Aging and Life Extension: Unexpected Lessons from Evolution

This is the text of a brief presentation that I delivered yesterday in DC at a symposium on radical life extension.  In a new experiment (for me), I’ve prepared a self-presenting powerpoint, with voice and images that you can view either with PPT software or as a Youtube video.


In the old view of aging, evolution has neglected her children in old age because in the wild, hardly anyone ever survives to old age. So the body is permitted to fall apart. Damage accumulates. The body wears out like an old machine.

Another part of this picture is that all the stresses of modern life are accelerating aging.  Pollution, pesticides, radiation, and high-fructose corn syrup are stresses that the body just wasn’t evolved to cope with, and they wear us down faster, shortening our life span.

But in the 1990s, evidence against this picture began to accumulate. For one thing, aging takes a huge bite out of fitness in the wild. Animals do live long enough for aging to be a factor in the death rate. For another, people are not cars. A car wears out faster the more you drive it.  But our bodies respond to stress by overcompensating so that the more active we are, the longer we live. Animals too, live longer with intense exercise. It’s called “hormesis”. Other kinds of stress, like starvation and certain toxins, radiation, infections, heat and cold also increase life span, paradoxically. If the body were just wearing out, this would be very hard to explain.

A third point against the theory is that genetic scientists began to discover “aging genes”. I define an aging gene to be one that can be deleted with genetic engineering and the animal lives longer without it. Dozens of such genes are known now in every lab species where they have been sought. The record is for a gene known as AGE-1 in lab worms. When both copies of this gene are knocked out, the worms’ lives are extended tenfold.

A completely unexpected thing about these genes is that they come in families that span the entire biosphere.  Genes for aging in you and me are closely related to genes for aging in the fruit fly and the worm and even primitive yeast cells. This can only mean that aging genes are evolutionarily conserved. That is, they are an adaptation, a product of natural selection.

Aging is programmed into our genes as an adaptation

Evolution has arranged for us to die on a schedule.  We have genes with no other purpose than to destroy us. Suicide genes. Our bodies don’t wear out despite nature’s best efforts to protect us. On the contrary, aging is an active process of self-destruction, bequeathed to us by nature, programmed into our genes.

(One implication of this is that the selfish gene version of evolutionary theory is a very narrow window, defining one small part of how evolution works – but that’s a story for another day.)


No such thing as “natural anti-aging”

If you believe the old view, then nature is our friend. Our bodies are doing their best to resist the ravages of aging, and our job is to help the body out. Natural foods, in particular, support the body by giving it the fuel that it was evolved to work with. Low stress and a slower pace help preserve the body. Eat organic.

But in the new picture, moderate stress prolongs life span. Hunger is good for us. Intense exercise that makes us feel like we can’t stand it is one of the best things we can do for ourselves. Even poisons can promote longevity.

How can this be, that the body does so much better at forestalling aging when it is stressed?


What adaptive purpose is served by death on a schedule?

There’s an evolutionary story behind it which is the centerpiece of my own research. The reason that aging evolved is to take control of the death rate, to level it out so everyone doesn’t die all at once. In nature, starvation is the biggest threat to life. And it tends to kill everyone at the same time. When there’s no food for me, there’s probably no food for you either. There’s a famine and we all die together. This is called extinction. Not good for evolution.

Aging evolved for the purpose of helping to avoid population overshoot, to level out the death rate so the ecosystem can find its equilibrium. In this way, aging protects against extinctions. When there’s plenty of food and no one is dying of starvation, that’s when nature needs aging, to help raise the death rate. But when food is really scarce and some are dying of starvation, more death (from old age) is the last thing the ecosystem needs. So aging takes a vacation when the population is stressed.

This is the reason that things that prolong our lives tend to be uncomfortable.  We need to send the body stress signals to suggest that there’s already plenty of death in the air, and then aging will loosen its grip on us.


