Live longer!

Spring Chicken

So you want to live a long life, or at least age gracefully?

Bill Gifford has provided a well-researched and engrossing account of the quest for longevity. In his new book, Spring Chicken, Gifford critically examines the claims of scientists, enthusiasts and hucksters in their attempts to extend life using hormone replacement therapy, telomerase, supplements, drugs, exercise, caloric restriction, intermittent fasting and other practices. Along the way, he visits with a 108-year old investment advisor and a 76-year old female sprinter who can run a 6:58 mile, and he  takes a close look at mice, monkeys and microbes that live much longer than species norms.

I found the book hard to put down. That’s not merely because Bill’s hilarious account of my wintry swim with him in the Pacific Ocean appears in Chapter 12–as a bracing illustration of how hormesis builds stress tolerance.  I was captivated by reading of his up-close encounters with a diverse set of gerontologists, centenarians and odd, long-lived creatures such as the naked mole rat. Most interesting of all was his meticulous detective work in probing the major competing theories of aging, leading to some unconventional conclusions about what may or may not actually help prolong life and healthspan.


I294588-1-1_giffordSpring Chicken, which last month hit Amazon’s top ten bestseller list and was featured in entertaining interviews on NPR’s Fresh Air and Dr. Oz, stems in part from Gifford’s own personal reflections upon reaching middle age. He was struck by huge disparities in the way his older relatives and even his beloved dogs aged — not merely in the length of their years, but in the duration of their vitality.  As an athlete and writer for fitness and science magazines such as Men’s Health, Outside, Bicycling and Wired, Gifford wanted to  take a much deeper dive into the both the science and popular lore about how to prolong lifespan and health span.

Theorizing about longevity has a relatively short history, because until recent times the bigger problem was survival beyond childhood and youth. During the past two centuries, advances in sanitation, nutrition, and public safety (despite what you’d think from watching the news) have enabled an almost linear increase in average lifespan. The question now is what controls the upper limit on the maximum and average length of time humans live.

Theories of Aging.  There are numerous alternative explanations for why we age. Without oversimplifying too much, aging theories can be lumped into three big buckets.  Two of these competing theories have until recently dominated the discussion:  the genetic program theory, and the damage accumulation theory. While each of these two theories has a certain plausibility, Gifford’s book puts them through the ringer and shows where they fall apart. At the end of Spring Chicken, he turns to a third, relatively recent theory of aging that seems quite plausible:  the hyperfunction theory of aging.   This third theory fits quite well with my own thinking about why hormesis is good for you.

But let’s start with the two conventional wisdom about what determines lifespan.

The genetic program theory.  There is a lot of evidence to support the idea that aging is an inevitable result of genetic programs.  Every species has its own program, which more or less determines a fixed timetable for development and maximum lifespan, assuming the organism survives premature death by disease or accidents.  The big question is whether or not this programmed timetable can be altered.   On this question, gerontologists divide into two camps:  the pessimists and the optimists.

The genetic program theory, version 1:  the pessimists. A leading spokesman for the pessimists is Jay Olshansky, a gerontologist and demographer from the University of Illinois at Chicago. Olshansky believes that the maximum human lifespan is roughly the same as that lived by Jean Calmet, the current record-holder at 122 years.  He thinks that the maximum average lifespan of population won’t go higher than where it is today — about 85 years.  A healthy lifestyle, supplements and the conquest of disease won’t do much to change that; in fact, average lifespans may actually start to decrease.  Pessimists like Olshansky point to realities such as the Hayflick limit — the discovery by biologist Leonard Hayflick that mammalian cell lines aren’t immortal, but can only divide about 50 times before they inevitably die.  This appears to be an unavoidable consequence of a genetic “clock” controlled by telomeres — regions of chromosomes that become progressively shorter with each cell division cycle.

The selection shadow. The genetic pessimists also find support in an evolutionary principle called “the selection shadow”.  Natural selection favors genes that enhance the survival of individuals through the age of reproduction.  After that age, there is no selective pressure on the genome to promote a long and healthy life.  In short, evolution doesn’t care about longevity of the body (a.k.a. the “disposable soma”) but only the passing of the germ line to the next generation.

Unknown-5A corollary of the selection shadow is a phenomenon called antagonistic pleiotropy:  traits that are adaptive for reproductive success in youth have secondary effects that are frequently detrimental after the age of reproduction.  For example, the same genes  that produce high levels of dihydrotestosterone and prostaglandin D2–thereby spawning robust hair growth in young men, a visual marker of health and sexual attractiveness in youth–eventually produce the secondary effect of reduced hair follicle size and male pattern baldness with progressive age.  (Presumably, these genes had greater selective value when the typical age of reproduction was younger).  Other examples of antagonistic pleiotropy include diseases such as:

  • Huntington’s disease – resulting from genes that increase fertility and immune health in childbearing years, but manifesting as a crippling form of dementia in middle age
  • Hemochromatosis – high blood iron levels that are protective against plague, but become ulimately inflammatory and toxic in midlife and old age

It’s likely that hardening of the arteries, skin wrinkling and other aging processes result from genetically controlled development programs that are beneficial in the bloom of youth but detrimental after the childbearing years.

