Of Mice And Men And Monkeys And - Aging
    By Greg Critser | July 21st 2009 10:05 AM | 5 comments | Print | E-mail | Track Comments
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    Last week, scientists announced the interim results of one of modern physiology’s most closely watched experiments: the effects of caloric restriction on the lifespan of non-human primates.

    The report was maddeningly mixed.

    Caloric restriction seemed to reduce the incidence of several diseases, but when it came to mortality—a somewhat important factor when it comes  to longevity— the data were  statistically not significant. We still do not know if caloric restriction works in primates, which, of course, we are.

    Is the culprit bad science? Cryptic binging at McBanana’s by the monkeys? Doubtful. Instead,  the answer may be summed up in one Disneyesque word: m-o-u-s-e.

    In modern biological science today, no one mammal reigns quite as mightily as the mouse. By various counts we use anywhere from 30 to 100 million of them every year to research everything from cancer to diabetes to depression to bone disease and arthritis. Hundreds of millions in public money are used every year to breed, house, and feed and genetically manipulate mus musculus, often to useful and relevant scientific ends.

    of mice and men and monkeys and longevity

    Yet so powerful is today’s mouse lobby—the “mouse mafia”—that is has blinded much of the scientific establishment, and in particular the science and “health” media, to this 24-gram creature’s limits. Nowhere is this more evident than in the realm of research about aging.

    For more than 80 years, biologists have been trying to tease out the mechanism behind one of nature’s greatest puzzles: why caloric restriction (CR)—adequate nutrition minus 40 percent of usual caloric intake—produces a 30-50 percent increase in lifespan in the mouse and rat, the only mammals, so far, in which caloric restriction works.

    It is a tantalizing fact, mainly for its suggestion that cousin homo sapiens might someday reap its benefit. Thus has the caloric restriction effect  prompted no end of academic theories, lifestyle advice (one that frighteningly bans pizza, burritos and BBQ), and nutritional compounds. The most salaciously tracked recent breakthrough comes in the form of the much-vaunted “CR mimetics” such as resveratrol, the Harvard University-sponsored anti-aging compound recently sold to Glaxo Smith Kline for $750 million. A pill that can elongate life and health span--and with pizza.

    The principal dogma behind caloric restriction and CR mimetics concerns the molecule known as IGF-1, short for insulin-like growth factor. IGF-1 is critical in humans—we would die without it—because it helps protect us from infection, inflammation, and heart disease, and because it keeps bones and muscles strong. But a counterintuitive mirror of this emerges in mice undergoing caloric restriction:  they live longer, and their IGF1 is reduced. Mice with low IGF1 are also healthy, with reductions in several age-related diseases.

    But when it comes  to aging in humans, low IGF-1 is quietly turning out to be a bust. CR people, the few pizza-free masochists who can endure the regimen, show normal  IGF-1 levels, along with a slower rate of artery-aging , but is still too soon to judge its effects on lifespan. (Although a growing body of evidence suggests the gain may be as small as six pizza-free years.)

    A much touted recent study of Ashkenazy centenarians showed another troubling fact—only a miniscule percentage of these remarkable people turned out to have impaired  IGF1. More: the much-vaunted resveratrol compounds seem to only work in fat-eating obese mice; normal mice given the red wine derivative experience no increased lifespan.

    This week’s announcement about monkeys on caloric restriction for 20 years showed an important decrease in age-related muscle loss, which suggests that their IGF-1 may be a little closer to normal. Humans on caloric restriction diets have such boney derrieres that one of their chief complaints is discomfort in sitting, along with coldness, crankiness, and a lack of interest in Penelope Cruz.

    So why the continuing scientific dogma? Cash is one factor. Enormous investments of public and private dollars require belief and constant justification.  Another reason is what might be called “gerontological correctness”—GC.  In establishment gerontology, reduced IGF-1 is seen as the perfect scientific foil to the fact-light anti-aging crowd’s advocacy of human growth hormone, the hormone that stimulates increased IGF-1.  (So rabid is gero-hatred for HGH that two key testimonies in baseball’s HGH hearings came from…gerontologists, who used mouse data to justify their opposition to its use.) Although there is good reason to be wary of HGH use—mainly for its affect on one’s wallet—moderately ratcheted-up IGF-1 is likely not one of them.  GC big mouths can’t stand the fact that the actress Susanne Somers might have something they don’t, besides nice legs.

    There is one other reason, one that implicates us all: The understandable—and sometimes hypocritical—uneasiness we have about using monkeys for research. We want to live healthier, for longer, but we don’t want to feel bad about how we get there. Mice are easily abstracted. Monkeys…not so.  I understand that; someday we may decide that confining and experimenting on animals is indeed unnecessary and even a violation of mammalian dignity. But we are not there yet.

    Is there a midway point? Perhaps. A  non-endangered,  short-lived primate might hold the critical key between longevity, IGF-1, and humans. There are several possibilities. One is the marmoset, a — okay, cute — Brazilian tree critter that only lives 7-9 years, about the length of one NIH grant (maybe its most important selling point). The marmoset’s key muscle groups age like ours; like average humans, it does not have compromised  IGF-1 levels. The cotton top tamarin is another candidate.

    As sentient, rationale, information-retaining beings, we naturally  desire more—especially more life. If we really want it, science has to take off the blinders, and we’ve got to get a lot more tough-minded. As Bette Davis once remarked, “Growing old ain’t for sissies.”