Implications for ROS theory and oxidative damage

In the old view, oxidative stress is the enemy, a kind of rusting from the inside out. But in the new view, oxidative stress is part of the signaling that tells the body to protect itself.  Anti-oxidants – vitamins A, C and E were tried and tried, in animals and in humans – and they actually increase mortality.  Intense exercise, on the other hand, generates loads of free radicals and it’s actually the free radicals that signal the body to go into a protective state. Taking anti-oxidants before you exercise can nullify some of the benefits!

So what’s the message that evolution has for us concerning how we can live longer?  Three things:

  1.  “Natural Anti-aging” is an oxymoron

  2. There is a shortcut to life extension based on hormonal signaling.

  3. As life extensionists, we are advocates for conservation and birth control.

We’ve already talked about #1. There is no such thing as “natural anti-aging”. Aging itself is natural. We can only extend life span by fighting with nature, manipulating or tricking evolutionary programs.  We do this with exercise, with hormesis, with caloric restriction and its mimetics. But that trick is limited to the built-in buffer that nature has provided – probably 5 to 10 years of extra life.


To go beyond 10 years, #2 is deeply promising. The old view was pessimistic. Since evolution has already done its best for long life, we’re going to have to think of something that evolution hasn’t been able to come up with in a billion years. But if we think that our genes have a built-in death program, then all we have to do is to thwart that biochemical program. Turn it off. Throw a monkey wrench into the suicide machine.

Interfering with biochemical pathways is something that the pharmaceutical industry is really good at. Hormones and receptors are lock and key molecules. You make a molecule that sticks in the receptor, and this blocks the action of the hormone. This approach to anti-aging is very promising.

In this new picture, where aging is programmed self-destruction, the body must have some way of knowing how old it is. This implies that there is an aging clock, or more likely, several redundant clocks. There is the very exciting promise that we might be able not just to slow down the aging clock, but to reset the hands to a younger state.

The one aging clock that we already know about is telomere length.  I have written in this column about telomeres, and you have heard the story elsewhere, I’m sure. With every cell division, our stem cells lose a little DNA, from the tail of each chromosome. Telomere length is inversely related to mortality, in humans and in animals. Short telomeres contribute to all the diseases of old age.

There are several herbal products available NOW [1,2,3,4] that offer some ability to lengthen telomeres. Enough to slow the clock, but not enough to actually set the hands back. There is research going on in several private companies, seeking ways to do a better job of re-setting the telomere clock using designer chemistry.  The best lab that I know of is Sierra Sciences, and they are presently stalled for lack of funds – a great opportunity for investors to step forward.

We know that telomere length is an important clock, but we also know that it is not the only biological clock. A hot topic in research the last year or so is the epigenetics of aging.  Which genes are active and which are inactive? This is “gene expression” and it changes with age. I have floated the idea just this year that gene expression constitutes a powerful aging clock. That if we can direct the old body to activate a young gene profile, then the body will respond by turning itself young.

You might think that there’s some kind of “youth serum,” something the body isn’t able to make when it’s old that it used to make when it was young. But the fact seems to be more the opposite: that there are blood factors that the body makes when it’s old but not when it’s young that are turn on the suicide program.


Life Extension must be Balanced with Conservation and Population Control

#3 is my final message to you. You and I are part of a community dedicated to extending the human life span. We are succeeding, and this is a wonderful thing for every individual who receives the benefit. But evolution tells us that in addition to individual good there is a separate collective good. What is good for every individual may be disastrous for the community. This is the tragedy of the commons.

In fact, aging evolved for the purpose of controlling population overshoot.  For 150 years now, humans have succeeded in extending our life spans worldwide. The individual result has been an enormous lifting of a burden of suffering and fear of untimely death.  But the collective result has been that humans are a blight on the biosphere. The rate of extinction is unprecedented – higher even than the great dinosaur die-off of 65 million years ago. There are resources that were built up over millions of years, and we’re using them up as if they belonged to us, with no consideration of future generations, or other life forms.

We, as the world’s top predator, depend on a diverse ecological base of plants and animals, ocean and land species, insects, algae, plankton, bacteria… If we destroy that base, we destroy ourselves. And we are destroying it, with reckless abandon. People who imagine that the world can be turned into a great farm to support tens of billions of humans understand nothing about ecology.  The robustness of the natural world depends on diversity.