There is a flip side to antagonistic pleiotropy:  organisms with mutations that promote longevity tend to reproduce later, so they are out-competed and get bred out by younger, more prolific reproducers. This has been shown by Gordon Lithglow in the C. elegans worm.  Worms mutated to knock out the daf-2 gene lived twice as long as normal worms. But when these worms were mixed with normal worms, they reproduced more slowly and the long-lived worms were bred out of the population after only four generations!  In humans too,  such “longevity genes” tend to get bred out of populations:  A study of centenarian Ashkenazi Jews found that they tended to have fewer children and had them later in life, even before the age of birth control.  So living longer seems to be advantageous for the individual, but not for the species.

The genetic program theory, version 2: the optimists. Not all the genetic program theorists are pessimists.  James Vaupel, Director of the Max Planck Institute for Demographic Research, is impressed by the finding that there has been a steady, almost linear increase in lifespan over the past two centuries. Since 1840, average lifespan has increased at a very steady rate of about 2.4 years per decade.  Up until about 1950, this was mainly a result of eliminating the causes of death in childhood and youth — childbirth mortality, infectious disease, malnutrition.  Since 1950, lifespan has increased mainly by attacking “diseases of old age” – cancer, cardiovascular disease and the like.

Some of the “optimists”, like Aubrey De Grey, believe that there is no fixed upper limit on age.  He’s a true zealot for the cause of life extension, once claiming on the program 60 Minutes that some people now alive would live to be 1000 years old, outpacing Methuselah of the Bible.  Until now, longevity has been increased slowly by tackling one disease at a time.  But is aging the result of old-age diseases like cancer, diabetes, cardiovascular disease and dementia?  Or is there some fundamental “root cause” driver of aging that happens to result in these diseases?  De Grey wants to identify and attack the root causes of aging.

The burgeoning field of “anti-aging medicine” is based on the idea that we can slow the pace of the genetic program by compensating for deficiencies that develop over time in the inputs. Recently, the Palo Alto Longevity Prize has been organized as a “life science competition dedicated to ending aging”.  Two  $500,000 prizes have been offered to teams that can increase lifespan by 50% relative to a control mammal, or restore the HRV of an aging mammal to that of a youth.

Perhaps the genetic program can be “hacked” — either by changing the inputs or by modifying the program itself.  What are the inputs?  Primarily hormones and supplements.  Presumably our developmental genetic programs “run down” as we age because hormone and nutrient levels run down. To extend life, we need to replenish, restore, and re-energize.

Restoring hormones. Some of the more amusing stories in Spring Chicken concern the history of hormone replacement therapies.  Gifford traces this back to nineteenth-century experiments by Charles Edouard Brown-Séquard, who injected himself, then others, with extracts from crushed testicles from dogs and guinea pigs.  He experience renewed vitality and commercialized his testosterone-rich concotion as “Séquard’s Elixir of Life.”   The fad died along with Brown-Séquard five years later. While the results were variable and short-lived, the experience of restored stamina led ultimately to what continues today as a hopeful set of treatments to extend life and physical prowess using more standardized infusions of testosterone, estrogen, growth hormone, and other steroid hormones.

Unknown-3Hormone replacement therapy (HRT) was a mainstream therapy for decades until 2002, when the Women’s Health Initiative study found strong evidence of increased breast cancer among women using estrogen supplements.   At that point, some explained this negative result as a consequence of using unnatural, synthetic forms of estrogen, and failing to balance the estrogen with progesterone and testosterone.  Suzanne Somers and others now advocate the use of “bioidenticals”, which presumably restore the natural hormones in proper balance.  However, studies even with bioidenticals raise safety concerns for use beyond about 3-5 years, after which elevated levels of estrogen and other hormones can elevate the risk of atherosclerosis, cancer or dementia.  Similarly, extended use of testosterone and human growth hormone has been linked to increased risk of cardiovascular disease, stroke and death.   It seems that hormones which help promote growth and sexual maturity in youth can indeed have negative consequences when introduced later in the genetic program,

great_dane_chihuahuaA deeper challenge to the rationale for hormone replacement therapy comes from research showing that a “deficiency” of hormones is no impediment to a long life, but may actually prolong life.  The longest living lab mice actually have no growth hormone receptors. Mice that are genetically altered to stop producing growth hormone in fact live twice as long as normal mice. Chihuahuas lack growth hormone but outlive most larger dogs.   It’s not just smaller animals that tend to live longer.  The Larone “little people” of the Andes Mountains have a rare genetic mutation, similar to that of the dwarf mice and Chihuahaus, resulting in lack of growth hormone receptors, short stature and old age.  They appear to be resistant to cancer and diabetes. As Gifford reports, “They eat whatever the hell they want, they smoke, and they drink, and they still live pretty long.”

Mechanistic studies confirm that growth hormone stimulates IGF-1, the growth factor that stimulates cell growth and division and spurs associated aging processes.   So maybe hormone supplementation is not the panacea proffered by some in the anti-aging medicine field.

