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.

____________

* 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. 

_______
*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.

 ————-

*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.