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Life Extension: Science or Pipe Dream?

Wouldn’t it be great if we could find a way to prolong our lives and to keep us healthy right up to the end? Ponce de León never found that Fountain of Youth, but science is still looking. What are the chances science will succeed? How’s it doing so far?

In his new book The Youth Pill: Scientists at the Brink of an Anti-Aging Revolution, David Stipp tries to answer those questions. From the title of the book, I expected hype about resveratrol or some other miracle pill; but instead it is a nuanced, levelheaded, entertaining, informative account of the history and current state of longevity research. It makes that research come alive by telling stories about the people involved, the failures and setbacks, and the agonizingly slow process of teasing out the truth with a series of experiments that often seem to contradict each other.

Anti-aging can mean several things. Extending the average lifespan is not the same as extending the maximum life span. Extending lifespan is not the same as preventing the degenerative changes characteristic of aging.

We don’t even have a handle on why we die, why we deteriorate over time, or how it could benefit “selfish genes” for women to live past menopause. Several contradictory evolutionary explanations have been proposed. Comparisons with other species have not been helpful: every hypothesis has run up against counter-examples. Generally, the lifespan of animals correlates with body size; humans live longer for their size than expected. Some animals appear not to age. Naked mole rats are a fascinating anomaly: these animals that live in colonies underground and look like saber-toothed sausages live a long life for their size and appear not to show the usual changes of aging even though they have high levels of free radical damage and low levels of antioxidants (70 times less glutathione activity than mice).

Scientists hoped to find an aging gene that they could turn off. It’s not that simple. A large number of genes are involved in aging processes, and there are unpredictable interactions between them. Studying centenarians has provided inconsistent clues.

Antioxidants neutralize the free radicals that cause cell damage. They sounded promising, but their effect is modified by many factors, they can harm as well as help, and raising their levels with supplements may even turn off some of the body’s natural defenses.

Telomerase (the enzyme that keeps the ends of chromosomes from fraying as they age) was another false lead. Drugs that slow aging by boosting telomerase may cause cancer, and it turns out that telomere shortening isn’t the chief driver of body-wide aging.

The most promising idea is severe calorie restriction (CR). It prolongs life in several species, but this effect has not yet been verified in humans. And it is inconsistent and may have different effects at different ages and in different individuals. CR lowers body temperature and fertility and has other side effects. It is not an option most people would willingly choose.

Scientists have studied the chemical changes in CR humans and are looking for a pill that will cause those same changes while allowing people to eat unrestricted calories. Two main candidates have surfaced. Resveratrol (a substance found in red wine) seems to work: it allows overfed mice to live longer and stay healthier. It appears to have a number of benefits in lab animals, but human studies have not been done and it appears that very large doses will be required (comparable to the amount you would get by drinking 200 bottles of wine a day). Rapamycin extends the life of mice and prevents various diseases, but it also inhibits protein synthesis in the brain, suppresses immune function, and raises cholesterol. Researchers are trying to find related compounds that offer the benefits without the harms.

There are all too many variables that can interfere with the results of a study. In one experiment, the female mice lived longer with treatment but the males didn’t. They finally figured out that was because the males’ cagemates were killing them! Stipp does an excellent job of presenting the theoretical underpinnings, the experiments, and the difficulties of anti-aging research. The subject is overwhelmingly complicated, but he simplifies it enough to at least help the reader understand how very complicated it is.

There are longevity clinics and anti-aging products on the market offering all kinds of promises that go way beyond the knowledge. Futurist Ray Kurzweil takes handfuls of supplement pills and spends one day a week getting IVs and other treatments at a longevity clinic and he is convinced this regimen will keep him alive until science finds a way to keep him alive forever. The author of The Youth Pill is more conservative. He is enthusiastic about the promising research on pills like resveratrol and rapamycin, but he’s reluctant to start taking them “until enough clinical data are available to let me make a reasonably well-informed decision about optimal dosing.” Me too.

Posted in: Book & movie reviews, Herbs & Supplements, Pharmaceuticals

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20 thoughts on “Life Extension: Science or Pipe Dream?

  1. BillyJoe says:

    “Futurist Ray Kurzweil takes handfuls of supplement pills”

    According to this reference…

    http://www.boston.com/news/globe/magazine/articles/2004/10/31/the_futurist/

    Ray Kurzweil takes 250 supplement tablets per day.
    That’s equivalent to 15 tablets every hour, day in and day out, year in year out.

    Frankly, I’d rather die than do that.
    And, of course, there’s no guarantee it will make any difference. It seems he takes everything that has even been claimed to prolong life no matter how flimsy the evidence.
    Just in case.

    A sort of secular Pascal’s wager.

  2. passionlessDrone says:

    Regarding a CR diet, the joke goes:

    It may not make you live forever, it just feels like it.

    Curiously, it seems that you don’t even have to eat more calories to cancel out the benifit of a CR diet, you just have to smell food, at least if you are a fly.

    http://www.scientificamerican.com/article.cfm?id=the-scent-of-a-calorie-wh

    - pD

  3. daedalus2u says:

    This is interesting. I have been following the life extension research because much of the physiology of aging is regulated by NO. I think there are some fundamental misconceptions about what aging and senescence are, and the degree of difficulty in changing them.