Engineering longevity?  Aubrey de Grey has outlined a program he terms SENS: Strategies for Engineering Negligible Senescence.  Some of the SENS strategies involve somehow engineering the genome to reduce — or eliminate — the deleterious cellular processes that shorten life.  This seems to me to be a rather utopian idea, harboring the potential for unintended consequences.  Since genes are pleiotropic (they have multiple different regulatory functions individually and in concert), an innocent genetic “edit”–intended to confer a certain identifiable benefit– could risk causing deleterious secondary consequences, in respects that may not be immediately apparent.

Unknown-4Genetic studies found associations between shorter telomeres  (the “end caps” on certain chromosomes) and increased incidence of diseases of aging — such as cancer, cardiovascular disease and dementia.  At the same time, athletes and certain long-lived species exhibit well preserved telomeres.  So one of the more reasonable ideas for revamping the genetic program is not to monkey with the genetic code, but rather to slow the biological clock by reducing the rate at which telomeres erode. The discovery in 1984 of telomerase — the enzyme that repairs and restores telomeres – created much excitement within the anti-aging movement.  Companies like Geron were spawned to commercialize potential clinical uses for telomerase.

However, Gifford raises an excellent question about the connection between telomeres and aging:  Do shorter telomeres cause aging or are they a result of aging processes?  He cites a study of 4500 people which found that there is no link between shorter telomeres and mortality, after controlling for life-shortening behaviors like smoking and alcohol abuse.  Furthermore, there is evidence that activating telomerase might cause cancer. Cancer cells have much more telomerase then normal cells. And some animals with very long telomeres and lots of telomerase actually live a very short time, such as laboratory mice.

So much for the genetic programming theory.  Let’s now turn to the second major theory of aging.

The damage accumulation theory.  Another name for this theory is the “free-radical theory of aging”.  If you are one who takes vitamin or antioxidant supplements, you’ve no doubt been influenced by the theory that aging is caused by–or at least accelerated by– “oxidative stress”.  Oxidative stress is what happens when free radicals and reactive oxygen species (ROS) react with proteins, lipids, DNA and other biological molecules to cause molecular damage within the cell. Over time, this damage accumulates in tissues and organs such as skin, arteries, neurons, eyes — and especially in the mitochondria, the energy powerhouse inside each cell.  To some extent, cellular repair processes can partially reverse this damage. But according to the damage accumulation theory, at some point the damage starts to outstrip the repair capacity our cells — and the consequence is wrinkled skin, grey hair, hardened arteries, atrophied muscles, tangled neurons, and impaired immune defenses against infections and cancer.  In short — oxidative stress is proposed as the root cause of aging.

Hence the popular enthusiasm for antioxidants such as vitamins C and E, Co-Q10, glutathione and the like.  You can’t go into a pharmacy these days without seeing racks of these supplements.  Some people pop more than a dozen of these pills a day.

Spring Chicken does a beautiful job of skewering the damage accumulation theory, serving up one challenging counterexample after another.  I’ll cite just three that should give you pause:

  • Unknown-7The failure of antioxidant supplements to extend lifespan. If oxidative stress is the enemy of youthfulness, then taking antioxidant supplements should neutralize free radicals and ROS, inhibit the damage and extend lifespan.  But study after study in animals and humans has failed to show any evidence that it does so.  Studies of  vitamin C and selenium show no conclusive effect on longevity.   A study of more than 230,000 people found that supplementation with vitamin A, vitamin E and beta-carotene actually increased mortality risk.
  • The essential biological function of oxidative stress.  Exercise is known to immediately increase oxidative stress. An exercise study by Michael Ristow asked subjects to work out 5 days a week, and biopsied their muscles after the workouts. During the study,  half the subjects ingested high levels of vitamins C and E, while the others took placebo pills.  Both groups showed high levels of oxidative stress in their muscles after the workouts.  But those who took the antioxidants failed to show the training benefits achieved by those who took no antioxidants.  As I noted in my article, The case against antioxidants, this is actually no mystery.  While excessive and chronic oxidative stress may be detrimental, short term oxidative stress during exercise is actually a good thing; it is the basis for cell signaling between nerves and muscles.  Shutting it down can impair performance.  In addition, oxidative stress activates the Nrf2 pathway, upregulating production of the body’s own endogenous antioxidants, such as superoxide dismutase and glutathione reductase.  These endogenous antioxidants are turned on in the right tissues at the right time, for only as long as needed.  Unfortunately, consumption of high levels of antioxidant supplements shuts down the Nrf2 pathway and production of endogenous antioxidants and key repair enzymes.  Paradoxically, supplementing with antioxidants can increase vulnerability to the effects of oxidative stress.
  • Unknown-6The existence of animals that live long despite high oxidative damage. The naked mole rat is perhaps the most vivid refutation of the damage accumulation theory.  This small burrowing rodent can live about 30 years — about 6 times as long as the longest-lived known lab rat.  Naked mole rats must have very little oxidative damage in their bodies, right?  Wrong. Their tissues and organs are wracked with very high levels of oxidative “damage”.  And when raised in captivity, where they are exposed to higher concentrations of oxygen and even more oxidative stress than they would see in their natural life, they live just as long.  In fact, naked mole rats seem to benefit from a very robust stress response — hormesis — that helps them outlive their more ordinary rodent cousins.  Their prodigious hormetic ability appears to lie in a high functioning proteasome, the cellular system that removes and repairs damaged parts.  When lab rats die of old age, it’s usually cancer that gets them. The naked mole rat just doesn’t get cancer.  And it’s not alone; there are many other long lived species that exemplify old age in the face of extreme accumulation of damage.