If our dream of extending human life span is not to turn into a nightmare of famine and resource wars, then you and I must split our time between promoting life extension and promoting (1) conservation – the environmental footprint of each human, and (2) population control, bringing down the birth rate to match the falling death rate.


Creative Deprivation: How to Get Less from Your Food

When it comes to calories, inefficiency is the name of the game.

We know that less weight is healthier and leads to longer life, but the desire to eat runs deep, and dieting through willpower works for almost no one.  So we look for tricks that will let us eat more and weigh less.  Two articles from Scientific American this month are most enlightening.  One demonstrates that the number of calories we extract from food varies widely from the standard method as reported on the label.  The other recounts ways in which some foods triggers hormonal signals that say “burn me!” while others tell the body to “store me as fat!”

There exist a handful of people who can keep weight off through willpower alone, but they are vanishingly rare.  A study I like to cite reports the weight change after three years of people who restrict food with guidance, support and medical supervision. The bottom line is that the average dieter gains weight.  Here’s a review article called Diets are Not the Answer.

Measuring food energy

A calorie is a measure of the chemical energy content of food.  In the 19th century, the first, crude theory posited that what the body does with food is equivalent to burning it in oxygen.  The first methodology for determining the calorie content of food was simply to burn it in a chamber surrounded by a water jacket, and measure the increase in temperature of the water.  Amazingly, this crude measure became standard and has gone unquestioned for 120 years.  An article by biologist Rob Dunn of North Carolina State University questions this practice in a challenge that is long overdue.

Usually, we think of efficiency as a good thing.  But the efficiency with which we use food affects how much fat we store from a given number of calories.  If we want to eat more and weigh less, efficiency weighs against us.  For every calorie we put into our stomachs, we get some fraction of a calorie out as food energy, and that fraction can vary widely with the type of food, how well we chew, whether the food is cooked, and the particular mix of bacteria in our guts.

Factors affecting our digestion efficiency

  • Fruit, tubers, and flour are easily digested and calories are readily available.

  • Nuts and seeds are often rich in fat, so they register as high-calorie foods.  But they are harder to digest, and the body gets less from them.  Seeds that are unchewed go right through us.  In fact, many plants use animals to help disperse their seeds, and evolution has designed the seeds to survive digestion.  Most nuts are partially chewed, and some small pieces pass through undigested.  There is a big difference in available energy from eating peanuts and peanut butter, though the labels will list the identical calorie content.

  • The body needs to expend energy in digestion, and this can take a substantial bite out of the available food energy.  Cooking breaks down the cell walls in meats and vegetables, and they are digested more thoroughly and with less energy expenditure.  If you’ve ever tried a raw food diet, it’s very hard to gain weight, no matter how much you eat.

  • Food fiber is not digestible by the bacteria that inhabit human stomachs, so its calorie content contributes negligibly to what we actually absorb.  Even better, a high-fiber diet reduces the time that food spends in the intestine.  A rapid transit time is healthier in terms of the quantity and the quality of the extracted nutrition.

    Transit time varies with the calorie density of your food, as well as the fiber content of the diet.  Vegetarians have shorter transit times than carnivores, simply because there is more volume for the same calorie content.  A typical American diet of meat and starch leads to a transit time of 3 days.  By eating lots of greens, drinking extra water, and supplementing with raw wheat bran (an acquired taste, to be sure, but it costs practically nothing in bulk), you can get your time down to 18 or even 12 hours.  It could make a big difference in your weight.

    Measure your transit time by eating beets with a meal, and noting when your stool shows red.

  • The last factor is the mix of your intestinal flora.  Some bacteria do such a good job of digesting your food that they take most of the calories for themselves, leaving little for you.  Others are more generous.  (Remember, inefficiency is the name of the game.)  It is known that people show a lot of variability in the kinds of bacteria that inhabit their guts, but the science of how to manage your unique microbiome is in its infancy.  Here is a New York Times Magazine article by Michael Pollan from last May.