    As I see it, senescence is a “feature”, a “feature” along the same lines that anaphylaxis is a “feature” and the ability to run oneself to death while running from a bear is a “feature”.

    It is related to the Bruce Ames idea of “nutrient triage”, but is somewhat more fundamental, it is in effect “ATP triage”. In the nutrient triage hypothesis, physiology allocates nutrients according to nutrient availability and the relative importance of pathways utilizing nutrients. When there are insufficient nutrients, pathways with the lowest priority get shortchanged. In a metabolic crisis, pathways to keep the organism alive are the highest priority. Pathways to repair those pathways are lower priority and pathways to repair the repair pathways are lower priority still.

    Since ATP is used by essentially every pathway, efficient allocation of ATP will divert ATP away from pathways that keep the repair pathways repaired when ever there is insufficient ATP. This results in eventual degradation of those repair pathways and cascades into the rest of physiology over time.

    What we call senescence is the inevitable consequence of efficient allocation of ATP. Changing that would require changing the fundamental ATP allocation paradigms of physiology. Those derive from deep evolutionary time and cannot be changed so easily. I presume there are also pathways to deal with senescence from ATP triage, I think telomeres are a feature to compensate for replicative senescence of somatic cells and prevent organism death from cancer when DNA replication is not perfect.

    Nitric oxide is one of the fundamental regulators of ATP, where NO and ATP go up and down in sync due to their joint action on soluble guanylyl cyclase. States of low NO are also states of low ATP and vice versa. When there is insufficient ATP, cells induce ischemic preconditioning and reduce ATP demand. My hypothesis is that the reduced ATP demand of ischemic preconditioning is accomplished by the turning off of low priority pathways, all pathways that have a time constant longer than the expected length of the ischemic crisis can be turned off. This reduced ATP demand can only be transient (if cells could permanently reduce ATP demand they would do so and divert more ATP to reproduction), if ATP levels cannot be restored, there will be damage and that damage will occur in the longest time constant systems, systems relating to health in the distant future, systems relating to very long term cell repair.

    I think the focus on antioxidants is wrong. Free radicals are extremely important signaling molecules (they are ideal signaling molecules, they are small, highly reactive, diffuse rapidly, react rapidly and have a low background). Use of free radicals as signaling molecules implies the proper background level of antioxidants in various tissue compartments. Physiology has to regulate the background level of antioxidants (as it regulates everything else) for free radical signaling pathways to work properly. In every large, long term, blinded study of supplemental antioxidants there has been no positive effect; there have been either no effects or very slight negative effects (usually below statistical significance). My interpretation is that physiology is generating more superoxide to destroy the excess supplemental antioxidants, and this excess superoxide is having adverse effects.

    Superoxide is an anion, and is virtually always generated to the inside of vesicles, either mitochondria or microsomes where it is confined by the lipid membrane. NO can diffuse through the lipid membranes and reacts with superoxide at near diffusion limited kinetics, so superoxide on the inside of a lipid membrane will affect the NO levels outside the membrane. Many of the effects of oxidative stress are not mediated directly by high superoxide, but are instead mediated indirectly by low NO levels produced by that high superoxide. I think this is the main mechanism by which stress (a low NO state), exacerbates essentially all diseases characterized by low NO.

    I don’t think there have been any long term studies on supplemental resveratrol. I suspect they would end up like all the other long term studies on supplemental antioxidants, showing no or slightly negative health effects. The state of oxidative stress is too important to be determined by nutritive quantities of random dietary antioxidants.

  4. qetzal says:

    Ray Kurzweil takes 250 supplement tablets per day.
    That’s equivalent to 15 tablets every hour, day in and day out, year in year out.

    Frankly, I’d rather die than do that.
    And, of course, there’s no guarantee it will make any difference.

    I’d say it’s a very good bet it won’t help. Consider that any given compound almost certainly has at most a small effect. There’s no reason to believe that all effects will be positive. Most likely, some compounds will have modest benefits, others will have modest detriments, and most will have essentially no effect. Even the compounds that might be beneficial will likely have deleterious effects at excessive doses.

    So, what’s the chance that Ray’s regimen of 250 pills a day just happens to have most or all of the beneficial compounds, all at beneficial doses, with no significant countereffects from deleterious compounds or doses? Just about zero, is my guess.

  5. Henchminion says:

    The most promising idea is severe calorie restriction (CR). It prolongs life in several species, but this effect has not yet been verified in humans.

    No one has studied the effects of famine on humans? Seriously?

  6. DevoutCatalyst says:

    > Frankly, I’d rather die than do that.

    Now I don’t take any supplements, but I don’t think Ray’s pill habit is impinging on his quality of life or placing undo time constraints upon him. Any time I’ve emailed him he responds promptly, avuncularly — sometimes within minutes. Proving nothing at all, but just saying…

  7. Ken Hamer says:

    [quote]So, what’s the chance that Ray’s regimen of 250 pills a day just happens to have most or all of the beneficial compounds, all at beneficial doses, with no significant countereffects from deleterious compounds or doses? Just about zero, is my guess.[/quote]

    Well, unless he chokes.