What we can we take away from the failures of the genetic program theory and the damage accumulation theory to explain aging and extend life?  I think Bill Gifford summarizes the complexity of the situation most aptly:

What is clear is that aging is a lot more tricky than most people realize–and that simply putting something back, like growth hormone or whatever supplement happens to be trendy at the moment, isn’t going to solve the problem… “Imagine you have a symphony written by Mozart,” says Valter Longo, a professor of biology at USC and a leading researcher on aging. “Taking growth hormone or a supplement or whatever is like going to the cello player and saying, ‘Can you just make it a lot louder?’ Chances are, it will screw things up. (SC, p. 61).

The hyperfunction theory.  What if aging is a result not of deficient inputs to the developmental program, or external insults to the program — but rather a result of the program going into overdrive, becoming a “runaway” program?  Overactivity rather than underactivity or underprotection.  That may at first sound like a bizarrely improbable and iconoclastic theory.  But the hyperfunction theory of aging is gaining credence as a plausible explanation with some surprising and hopeful consequences.

Major proponents of the hyperfunction theory include Mikhail Blagosklonny, David Gems, Yila de la Guardia, Linda Partridge and Valter Longo. They agree with the genetic program theory that life is governed by a “program”, but it is a developmental program, not specifically an aging program. According to Blagosklonny, aging can be viewed a “a quasi-program, a useless and unintentional continuation (or run on) of developmental programs.”

imagesThe hyperfunction theory holds that the diseases of aging come about from growth signaling pathways “running on inertia”, resulting in over-stimulation of normal cell functions. Classic examples of hyperfunction or overdrive can be seen in the overactive inflammatory processes of  cardiovascular plaque formation, platelet aggregation in stroke, rampant cell division of cancer, unchecked lipogenesis in obesity, or beta cell burnout and runaway glycogenesis in diabetes.  Hyperfunction ultimately leads to a loss of homeostasis, marked by elevated blood pressure and blood glucose, leading to organ damage.

At the very root of these runaway processes is a central regulatory pathway known as mTOR — short for “mammalian target of rapamycin”.  (In his book, Gifford uses the less common shorter acronym TOR, as this same growth pathway is found even in yeast and worms). In normal developmental, the mTOR pathway drives the growth processes of youth, to help ensure the organism reaches the age of reproduction in good health.  But when the mTOR-driven growth processes are sustained into middle age, running at full throttle and beyond their usefulness, these processes can backfire.  Seen in this light, what we referred to earlier as “antagonistic pleitropy” is not an accidental secondary result of early development functions, but a predictable consequence of “too much for too long”.  For example, in young males, mTOR induces the growth hormones and sex hormones that drive normal development and enable useful primary and secondary sexual characteristics;  but beyond the age of sexual maturity, the continued secretion of elevated testosterone levels can lead to the “hyperfunction” of male pattern baldness.

How do the hyperfunction theorists view oxidative damage?  According to Blagosklonny, oxidative damage is not a cause of aging, but rather  a consequence — collateral damage from  the mTOR-driven inflammatory processes underlying aging processes like cancer, atherosclerosis, osteoporosis, diabetes, hypertension, obesity and dementia.

If you accept the hyperfunction theory, then life and health span can be lengthened by “turning down the throttle” as we move past youth into middle age, calming the mTOR pathway.  This strategy can take be executed using a variety of tactics:

  • Drug compounds such as metformin or rapamycin, which directly inhibit the mTOR pathway, can help rein in excessive cellular function and blocking inflammatory pathways.  Both compounds have shown efficacy in treating diabetes and hypertension. Blocking the TOR pathway in yeast triples lifespan.  In mice, rapamycin has reduced cancer incidence, increased tendon elasticity, and dramatically extended lifespan.  Could rapamycin be useful in extending human lifespan. Perhaps, though one downside is that it sometimes suppresses immune function.  The is also some evidence that natural products such as caffeine, green tea, curcumin and resveratrol act as mTOR inhibitors.
  • Dietary restriction is a powerful way to inhibit mTOR.  Valter Longo observes that diets high carbohydrates and proteins they increase levels of nutrient sensors like insulin and mTOR, activating growth inducers such as leptin, IGF-1 and growth hormone.  These hormones and inducers are are beneficial in the short term, but if overextended they promote obesity and the associated metabolic syndrome of diabetes, hypertension, cardiovascular disease and dementia.  Longo points to long-lived residents of Calabria, Italy, like 109-year old Salvatore Caruso, who eat a diet low in both carbohydrates and protein.  Ron Rosedale similarly emphasizes the value of restricting carbs and protein in suppressing mTOR in order to extend lifespan. Rosedale further links mTOR to the thyroid’s control of metabolic rate.   In this context, I find very illuminating his analogy comparing mTOR and thyroid control of resting metabolism with the idle of an automobile:

    Unknown-9In calorie-restricted animals, researchers generally see a lower free T3 [thyroid hormones].  They also see lower T3 in centenarians, people who live past 100. When you see a lower free T3, it’s really indicative of kind of a longevity phenotype. It’s indicative of what you might even call, non-hibernating hibernation. And one clue that this lower T3 is healthy is that people who have it generally report that they function better.  If it happens to you, on a low-carb diet that you’ve become adapted to over time, you’re not weak. You generally have more energy. Having your T3 level go lower, in a healthy way, is like being able to turn down the idle of a car when it’s tuned properly, so that at rest it doesn’t have to waste as much energy.  In an efficiently running car, the resting “metabolism” of the car is lower.  And if you want to get power from that car, if you want to accelerate, that’s better too.  When a car is well tuned, it allows for a lower idle speed, and it will actually accelerate faster, and the engine itself certainly will have a much longer lifespan. It’s functioning better.

  • Intermittent fasting is perhaps the single most effective and practical way to turn down the mTOR pathway and the ensuing growth cascade of hormones like insulin and IGF-1, and associated pro-inflammatory cytokines like interleuken-6. Intermittent fasting– or IF as it’s popularly called — has been shown to induce autophagy, a cellular “house cleaning” process that efficiently removes glycated proteins, damaged nucleic acids and other cellular “junk” when one abstains from food for about 12-18 hours.  University of Florida researchers recently found that IF boosts expression of the longevity-promoting SIRT3 protein (although taking vitamin C and E supplements cancels out this benefit, apparently by neutralizing the mild oxidative stress).   IF has particular benefits for the brain.  Not only does the ensuing autophagy facilitate removal of damaged proteins and lipids that accumulated intracellularly, but it boosts levels of brain-derived neurotrophic factor (BDNF) that stimulates neurogenesis and help regenerate tau protein that becomes phosphorylated in Alzheimer’s disease. Gifford notes that Mark Mattson and others have shown that these benefits of IF don’t require any net calorie restriction, but derive only from the pattern of allowing adequate breaks in the pace of food intake.  This fact impressed Valter Longo, who was rightly horrified by the negative health consequences of more extreme calorie restriction, such as that practiced by Ray Walford of Biosphere fame.  In his own research,  Longo found that introducing a period of IF prior to chemotherapy increased the effectiveness and decreased the side effects in both mice and human trials. He theorizes that switching normal cells to a “low mTOR” state is protective, while the same low mTOR state is highly stressful to fast growth-oriented cancer cells.
  • Exercise is also a highly effective way to keep mTOR in check and maintain mitochondrial function.  Gifford notes the work of Mark Tarnopolsky of McMaster University in showing that regular exercise activated molecular processes that repaired defective mitochondria DNA in lab mice.  As already noted, exercise induces short term oxidative stress which paradoxically improves stress resistance. Studies by Bo et al eludicate the underlying mechanism::

[O]ur data suggest that regular exercise training stimulates mitochondrial biogenesis, a rejuvenation of the mitochondrial network via fission and fusion, and an improved efficiency of mitochondrial energy transfer….[T]he accumulation of oxidative damage can be decreased either by lowering the generation of ROS (caloric restriction) or by regular exposure to a small amount of ROS (such as mild exercise) that could result in slight oxidative damage, which then leads to up-regulation of antioxidant systems and amelioration of mitochondrial remodeling.

Hormesis and stress resistance in aging.  Towards the end of his book, Gifford muses that there is no real “secret” to aging:

Use it or lose it may be the best we can do for now”.

I think that the hormesis, the stress response, is the best explanation for the effectiveness of  “use it or lose it” in extending life and healthspan. The hyperfunction theory provides a plausible framework to explain the anti-aging benefits of many types of hormesis, including calorie restriction, protein restriction, and intermittent fasting.

Advocates of a “paleo” diet and lifestyle are fond of looking to evolution as a guide for maximizing health and longevity.  But, as Ron Rosedale points out, evolution doesn’t care about you after you reach the age of reproduction and a bit of child rearing, so the yardstick of evolution isn’t all that useful as a guide for living to a ripe old age. We need to use science to hack the “unnatural” post-reproductive phase of  genome expression.

Evolution selected for the mTOR pathway to channel energy towards reaching sexual maturity and passing along the genes to the next generation.  Eat a lot of protein and carbs in your youth and you’ll grow big and strong and optimize your fertility. But if the hyperfunction theorists are right, that’s not a good plan for living a long and healthy life, because those very growth processes lead to the diseases of aging unless tightly reined in as we get older. Life is loosely guided by a program that is highly “plastic” or adaptable, a program that responds to stimuli. As such, the “life program” for mammals like ourselves can be divided into two phases: the pre-reproductive and post-reproductive phases.  In the pre-reproductive phase, it is indeed beneficial to stimulate the growth and reproduction programs, to gain mass, strength, immunity and fertility.  That’s important.  Undernutrition during this phase can be a liability in reaching maturity. During the post-reproductive phase of the “program”, however, the game changes. Prolonging the stimulation of growth can lead to the conditions that we think of as aging:  heart disease, stroke, hypertension, diabetes, cancer, dementia. So during this second phase of life, in the selection shadow, it’s a good idea to pull back in order to avoid the pitfalls of hyperfunction.

