the community come into conflict that the distinction between individual fitness and group selection becomes interesting and important.  The subject is called “evolutionary altruism”, and it includes

• the “sentinel” meerkat who risks her own skin by standing tall and calling loudly to warn the mob of a nearby eagle (ref)

• yeast cells that commit suicide en masse when a colony is starving, 95% turning themselves into food for the remaining 5 (ref)

• many kinds of mammals have been observed to adopt an orphaned baby, feed it and raise it with their own. (ref)

Aging is a trait that destroys individual fitness, but it is beneficial for the community, and aging is an essential ingredient in the recipe for a stable, robust ecosystem.  Aging is an extreme example of evolutionary altruism because nearly everyone bows out on a fixed timetable, leaving a big chunk of their fitness on the table, and because there is no particular beneficiary of the altruism, only a vacancy in the niche that could be filled by anyone, really.

History of Evolution: how did we get here?

Darwin was primarily a naturalist, not a theoretician.  He traveled the world collecting examples, and described his theory entirely in terms of stories and observations of animals and plants.  Following Darwin fifty years later in their native England, R. A. Fisher was a giant who gave shape both to evolutionary theory and to all of modern probability and statistics.  Fisher was a mathematician with only a shallow knowledge of biological phenomena.  Decades before computers were available, he worked with equations that required broad, simplifying assumptions to be solvable.  Yet his conception of how evolution works has molded  evolutionary theory continuing to this day.  Many biologists forget that the simplifying assumptions were made for computational convenience, and have come to regard them as fundamental laws of nature.

What is worse: in one of the most crucial accidents of scientific history, it happened that Fisher was a passionate social Darwinist.  In the early years of the 20th Century, eugenics was a science and social philosophy with a great deal of currency, especially among the Fabian Society, a visionary, liberal social movement that sought to reform the traditional, rigid British social structure.  (It was not until 30 years afterward, due to Hitler’s atrocities, that eugenics was discredited, and the very word became anathema to polite society.)

Fisher believed that protecting and improving the human genetic legacy was the most important social imperative of his time.  Fear of the ongoing dilution of the gene pool inspired a passion comparable to today’s movement against global warming.  Fisher thoroughly conflated the ideas of “good genes” with wealth and social standing.

We must face the paradox that the biologically successful members of our society are to be found principally among its social failures, and equally that classes of persons who are prosperous and socially successful are, on the whole, the biological failures, the unfit of the struggle for existence, doomed more or less speedily, according to their social distinction, to be eradicated from the human stock…In societies so constituted, we have evidence of the absolute failure of the economic system to reconcile the practice of individual reproduction with the permanent existence of a population fit, by their mutual services, for existence in society. (ref)

Though his inventiveness and mathematical proficiency made him uniquely brilliant, Fisher was ideologically very much in the same league with social Darwinsts of his day.  Ever since Francis Galton and Herbert Spencer in the 19th Century, Darwin’s theory has been misappropriated in the defense of class privilege and the excesses of capitalism.

The dominant view, continuing to this day, is that there is no such thing as “group selection”, that cooperation in biology is always illusory and that the “selfish gene” explains all.  This picture has been shaped and tainted by social Darwinism and capitalist ideology.  In the 1970s and 80s, contemporaneously with the discrediting of group selection in all its forms, unregulated, pure capitalism was also emerging as the one true economic system.  Both these views seem to me dogmatic, but they are entrenched and fiercely defended.  Every researcher who has written about multi-level selection has tales to tell about journal editors and referees who have refused even to consider their work.

In contrast, the new view – the emerging view as articulated by David Sloan Wilson, persisting through his long career – the emerging view in the evolutionary community is that the “selfish gene” is but one mechanism among many.  Darwinian selection takes place on multiple levels simultaneously, and in those interesting cases where there is a conflict among different levels of selection, a detailed analysis is necessary to see whether it is the collective good or the selfish interest that wins out.

Theories of aging derive from beliefs about evolution

We have learned well that “nothing in biology makes sense except in the light of evolution,” [Theodosius Dobzhansky]  Evolutionary dogmatism has bequeathed to gerontology a false and distorted picture of what aging is, where it comes from and how it works. This mistaken foundation has led an entire community of researchers astray, and medical research has been (mostly) blind to one of the great opportunities for life-saving science.

Just because aging as an altruistic trait is so hard to understand theoretically, biologists have been reluctant to acknowledge abundant evidence that aging is programmed into our genes, without tradeoff or benefit to the individual.  One result of this denial is that there are some simple ways to thwart the aging genes, to turn them off, but research on these strategies has remained unfunded in a backwater, because most scientists think it can’t be so simple, and “there must be a catch”.  (I have written about some of these here and here and here.)

I’ll continue this topic next week, focusing more on aging, how our understanding has been shaped by evolutionary ideology, and how an alternative evolutionary explanation for aging opens new possibilities for practical medical applications.

For decades, we have been treating cancer by hammering away at cancer cells with radiation and chemical poisons.  Fearful that even one surviving cell can seed a recurrence, we routinely apply the maximum tolerable dose, with side-effects ranging from nausea and hair loss to permanent impairment of the immune system.  Is there a better approach?

Cancer is an aging-related disease. There are very different views on how aging impacts on cancer development in humans. A dominant view believes that somatic cells accumulate mutations during aging until the point where mutations cause cells to be changed into cancer cells that then clonally expand into populations of cancer cells. The premise of this theory is that cancer begins when the first cancer cell is formed and undergoes uncontrolled clonal expansion.