  8. Ken Hamer says:

    “…or how it could benefit “selfish genes” for women to live past menopause.”

    Walking through an ancient (by west coast standards) cemetary in Rhode Island recently, it appears that not very long ago they did not.

  9. Ken Hamer says:

    “but I don’t think Ray’s pill habit is impinging on his quality of life or placing undo time constraints upon him.”

    How much is he spending?

  10. Scott says:

    No one has studied the effects of famine on humans? Seriously?

    People suffering famine generally experience other effects which would swamp any beneficial effects of the calorie restriction. For example, starving to death. A severely calorie-restricted diet that’s still nutritionally adequate is a non-trivial challenge.

  11. Harriet Hall says:

    Re: Ray Kurzweil’s quality of life:
    He spends one whole day a week at a longevity clinic getting IV vitamin infusions and other treatments.

    And I can’t help but wonder about interactions between the different treatments. Some of those supplements might counteract each other.

  12. daedalus2u says:

    Ken, I think you are asking the wrong question.

    As the numerous tissue compartments in humans evolved pathways to prevent senescence, why did preventing senescence of the female reproductive system offer such insignificant reproductive benefits that it did not happen?

    I suspect that because the chances of maternal death during childbirth are so high in humans (~1% per pregnancy before the modern era), and because the chances of death during childbirth increases with age, there comes a time when the potential benefits of pregnancy don’t outweigh the risk of death.

    Humans are pretty unique among mammals in the high risk of maternal death during childbirth. The size of the female pelvis has not increased as rapidly as brain size has.

  13. DevoutCatalyst says:

    >How much is he spending?

    He’s a wealthy inventor, would suspect his discretionary income is rather high.

    >He spends one whole day a week at a longevity clinic getting IV >vitamin infusions and other treatments.

    Beats golf, but point conceded.

  14. DevoutCatalyston 13 Jul 2010 at 5:31 pm

    >He spends one whole day a week at a longevity clinic getting IV >vitamin infusions and other treatments.

    Beats golf, but point conceded.

    Wow, I’ve never played golf, (except miniature) but it can’t be that bad.

    I gotta say though, since I’m superstition, that putting all that effort into anti-aging just seems a big jinx hazard. It’s just asking to get hit by a bus crossing to street to the longevity clinic. That’s from a layman’s perspective, though. :)

    Slightly related, I heard an interesting report on the research into genetic variations in people who live over 100 the other day. http://www.npr.org/templates/story/story.php?storyId=128244121

  15. youdell says:

    “Slightly related, I heard an interesting report on the research into genetic variations in people who live over 100 the other day. http://www.npr.org/templates/story/story.php?storyId=128244121

    The above study is a bit of a sham

    http://scienceblogs.com/geneticfuture/2010/07/serious_potential_flaws_in_lon.php

  16. BillyJoe says:

    Come on, swallowing 15 tablets every hour for the rest of your (miserable) life has to impact on its quality.

    Most people can’t persuade themselves to take even just one BP tablet a day.

  17. youdell – Thanks for the link. That’s why I read SBM comments. It’s always good to find out what the relevant scientists think of a report rather than just what the journalists think.

  18. squirrelelite says:

    A little off topic, but this was the most recent thread about herbs, so I thought I would note it here.

    I stumbled across this in an Ancient History blog I check out from time to time.

    Researchers at the University of Pennsylvania have been studying “herbs, tree resins, and other organic materials dispensed by ancient fermented beverages like wine and beer.”

    More information is posted on their web site here:

    http://penn.museum/press-releases/791-anticancer-activity-found-inherbal-additives-of-ancient-alcoholic-beverages.html

    As one paragraph notes:

    “Over the past two years, researchers working on a unique joint project, “Archaeological Oncology: Digging for Drug Discovery,” have been testing compounds found in ancient fermented beverages from China and Egypt for their anticancer properties. Several compounds—specifically luteolin from sage and ursolic acid from thyme and other herbs attested in ancient Egyptian wine jars, ca 3150 BCE, and artemisinin and its synthetic derivative, artesunate, and isoscopolein from wormwood species (Artemisia), which laced an ancient Chinese rice wine, ca 1050 BCE—showed promising and positive test tube activity against lung and colon cancers.”

    A review article was published in the International Journal of Oncology in July 2010:

    http://www.spandidos-publications.com/ijo/37/1/5

    I think I read they are getting ready for a Stage I study on effects against lung cancer.

    Sounds interesting, anyway.

    Is there in truth medicine in wine?

  19. BillyJoe says:

    DevoutCatalyst

    “Now I don’t take any supplements, but I don’t think Ray’s pill habit is impinging on his quality of life”

    Okay, go to your medicine cupboard and select 15 tablets. Now, lay them on the breakfast table in front of you. Swallow all fifteen tablets before breakfast. Now repeat this every hour for the rest of your miserable life. Now tell me that it is not impacting on your quality of life.

  20. BillyJoe says:

    …oops, sorry, I already sort of responded to this.

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