The average Russian intestine is 5 feet longer than the average Italian.



When it comes to calories, we’d prefer that the food we eat go right through us without being absorbed.  But for supplements, herbs, medications, and vitamins we want maximal assimilation.  Best to take supplements at a different time of day from high-fiber meals.  Some can be absorbed well in a fasting stomach.  Other supplements are absorbed better with food, and some go better with a meal that includes fats.  A light, low-fiber meal leads to better absorption than a fiber-rich meal.


Carbohydrates vs Fats

Another article in this month’s Food Issue of Scientific American explores a theme that has been the theme song of Gary Taubes for fifteen years now.  His thesis is simply that eating carbohydrates signals the insulin metabolism to store fat, while eating the same calorie content as fat or protein, the calories are more likely to be burned.  I think he’s right.

Taubes is far from the first to present this idea to the public.  Robert Atkins said the same thing to the last generation.  Barry Sears tried to lead us through the biochemistry in his Zone books.  I’m old enough to remember Calories Don’t Count, by Herman Taller, which launched my mother on a low-carb diet in 1961.

Taubes builds his case on the fact that during the same time period when American and European consumers were being sold a lower fat diet (beginning about 1980), the obesity epidemic was born.  I’m usually dubious of cross-cultural epidemiology because there are so many potential confounding factors active at the same time.  But in this case, Taubes’s case is built on sound physiology as well.  Carbohydrates require minimal digestion, and appear in the blood stream instantly as glucose.  Insulin is secreted to moderate glucose in the blood, and signals the body to remove the glucose and store it as fat.

Taubes is a journalist, not a scientist.  I have to read between the lines to fill in the science.  But the advantage of his investigative approach is that he tells some of the political backstory about how commercial food interests have derailed government scientific investigations, distorting the results that are reported to the public.  Taubes details the experimental design of a study which he has initiated that might eventually resolve the split in the nutritional community over low-fat vs low-carb diets.

It was just a few years ago when “high-fructose corn syrup” was considered to be an attractive ingredient to list on a label, because “sugar” makes us think of an unnatural, refined product, while “fructose” derives its name from being the predominant sugar in (natural) fruits.  Now fructose has been singled out as the worst carbohydrate, with the most direct and immediate effect on the signaling that moves the body toward obesity.  A 2011 British study drills down to the biochemistry of AMP and ATP.  When the mitochondria burn sugar to deliver usable energy to the cell, their deliverable product is ATP.  When the cell deploys the energy, ATP is returned to its low-energy form, AMP, and recycled.  Glucose or sucrose are two common dietary sugars, and they increase the amount of available ATP, which signals the body to stop eating and use the available energy.  But paradoxically fructose triggers the opposite signal, depressing ATP and stimulating the appetite for yet more food, while storing the energy as fat.  It is this mechanism that makes fructose more dangerous to health than other carbohydrates.

Adding fuel to the fire, fat cells themselves are a source of insulin and its inflammatory cousin IGF-1.  Circulating insulin and IGF-1 close the feedback loop that keep the body’s metabolism in an obese mode.  A side-effect is elevated risk of cancer.


Low-protein vs Low-carb diets

There are two schools of thought on the broad basis of a pro-longevity diet.  The first seeks to restrict protein, because in lab studies, protein-restricted animals show increased life span even if calories are not restricted, and because IGF-1 is lower in protein-restricted humans.  The second seeks to restrict carbohydrates (and fructose especially) based on the above analysis of the insulin metabolism. For the last 12 years, I have pursued a low-carb, high-fiber vegetarian diet coupled with intense exercise, and it works well for me.  I don’t eat grains or potatoes, but I do eat a good deal of fruit.  I don’t know if fruit is simply my personal weakness, or if it helps me to keep up the energy for a very active life style.

I know others who have had success with the low-protein approach.