Another view believes that having cancer cells in the body is not necessarily a problem. This theory holds that cancer cells are formed continuously in our bodies on a daily basis but that their presence in our body can reach a dynamic balance with our body’s pre-existing ability to remove them, after they formed. Such a hypothetical natural ability to remove cancer cells was termed a cancer “surveillance system” about 100 years ago by Paul Ehrlich (1909). As long as this balance is maintained, the presence of cancer cells would not pose any health problem. Clinically significant malignancies can form only when such a dynamic balance is tilted in the direction of having more cancer cells, less surveillance against them, or both.

- Zheng Cui

In the early part of the last century, we learned to kill invading pathogens with antibiotics.  A generation later, we sought to apply the same approach to cancer cells.  The classic approach to curing cancer has been to kill the cancer cells, but it turns out that is difficult to do without collateral damage to healthy body tissues*.  So research has focused on selectivity.  We are seeking approaches that kill malignant cells more reliably while sparing normal cells more completely.

Too often, we find that such treatments drive cancer into remission, but cancer recurs in a few years or sometimes months.  According to the standard thinking, the treatment killed all but an undetectable handful of cells, but as long as even one malignant cell remains, it will multiply unchecked, eventually recreating the full pathology.  Hence standard treatments are pushed to the limit, where side-effects are fatal for some patients.

But all around the edges of the cancer literature, there are alternative pictures that may better describe the broad clinical phenomena of cancer.  There is an enormous and varied literature of alternative approaches to cancer.  I can’t begin to survey them, but this brief article offers my personal impressions of one vein in the literature that I find compelling.  This is the view that cancer is a systemic disease, a failure of the body’s central controls, especially the immune system, that continually detects cells that are cancerous or pre-cancerous and eliminates them, or induces them to eliminate themselves via cell suicide (apoptosis).  Perhaps mutations produce potential malignancies through our lives on a daily basis, but these are efficiently eliminated by the immune system before they can do any damage, just as invading microbes are kept in check.  In this picture, the reason that cancer so often recurs after treatment is not that the treatment has missed a few cells, but that the original systemic weakness that permitted the cancer to escape the body’s defenses in the first place has not been addressed.

 Reasons to believe that rogue cells are not the essence of the problem

Here are three pieces of evidence in favor of this picture: 

• Cancer is primarily a disease of old age.

  Cancer risk climbs rapidly with age.
  Most researchers have explained this by positing that mutations in a cancerous lineage accumulate over many years until the last safeguard is gone, and the cell can wreak its havoc.  But this remains purely hypothetical, since an increase with age of “partially converted” cells has never been observed.   Meanwhile, it is well known that the immune response is weakened in older persons.

so that the same malignant mutations that were caught and promptly eliminated in a younger person may sometimes progress to active cancers in an older person. 

• Recurrent cancers are usually susceptible to the same chemo treatment that was effective the first time.  This indicates that the recurrence does not regrow from the few mutant cells that manage to survive the first round of chemotherapy.  These survivors have been selected for resistance to that particular agent; we should expect that the chemical agent that failed to kill them in the first round would have no more success in the second.   (The situation is exactly analogous to antibiotic resistance, which develops reliably in bacteria that survive a first round of antibiotic treatment.)  Since chemotherapy represents a powerful selection pressure for resistance to a particular chemical agent,  only if the recurrent cancer had mutated anew from formerly healthy cells would we expect the same chemotherapy agent to work twice.

• Genetic diversity within tumors.  A study in the New England Journal  last year looked at genetic diversity of cells taken from the same cancer.  They found evidence of convergent evolution.  In other words, all the cells they sampled were able to evade the body’s anti-cancer safeguards, but they did so in several different ways, with different genes.  This indicates that, even within a single tumor, cancer cells are derived from multiple progenitors.  This is a strikingly significant observation.

Where is the bottleneck in the progression of developing cancer?  Results like these suggest that the problem is not the mutations leading to a malignant line of cells that is the signal event, because this happened several times.  Maybe a stand-down of the body’s immune defenses is the most important event leading to clinical cancer.

If neoplastic conversion has already taken place several times independently, then it is a fool’s errand to stamp out every last cancer cell.  If cancer has already evolved from healthy cells multiple times within the same patient, then the monster is sure to recur unless we treat the cause, which is the weakness of the body’s innate defense.

Alternative directions

There are hopeful, if underfunded initiatives that seek to treat cancer by supporting the immune system rather than by poisoning cancer cells.  Quoted at the beginning of this blog is Dr Zheng Cui of Wake Forest Institute, who fortuitously discovered that he could reliably cure cancer in mice with a transfusions of granulocytes (a type of white blood cell) from a strain of cancer-resistant mice.  In the past few years, Dr Cui has applied this concept to humans.

Dr Shimon Slavin (who recently moved from Tel Aviv to the International Center for Cell Therapy and Cancer Immunotherapy in Hong Kong) has experimented for decades with immune cell transplants from a healthy donor into a cancer patient.  The procedure reliably eliminates cancer, but a serious (sometimes fatal) side-effect is graft-vs-host disease (GVHD), because the transplanted immune cells attack not just the cancer but the patient’s healthy cells as well.

Cancer vaccines are a growing field, already the largest class of alternative cancer treatments. 

Meanwhile, conspiracy theorists claim that enormous profits from the classical cancer treatments have created an interest group that undermines investigation of the most promising alternative approaches.  They may be right.

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*In fact, most cancer treatments target cells that reproduce rapidly.  Cancer cells reproduce rapidly, but so, too, do stem cells of the immune system.  So it may be common for cancer treatments to increase the likelihood of cancer developing anew.  “chemotherapy may disrupt potentially competent immune surveillance mechanisms leading to disease recurrence following successful tumor bulk reduction by chemotherapy.”   (A.J. Barrett)