Unknown-10But reining in the growth programs is not enough, in my view.  It’s especially important during this second phase of life — middle age and old age, to also keep your defense and repair programs humming, because you’ll find that they come in handy.  Strong muscles and bones and a well-tuned brain are an essential foundation for thriving in old age. And that’s where hormesis comes in. By activating our stress responses (within reason), our metabolisms are forced to channel energy way from “growth and reproduction” programs to support “defense and repair” programs.  This goes well beyond merely manipulating diet and energy status to lower the mTOR pathway.  We need stress to thrive as we age! Intense exercise and cold exposure can be effective in stimulating the activation of defense and repair pathways. Those essentials are nurtured by activating the hormesis programs, by means of nutrient limitation, judicious intake of “hormetins” like caffeine, green tea, curcumin and plant phytochemicals, and routine exposure to environmental stressors like vigorous exercise, exposure to cold and heat, and mental challenge.

The hormesis programs provide what it takes to keep us sharp.  They represent the physiological basis for Bill Gifford’s prescription to “use it or lose it”.

Spring Chicken does a nice job of deflating the population misconception that the secret of a long life is a simple matter restoring vitality by injecting some magic hormone, or trying to dodge the onslaught of oxidative stress by gulping fistfuls of antioxidants. Perhaps drinking coffee and supplementing with metformin will help a little.  But if you want to live a long and graceful life, it’s probably more important to moderate your eating, stay physically active and continually challenge yourself.


  1. Ann

    Thank you so much for this high-level overview. I feel like I’ve been groping around different parts of the “elephant,” reading piecemeal accounts written from various perspectives and using different assumptions, leading to back-and-forth convictions, bafflement, and paralyzing uncertainty. Now you’ve shown me the whole animal.

    This post is gold.

  2. When one gives it a bit of thought, it seems that all three theories have their respective merits. While genetic programming might not help predict our dying age, it puts our lifespan within a rough timeframe. Although it’s highly plausible that hormesis could be adapted into our lifestyles to prevent accumulated damages, it’s still not enough to turn the clock entirely backwards. In any case, the take-home message is that death is a certainty, but not the aging process 😉

    All in all, I really like the way how the concept of hormesis complements the hyperfunction theory of aging, but the mantra “use it or lose it” seems to suggest that there might be another “hypofunction” theory of aging? I don’t know, there is this “minimize this” theme that makes me feel that we might be missing something…

  3. donjoe

    Hmm… I always thought de Grey was in the “damage accumulation” camp, with the “7 types of damage” explanation forming the basis of his SENS approach. It’s strange to see him classified in the “genetic program” camp.

    “judicious intake of “hormetins” like caffeine, green tea, curcumin and plant phytochemicals”

    … and alcohol? (For those who have enough control to keep consumption moderate.)

    • Todd


      Well, I concede your point. At least partially. Aubrey de Grey and his SENS foundation is indeed concerned with damage accumulation, so I could have put him in that camp. Part of his SENS strategy looks at regenerative medicine as a way to replace organs that fail as a consequence of accumulated damage. But SENS is a multifactorial project and includes major elements focused on genetic modification or changing the genetic program. SENS has an effort called “mitoSENS” (boosting the mitochondrial DNA) and “ApoptoSENS” (genetically engineering cells to commit suicide once senescent). So he fits equally well within the genetic program camp. And he fits in with the “optimist” camp in that he is not content just to slow down the rate of oxidative damage, but wants to re-engineer us to become more resistant — or even immune — to aging-associated damage.

      The challenge in writing a short blog post on a complex topic like aging is to lay out and vividly illustrate the main themes and positions succinctly and simply, without getting too mired in the complexity of hybrid positions that blur the boundaries. So the danger is oversimplification, hence my caveat in starting out:

      “There are numerous alternative explanations for why we age. Without oversimplifying too much, aging theories can be lumped into three big buckets.”

      Well, perhaps I oversimplified a bit. So your comment is well taken. But hopefully the main lines and flow of the debate came through.

    • Joshua

      I’m loving your link about the connection between moderate drinking and improved health / lower mortality! I think I’ll have a drink or 2 after work today. 🙂

  4. Van

    Here are a few notes from a piece I read by Michael Eades MD with regards to antioxidants. I would appreciate your comments.

    Researchers have given zillions of subjects huge quantities of various antioxidants without any real change in longevity. Antioxidant supplements go into our blood, and most of the free radicals and free radical damage isn’t in the blood; it’s deep within the mitochondria. If the membrane doesn’t work the entire mitochondrium is compromised.

    Antioxidants that we take in supplement form don’t make their way into the interior of the mitochondrium.

    Intermittent fasting increases the saturation of the membranes. Animals that live longer have more saturated membranes.

    How can we increase the saturation of our membranes?