Theoretically, it is possible to combine the two approaches with a diet that is overbalanced toward fats and fiber.  Are you old enough to remember Frances Moore Lappé’s campaign to get us to eat complete protein by combining the 8 essential amino acids?  Well, now it turns out that incomplete protein (from vegetable sources like lentils and almonds) helps to keep the body in its protein-deprived state, promoting both health and longevity.  (To her credit, Lappé changed her recommendation about complete protein many years ago, as the new science became available.)  A diet that restricts both carbs and protein (think avocado salads with olives and walnuts) seems extreme, and I have not seen any studies.  Perhaps it is the next cutting edge, or it may just make you feel crummy.

Strategies for Engineering Negligible Senescence – Report from SENS-6

Aubrey de Grey has rallied the world’s scientific community and its funders to attack the biological basis of aging, which underlies the majority of disease and suffering in the developed world. Since 2003, he has organized bi-annual conferences, bringing together innovative biologists, medical researchers and a few policy wonks to share knowledge and perspectives, to coordinate and support each others’ efforts. Below I report highlights from this year’s meeting, SENS 6, which I attended last week at Queens College, Cambridge.


Caloric Restriction in Monkeys – Reconciling Two Studies

This year and last year, two parallel studies of caloric restriction in rhesus monkeys reported their results. Science reporters framed their conclusions as contradictory. In Madison, the CR monkeys lived longer, while in Baltimore, they did not. Both studies reported robust benefits for many aspects of health in the CR monkeys. What I learned last week was that the Baltimore monkeys had a much leaner diet than the Madison monkeys. In fact, the control monkeys in Baltimore – those that were supposed to be “fully-fed” – got about as many calories per day as the CR monkeys in Madison. A natural interpretation of the two results is that modest CR extends life span but that severe CR doesn’t extend life span further (though it may improve health and lower rates of cancer and heart disease).  Read more

Another interesting subplot: the Madison diet formula was both high-fat and high-glycemic index, while lower in protein than the Baltimore formula. The Madison diet was completely synthetic (so it could be precisely controlled) including 28% sucrose. The Baltimore diet was based on whole grains and fish meal, with the rationale that there are micronutrients in whole foods that may be important though we have not yet catalogued them. When two groups of mice were fed on these two formulas, adjusted to the same number of calories, the ones on the Madison diet gained weight while those on the Baltimore diet did not. This echoes a theme that is reported in Scientific American this month: the body’s caloric budget is not the primary determinant of obesity. The same number of calories from different sources can have dramatically different effects on metabolism. I’ll write more on this next week.


Exercise vs Caloric Restriction

For the last ten yeas, Luigi Fontana of Washington University St Louis has been conducting an ongoing study of two groups of people who exercise fanatically (by middle-class US standards) and who seriously restrict their food intake (same standard). Both groups have dramatically improved biomarkers compared to the average American couch potato. There are some differences between the two. Exercise seems to be better for lowering markers of insulin resistance – the “metabolic syndrome” or “Type 2 Diabetes” that underlies the diseases of old age. Diet works better to lower cardiovascular risk factors. Both work to lower indicators of cancer risk.  (It will be many years before there is data to evaluate the effect of CR on human mortality.)   Read more


An aging clock in the brain

Dongsheng Cai of Einstein Medical Center in New York reported that age-related inflammation is especially prominent in a region of the brain called the hypothalamus, which is known to regulate body rhythms. The hypothalamus is especially sensitive to a signal hormone called NFkB that has damaging effects over the whole body. In experiments with flies and mice, life span can be extended by blocking the action of NFkB. Read more



Frank Madeo of University of Graz in Austria reported on experiments with a small molecule called spermidine. Fed to yeast cells, it increases life span dramatically, with smaller but still significant effects in flies and worms. Life span of mice can be increased by about 10% with spermidine in the diet. The mechanism seems to be stimulation of the process called autophagy, by which each cell cleans up its waste products, digesting them in organelles called lysosomes. Spermidine is part of the body’s metabolism, but its concentration declines with age. It is not available as a supplement, to my knowledge. The best dietary source is a Japanese fermented soy product called natto, which is famous for its vile flavor. Other dietary sources include soy products and wheat germ. And yes, it is found at high concentrations in semen.   Read more