    Greg Critser is the author of the forthcoming Eternity Soup: Inside the Quest to End Aging (Harmony); his lab animal blog, Mouse Farm, is at, or subscribe with this button: Mouse Farm Greg Critser


    Big Mouse?   I wonder if they are funding the animal rights groups who want to put an end to primate testing.

    Longevity? Notice that very old men are thin not obese. Cellular regeneration is very important when this process stops you die. If you are male and around 40 if you donate blood you reduce your risk of heart attack and stroke. At the same time you are making new blood cells in your bone marrow. I believe there are cumulative things you can do to extend a healthy active life. One thing is sex it's good for male longevity. The immune system becomes so good as you age it starts working against the body. If you address that you can avoid a lot of problems and have better health. Stem cell regeneration of organs is exciting the idea of extending life with a new body. If you regenerated the brain would you still retain your knowledge and memories? This is great age of knowledge.

    Russell Ade Scientist Simple Solutions for Complex Problems
    Dave Deamer

    Hi Greg,

    Let’s go a little deeper into the underlying causes of aging. The main thing to understand, which I don’t often see stated explicitly, is that the process of aging has multiple, additive, causal factors. Here are five that I can think of right off hand, and there are probably quite a few more:

    1. Cross-linking of collagen and other extra-cellular connective tissue fibers produces a general loss of flexibility. This causes the changes in external appearance that we associate with aging, and is an inevitable result of living in an oxidizing atmosphere and using oxygen as an energy source. Oxidant stress also inflames the tissues lining arteries, leading to the loss of flexibility and scarring called arteriosclerosis.  

    2. Accumulation of cross-linked and indigestible lipid in lysosomes is another product of oxidation damage. You can actually see this stuff in the heart and brain cells of elderly mammals, where it is referred to as lipofuscin or age pigment. Again, this seems to be inevitable, but the accumulation can be slowed by antioxidant nutrients such as vitamin E.

    3. Accumulating damage in mitochondria. We have hundreds, even thousands of these little guys in all cells except red blood cells, and they are essential for energy production as ATP. But they use oxygen to do this, and as a result they produce reactive oxygen species (ROS) such as hydrogen peroxide. The ROS are mostly taken care of by protective enzyme systems, but inevitably some leak out and damage other cell components.

    4. Accumulating damage to DNA. In non-mitotic cells like muscle and neurons, DNA is not synthesized, only repaired. As  result, somatic mutations slowly accumulate over time and ultimately overwhelm  cellular functions or produce cancerous transformations.

    5. The result of these molecular damage processes is that the immune system and endocrine system slowly drift away from homeostasis, producing some of the systemic symptoms of the aging process.

    When I first went into science as a career, I thought it would be very sensible to work on aging. But as I learned more about the multiple causes, I became increasingly pessimistic that we could ever do much more than extend longevity by more than 20 - 30 percent, so I went into other lines of research. What do you think? Is there reason to be optimistic about, say, doubling human longevity?

    Greg, Excellent article,

    I've always been bothered by the fact that we already know that mice are far worse at living long than we are (at getting cancer and at many other things). If economics were not a factor it would be far more insightful to study elephants who, by weight, are far more resistive to cancer than we are. Making advances in mice may often be merely helping the catch up to us, not learn anything beyond us.

    Dave, I think there are many reasons to be optimistic, but not about doubling the life span, but about eliminating the effects of aging altogether.

    Not the least of these reasons to be optimistic is that biology is slowy (with the exponential increase in computing power) becoming tractable. Being discourage by the handful of factors you named is understandable for the time you chose your career path, but today even the 30,000 genes to understand isn't such a major hurdle given that anyone can purchase a computer and genetic testing tools continue to lower and higher in capabilities with each generation of tools. This will only accellerate. Genetics isn't the end, though. It is the study of epigenetics (the genes that express them) that will take things to a higher state.

    Here's why I say more than doubling, total eradication of aging is at hand. We are finally seing individual molecular bonds (not just the atoms), and with each generation of tools we'll get better. Recently the UK upped the life expentancy by 12 months within 12 months. If you do the math, that rate, if continued, means we already have reached the goal.

    But here's the thing. While the preponderant of Sens, Aubrey deGrey, may be mistaken on his factors of aging, he is correct in his overarching idea that engineering is not about knowing all the root causes of anything, but about understanding how to brute force past those root causes to a solution. In other words, you don't have to know why your engine oil gets dirty, nor do you need to perfect the engine to a level that it never gets dirty, you just need to replace your engine oil periodically.

    In genetic and epigeneitc terms this means correcting the correctable factors (cross linking, telomere lengthening and the like), and programming apostatsis (programmed cell death) in the cells with uncorrectable factors, using stem cells to recreate tissues to replace what needs to be where it needs ot be and things of this nature, all of which are too far beyond us today to sound doable, but with each passing decade more will become doable.

    And here's where the leap-frog effect comes into play. If we can, not double the lifespan, but simply add 24 months life expectancy every 12 months that goes by, then look not at the current state but at the long term effect of those continued advances the life expectancy is essentially infinite already.

    This is happening now not through direct intervention into aging process but through better average sanitation and health practices. But each small step (sirtuin, TA Sciences, Sens and others) will make enough of a difference to make it to the next step.

    I think of it like a cross country automobile trip. We don't need to gas up to make it from Boston to LA. We only need to gas up to make it to the next station, and that's what is happening on a broad scale to those who take their health and longevity seriously.


    yes, these are the principle domains of cellular disharmony and its consequent decline of cellular repair mechanisms.
    i agree that the prospects for doubling the human health span are bleak, but further extension of what has become known as healthspan is likely--if you have money!
    thanks for your beautifully stated primer.
    i am at