    1. By eating more saturated fat.

    2. By keeping insulin levels low.

    There are enzymes in the cells that both increase the length of fatty acid chains (called elongase enzymes) and those that desaturate (called desaturase enzymes) the fats. The desaturase enzymes can make fats less saturated. Insulin appears to activate these enzymes, so chronically elevated insulin levels would tend to keep the fats in the membranes less saturated and more susceptible to free radical attack. I would venture that this is one of the reasons that hyperinsulinemia shortens life. One of the constant findings in studies of centenarians is a low level of fasting insulin, which would make sense given the ability of excess insulin to make the membranes more prone to free radical damage.

    Many people seem to think that the cellular membranes won’t function well if they contain more saturated fat. They believe that a more rigid membrane creates problems for the proper operation of all the receptors and other large protein structures that reside in the membrane. They are right in a way, since a certain degree of fluidity is necessary, but they are wrong in their belief that the degree of rigidity or fluidity of the membrane is determined by the degree of saturation of the fats in the membrane. It’s determined by methylation.

    Methyl groups for methylation of the fats in the cellular membrane keep them more fluid while at the same time more saturated. The degree of rigidity or fluidity of the membrane is not determined by the degree of saturation (rigidity vs fluidity) of the fats in the membrane. It’s determined by methylation.

    An effective eating plan maintains the carbohydrate to protein ratio, and provides plenty of good quality saturated fat to help protect the cellular membranes from oxidative damage. It provides plenty of methionine, which is both a source of sulfur for the antioxidants in the mitochondria and a source of methyl groups for methylation of the fats in the cellular membrane… thereby keeping them more fluid while at the same time more saturated. And it keeps insulin levels low so that the fats are not desaturated more than necessary, once again keeping the membranes less prone to free radical damage.

    I watched your excellent video presentation on IF/hormesis. Thanks.


    • Todd

      Hi Van,

      Thanks for forwarding your notes from Mike Eades’ article.

      My comments:

      1. I fully agree that antioxidant supplements are typically ineffective because they typically increase blood levels rather than protecting mitochondria. But even worse, they often inhibit your body’s ability to synthesize it’s own endogenous antioxidant enzyme systems, which are far more potent and focused in their effectiveness than antioxidants “dumped” into the bloodstream.

      More on that here:

      2. I agree that a low carb / moderate protein / low insulinogenic diet has a beneficial effect on cellular membrane fatty acid composition. And I support inclusion of saturated fats in the diet. But I don’t agree with the blanket statement that higher saturated fatty acid content is preferred IN CELL MEMBRANES. For one thing, it depends on the specific saturated fatty acids. Some fatty acids are more pro-inflammatory than others, e.g. palmitic acid. And while saturated fatty acid in the diet is desirable, the level of saturated fatty acids in the diet doesn’t dictate their level in cell membranes. For example, Volek and Phinney showed (in their book, “The Art and Science of Low Carbohydrate Living” and in Lipids. 2008 Jan;43(1):65-77) that a carbohydrate restricted diet actually DECREASES the content of saturated fatty acids in plasma cell membranes, and results in higher concentration of unsaturated fatty acids, despite no increased intake of unsaturated fatty acids. This is because the low insulinogenic diet is anti-inflammatory and unsaturated fatty acids are “better preserved” in the cell membranes. It is wrong to assume that membranes are more “prone to oxidation” if they include higher levels of unsaturated fatty acids. Much more important is the overall pro- or anti- inflammatory state of the metabolism.

      So it’s a bit more complex that what Eades describes in the selection you cite.


  5. Van

    I consistently eat in a two hour window once per day. Glycemic control is maintained, and the plan neatly sidesteps insulin resistance and all the pathologies (cancer and cardiovascular disease in particular) whose incidence is increased by frequent eating.

    If you are maintaining glycemic control on a once daily eating plan, can you extend it to 48 hours a few times per week? Or is their a point when food restriction becomes a stressor on the body?

    As I understand, two things can happen. The body enters a catabolic state which radically increases the aging process. Second, the metabolic rate slows as a defensive measure against what the body perceives as famine. How long each individual can go without eating and not experience negative health consequences depends on the glycemic control issue, but can possibly be monitored by body temperature and heart rate. (My body temperature is consistently subnormal so this is problematic.)

    If you are unable to maintain body temperature and particularly if a low body temperature is accompanied by a very slow heart rate, maybe you have gone too far.

    Any thoughts on extending to 48 hours?

    • Todd


      Excellent questions: Is extending a fast to 48 hours beneficial, or counterproductive? Is there a point at which food restriction becomes a stressor on the body?

      I’m afraid that there is no simple answer beyond “it depends”. There is a lot of research on fasting and how long it takes for (a) the benefits of autophagy and low insulin, low mTOR to kick in; (b) the negative effects of catabolism, muscle loss, and hormone/neurotransmitter imbalances to become problematic. The problem with “studies” is that they are averages of individuals with very different genetic endowments and adaptive capacities. Because we are all different, my suggestion is to approach fasting incrementally, in small steps. Those who are adapted to 6 small high carb daily meals and are insulin resistant are advised to transition to fasting slowly, lest they experience hypoglycemic lightheadedness, irritability and energy challenges. I’ve provided some tips on how to make the transition to intermittent fasting in my post, Learning to Fast.