Alternative to Chemotherapy and Radiation

Dr M Rigdon Lentz (an American) runs a German clinic with a unique cancer treatment. Cancer cells protect themselves from attack by the body’s immune system by spitting out many “false target” molecules that attract killer T cells in the blood and distract them from the real culprit, the cancer cells themselves. Lentz’s procedure involves filtering these decoy molecules from the blood. Often this is sufficient to initiate a fierce immune assault on the tumors, which flare up hot and red. Lentz described some dramatic cures. He reports major regression of tumors in 70% of his patients, despite the fact that most of them have been treated previously with chemo and/or radiation and traditional oncology has given up on them.    Read more


DRACO – kills all virus-infected cells

Todd Rider of MIT is quietly witty on-stage and charmingly self-effacing, but his program is radically ambitious. He wants to cure all infectious disease.

DRACO is an acronym for Double-stranded RNA-Activated Caspase Oligomizer. Start with the observation that single strands of RNA are used in all cells, but double-stranded RNA is found only in cells infected by viruses. The DrACO molecule has three parts: One part speaks to the body’s “mail system” that looks at address tags on a molecule, and uses those to send them to a particular cell. DRACO molecules are targeted to a particular kind of cell that is infected. Part two is a detector of double-stranded RNA. And if dsRNA is found, then part three is activated: molecular signals that trigger cell death. The bottom line is that DRACO molecules can find cells that are infected with any virus, distinguish them from uninfected cells, and selectively signal the cell to destroy itself. It’s been tested in test tubes and in mice it cures, for example, the flu. Rider’s lab is producing only tiny quantities of DRACO at present, but by year’s end he hopes to ramp up production for much wider testing.   Read more


RTEs = Retro Transposable Elements

Half of our DNA consists of repetitious stretches of DNA that never get translated into proteins. This was once referred to as “junk DNA” or even “parasitic DNA”, but it probably plays an important role in evolution. One piece of evidence for this is that RTEs of recent origin (those unique to primates) are a lot more active and mobile. They’re the part of us that is presently evolving. John Sedivy of Brown University reported that senescent cells – cells that have depleted their telomeres – are far more likely to have active RTE’s. These DNA segments make RNA copies of themselves which can then be “retro-transcribed” back into the chromosome, with disruptive consequences. (Transcription = DNA→RNA, part of the path by which chromosomes control the cell; Retro-transcription = RNA→DNA, an unusual and often pathological process)    Read more


Retinoic Acid promotes regeneration of damaged tissue

Retinoic Acid is an ingredient in prescription cremes which treat acne and also aging skin. Malcolm Maden from University of Florida reported that retinoic acid promotes regeneration generally. Read more


Genetic therapy is much advanced

Frank Church of Harvard reported on the state of the art in gene therapy. Fourteen years ago, the first gene transplant experiments resulted in death of a (very sick) teen patient, and set the field back several years. But advances in the interim make it possible now to insert a gene safely into a large number of cells of a lilving body, and target them to a precisely specified position on a chosen chromosome. This is done using CRISPRs, which are short stretches of RNA with a distinctive palindromic pattern, used by viruses to find the right place to insert themselves into a host genome.
Read about CRISPR
Read about Gene Therapy


Plasticity of the brain

Jean Hébert of Einstein Medical Center in New York is working to inject neural stem cells into the brain, to grow new nerves. This might seem like an impossible challenge. Nerve cells regenerate at a rate lower than any other cell type in the body, and even if we got them to regrow, how would they come to carry the knowledge and skills that we have acquired during a lifetime? Hébert reports a hopeful and amazing fact: In patients with brain tumors that destroy function in one part of the brain, another part picks up the function smoothly and without noticeable disruption. This has been noted with fMRI studies based on Boca’s area, which houses language.   Read more