      But someone like yourself, who is already adapted to intermittent fasting, can be bolder in trying to extend the duration of fasting. The one downside you’ve specifically experienced is a lower body temperature and heart rate. If this bothers you, titrate back a bit. But don’t necessarily view those symptoms as negatives — as Ron Rosedale indicates in the articles I cite in my post, these symptoms likely reflect merely a “lower idle”, which indicates a well tuned metabolism and the prospect of a longer life with reduced risk of aging-related disease.


  6. Austin

    Todd, great work as always. 1) I’m 23, is it too early to begin IF? I have heard the brain continues to mature until about 30, and I don’t want to deprive myself of brain-nutrients. 2) Should I feed my older dog once a day instead of twice?

    • Todd


      No problem starting IF at 23. You’re pretty much done growing and maturing. Even with IF, you are switching between “growth” and “repair” cycles, and fasting or repair cycles are great for your brain, promoting neurogenesis as well as removing cellular debris.

      I’ve been feeding my beagle Charlie once a day since he was a year old. Beagles love to eat and eat and eat. He was getting thick around the neck and belly, and we learned that removing grains reversed that. We put him on a real meat dog food (Instinct) — one half can, once daily at dinner time. He is energetic and spry and full of life. Have had no problems at all since this transition. I notice a lot of plump beagles who drag along. Not our Charlie!

  7. I think that the genetic factor is crucial to achieve a long and healthy life.
    The second element is the style of living, the food we ate, if we workout, if we don;t drink too much and we don’t smoke, coffee and so on.
    The problem is the following:
    Many old folks can live a long life, but they lose their mind due to disease like dementia, parkinson and so on, so they have the ability to live long, but they live in pretty bad mental conditions.

    • Todd

      One of the main points of my article was precisely to highlight approaches that can prevent or delay dementia, allowing not just a longer life, but a mentally active longer life. Intermittent fasting (IF) in particular has been shown to up regulate BDNF (brain derived neurotrophic factor), which is strongly neuroprotective.

  8. bruno

    I’m not sure that low dose of anti-aging hormone (gh-testosterone-dhea) have bad effect with aging but for sure low hormone have a bad effect. mTor need more human reseach. No prove that decrease mTOR in human have a long better live

  9. Jesus

    Does anyone moderate the forums? Registered weeks ago and still not approved.

    • Todd

      Check again…I’ve approved all requests for the forum. What was the screen name you used?

      • Jesus

        You got me, thanks. <3

  10. Nate


    Great post, as usual. I have a couple of hormesis links I think you might be interested in.

    First off, there is a nephrologist, Jason Fung, who successfully treats his diabetic patients with intermittent fasting. He has a website, intensive dietary management, and a series of lectures. I think you might enjoy a couple of these lectures:

    The lectures are a little long, but really quite good. It’s quite gratifying to see someone actually cure a disease that has been with us so long. He says that most of his patients find fasting much easier than they thought it would be-and much, much easier than following a low calorie diet.

    Another possible hormesis link is a flashcard technology called “Anki”. It is basically flashcards on a computer. The thing that is different is that the program is set so that when you get the flashcards right, they appear at progressively longer intervals. Supposedly you remember things better if your memory is challenged right before you are about to forget something. There’s lots of memorization in medicine, and I find that I remember things much better now that I’ve been using it.

    I know it’s a little bit of a stretch, but I think of it as hormesis for the brain-stress on the memory at progressively longer intervals.

    Anyways, hope all is well with you.


  11. Van

    Hi Todd,

    You mentioned, “mechanistic studies confirm that growth hormone stimulates IGF-1, the growth factor that stimulates cell growth and division and spurs associated aging processes.”

    Intermittent fasting can increase growth hormone production significantly.

    Scientific data indicate that high levels of GH and IGF-1 will decidedly age you.

    Exercise in a fasting state stimulates production and release of growth hormone. Studies are mixed in their analysis of whether this growth hormone production is good or bad. The small amount of growth hormone released after high intensity exercise (not fasting) is good. The higher quantities of growth hormone provoked by exercise in a fasting state are probably not at all good.

    What about the increase in growth hormone with IF?

    • Todd


      My understanding is that GH and IGF-1 are beneficial in their natural context, e.g. in youth and adolescence, and in periodic spurts in modest amounts. It is only when they are secreted in excess that they lead to “accelerated” aging effects. In the case of intermittent aging and intermittent fasting, spurts of these growth factors are induced, but they quickly fall back to baseline. The key is to avoid chronic elevation.


  12. Hello,

    Thank you for this in-depth topic on the theories of aging. It was very informative and easy to understand; great job!

    About the last theory: I believe that all of the strategies you mentioned that would guard or work against cancer can be explained via increasing apoptosis, and thus just simply increasing the ability to screen for ‘bad’ cells and get rid of them. This would obviously protect against cancer, increase lifespan, and protect against the other way of getting rid of ‘bad’ cells – necrosing them via the immune system which leads to a lot of inflammation.

    Occam’s razor: I believe the ‘apoptosis’ theory encompasses everything stated about AMPk / mTOR, etc. while not invoking unnecessary assumptions about youth vitality vs longevity. What do you think?

  13. Great post, I must admit that I came to your blog thanks to that book :), but in Poland has been issued under different name.


Add Your Comment