Growing a liver on a lymph node

There is a long waiting list for liver transplants. In the US, 90% of patients with liver failure will die before they get a transplant. Some have proposed transplanting livers from pigs. Eric Lagasse of Wake Forest Inst for regenerative medicine has another idea. He has had success growing new livers from stem cells in the patient’s body. Liver progenitor cells are implanted in a lymph node, which seems to provide a favorable environment for growth. In mouse models, 70% are able to grow a functional liver “ectopically”, meaning in a part of the body where it does not belong.
Read more

New Take on Free Radicals

One of the oldest and best-established theories of aging holds that we age because of oxidative damage. In the classic version, the body exploits high-energy chemistry based on oxidation for an energy supply at the cellular level, but this involves constant exposure to these high-energy species and the free radicals that are their by-products, species which can attack sensitive biomolecules. Damage to these molecules accumulates over a lifetime, so the story goes, and makes the body gradually less able to maintain its balance. I’ve argued against the general idea that aging is an accumulation of damage, because of evidence that it is an active process, closely regulated like everything else about life. But new to me this week is a version of the theory by Spanish physiologist Gustavo Barja, in which some of the same chemistry is described as an active program of self-destruction. Barja argues that the process of burning fuel to produce energy can be extremely clean or it can be rather dirty. It is the “leakage” of free radicals during the process that causes the damage of aging, and this leakage can be quite fast, or it can be almost nil. Leakage is tightly-regulated in a way that determines life span. This is a unique lens through which to view aging. What does it help us to understand?

An old and (I believe) discredited view of aging is that the body ages the same way a tool rusts or a car wears out over time – because damage accumulates with wear and exposure to corrosion. The best-established version of this theory is based on damage in the cellular energy factories, the mitochondria, and it is called the Mitochondrial Free Radical Theory of Aging, MFRTA. I visited last week with a man who has devoted his career to studying the chemistry of mitochondria, and he has come to believe that indeed mitochondrial chemistry has a lot to do with aging, but this is not just damage that accumulates as a side-effect of the energetic chemistry. He thinks that this damage is purposeful and programmed, and has written an updated version of MFRTA

Everything that you have heard about free radicals, ROS (reactive oxygen species) and anti-oxidants derives from the MFRTA. Mitochondria are tiny energy factories. Hundreds of them in each cell of our body burn sugar and convert the energy to an electrochemical form, analogous to charging a battery. This is the Krebs cycle. The electrochemical energy (in the form ATP) is then used for nerve signals and muscle movements and manufacturing biochemicals – everything for which the body requires energy.

Classic MFRTA

In the original version of MFRTA theory, there are unavoidable by-products of the highly-energetic chemical reactions that power our bodies. These are free radicals or ROS, and they corrode the body’s delicate chemistry. There are quencher chemicals – antioxidants that help mop up the toxic waste. These include SOD, ubiquinone (coQ10), and glutathione, catalase, and vitamin C. But they are not 100% efficient at preventing damage. It is the buildup of damaged biochemicals that is the root cause of aging.

One of the attractive things about the MFRTA is its connection to evolutionary history. Once upon a time, more than a billion years ago, mitochondria were infectious bacteria. They invaded the primitive cells at the time, lived as parasites, and killed the cell with their powerful oxidative toxins. Over a long period of time, the parasites evolved to be friendlier to the host, and the host evolved to exploit the energy products of the parasite. Every eukaryotic cell, including all multi-cellular life today, is descended from this ancient symbiosis. Modern mitochondria are performing in the service of the host cell, and have no will of their own. But they retain the capacity to kill the cell, and in fact can serve as executioners when they are signaled to do so. This is apoptosis, or programmed cell death.

Problems with the MFRTA theory include:

  • Anti-oxidants don’t seem to extend life span when fed to animals or humans.
  • Exercise dramatically increases mitochondrial activity, but it actually helps you live longer. (Exercise promotes longevity in animals, too.)
  • In one dramatic experiment, worms that are missing both copies of the gene for the anti-oxidant ubiquinone lived ten times longer than “wild-type” worms in which this gene remains intact.
  • Long-lived animals generally have less anti-oxidant defense than similar-sized short-lived animals.
  • Damage to mitochondria hardly seems lasting, since hundreds of mitochondria are constantly recycling themselves, cloning themselves and even exchanging DNA with one another within the lifetime of a single cell.
  • MFRTA seems to address the “how” but not the “why” of aging. If ROS damage can be avoided by some animals that live a long time, why have other (short-lived) animals not learned this same trick?

Barja update on MFRTA

Gustavo Barja addresses some of these objections in his up-dated version of the MFRTA. In Barja’s version, the leakage of free radicals is not unavoidable; rather toxic by-products are borrowed (co-opted) for a purposeful self-destruction. Thus he turns the weakness of MFRTA into a strength, noting that the rate of leakage is dramatically variable from one animal species to another, and in different tissues at different times. This must be purposeful, and the purpose (aging death) is modulated according to environmental cues.

During exercise, there is much more mitochondrial energy generation (of course) but the rate of free radical leakage is dramatically lower. There is actually less ROS damage, even with a far greater energy throughput. This low leakage rate persists when exercise is finished, and is responsible for some of the health and longevity benefits of exercise.

(I’ve mentioned in this column evidence that free radical generation from exercise serves as a signal to bring protective chemistry into play that slows aging.  I haven’t yet figured out how to make this jive with new information that I learned from Barja, that ROS production is down during exercise.)

There is less free radical damage in a long-lived bat (40 years) than in a short-lived mouse (3 years), and it is because the rate of ROS production is lower in the bat. The bat actually has less free radical defense chemistry than the mouse, because less is needed, and this despite the bat burns so much more energy in flying than the mouse needs on the ground. This is a consistent pattern among long-lived species.

Long-lived animals also protect themselves by using biochemicals that are less vulnerable to ROS attack. In particular, double bonds are hot spots for chemical change. You’ve heard of saturated and unsaturated and polyunsaturated fats. “Saturated” means no double bonds, and “polyunsaturated” means many double bonds. Fat molecules (“lipids”) are essential parts of body chemistry, used to form membranes that separate one cell from another and one part of a cell from other parts. The punch line: long-lived animals have fewer double bonds in their unsaturated lipids, so they are less vulnerable to ROS corrosion.

A new and unexpected observation

Part of the problem with the MFRTA theory is that the damage is centered on the mitochondria, which are dynamic, “disposable” orangelles within the cell. Barja wondered how might it come about that mitochondria inflict permanent damage on the cell? Three years ago he found a clue. Mitochondria retain a bit of their own DNA, a relic from their historic origins as independent bacteria. Mitochondrial DNA (abbreviated mtDNA) is exposed to the ROS products of oxidative chemistry at close range, and is easily damaged. Sometimes the mtDNA is broken by the ROS.

What Barja found (in collaboration with labs of Juan Sastre and Maria Jesus Pertas) is that mtDNA fragments are released into the cell and even into the bloodstream. Some of these fragments find their way into the cell nucleus, and they can insert themselves into the nuclear DNA, where they might do great damage. There are many redundant copies of mtDNA, but only two copies of the nuclear DNA. Barja was able to detect sequences associated with mtDNA in samples of the nuclear DNA taken from tissues of young and old rats. There was consistently more mtDNA in the old rats than the young, and up to four times as much in some samples. This suggests that ROS damage occurring at the site of the mitochondria can transfer itself to the cell nucleus, and there it can persist and accumulate with age.

So here is a new twist on an old theory of aging. Could this out-of-place mtDNA be disrupting the normal activity of the nuclear DNA in regulating the cell? Could this be a means by which the mitochondria continue their ancient role as assassins?

Barja has shown that there is an association between mtDNA fragment and age. I have proposed to Barja that the next step is to see whether there is also an association with mortality. When two rats of the same age have different amounts of mtDNA out of place in the cell nucleus, is the one with the greater mtDNA likely to die sooner? Answering this question is a straightforward extension of Barja’s research, but such a study takes time; if all goes well, we’ll know in a few years.