Caution and Optimism about Lifespan Extension

There is a great review of anti-aging science in Nature by an Jan Vijg and Judith Campisi.

Life extension has been in the news with compounds like resveratrol -- a compound found in red wine -- shown to increase the life span of nematodes, yeast and most recently mice (though the mice in that study were on an unhealthy high calorie diet). Explaining how these compounds work is a more difficult challenge. We think that these compounds work by influencing pathways that regulate overall metabolism. We also think that these same pathways are altered by caloric-restriction -- a technique that robustly increases lifespan in a variety of species. We have good reason to believe that many of these pathways are conserved across species.

However, the authors add a note of caution to those hoping for indefinite lifespans. First, none of the drugs tested have shown lengthen life span in healthy rodents much less humans.

Second, there are good reasons to be skeptical that inhibiting pro-aging pathways in humans will have the same effect that it has in lower organisms. Humans have a much longer lifespan already. It may be that the pathways associated with short lifespan in other species have already been toned down in humans:

Life extension in model organisms may be an artefact to some extent. None of the laboratory animals considered 'wild type' has the genetic diversity of true wild strains, nor is the laboratory a natural habitat. For example, dietary restriction does not substantially increase longevity in some wild mice. Thus, laboratory breeding might select for a robust dietary restriction response. Two longitudinal dietary restriction studies in rhesus monkeys were initiated in the late 1980s. Interim results suggest that dietary restriction improves health (for example, less body fat, higher insulin sensitivity and favourable circulating lipids), but there is no evidence yet that dietary restriction increases lifespan to the extent that it does in laboratory rodents. Moreover, in monkeys (and by extension, humans) some benefits of dietary restriction, such as low IGF-I [Insulin-like Growth Factor 1] levels, may decrease cancer risk, but also increase the risk of osteoporotic fractures35. Thus, it might be necessary to reduce IGF-I signalling during early adulthood to prevent cancer, but increase it at older ages to prevent non-cancerous diseases.

Can we expect interventions that target the human IIS [insulin/insulin-like growth factor 1 (IGF-I) signalling] pathway, even with proper spatio-temporal regulation, to extend lifespan to the extent that they do in simple models? Among the pro-longevity effects of dampening IGF-I signalling is upregulated stress resistance. Notably, stress response is generally superior in cells from long-lived compared to short-lived species. In short-lived species, there is evidently sufficient opportunity for enhancing protective mechanisms. However, in long-lived species, there may be fewer such opportunities.

Furthermore, human physiology obviously differs from that of yeast, nematodes or flies. Perhaps less obvious are the differences between humans and mice. We should keep in mind that many anti-cancer therapies are successful in mice but fail in humans. Moreover, side or off-target effects of drugs that affect complex physiological pathways are already a problem. For example, cholesteryl ester transfer protein inhibitors, developed to increase high-density lipoprotein [HDL] cholesterol, did not decrease but increased the risk of heart disease. (Emphasis mine. Citations removed.)

And later:

Obviously, huge differences in longevity can arise as a result of evolution -- consider the longevity difference between nematodes (weeks) and mammals (years), or even between mice (~3 yr) and humans (~100 yr). Were these differences achieved evolutionarily by discarding pro-ageing pathways, or by creating new longevity assurance pathways? The notable conservation among known longevity-modulating pathways, and similarities between organisms such as mice and humans in genomic structure and organization, argue against this possibility. Of course, unique non-conserved pathways may yet be discovered. It is more probable that significant longevity was achieved by subtle changes in many genes over the course of evolution, not by single mutations with large effects, which often increase lifespan at a cost to reproduction or survival under stress. If so, interventions that target a single mammalian gene or even a single pathway may not increase longevity to the extent achieved by natural selection. This should not discourage the search for pharmacological interventions, but rather underscores how the shallowness of our knowledge about comparative evolutionary mechanisms can severely hamper efforts in this area. (Emphasis mine. Citations removed.)

While we are beginning to understand the molecular biology of aging, we should remember that mice are not humans. These systems are complicated, and -- as any person working for a drug company will tell you -- the effects of compounds in model organisms may not replicate humans.

Further, on a very basic level there are definition problems in this field. How does one distinguish between disease and what is called intrinsic aging -- or aging not caused by disease. Clearly, the intrinsic aging has an organic cause. However, if we were to identify that cause as say oxygen radicals, wouldn't we describe oxygen radicals as a disease? Are the oxygen radical a necessary consequence of cellular function? If so, how necessary? It is a gray area, particularly with diseases of old age that might have mixed causes between intrinsic aging and other risk factors:

Should we distinguish between ageing and disease? The answer to this question, which is still debated, depends on the disease and how its mechanism relates to 'intrinsic ageing'; that is, ageing-related changes that are not determined primarily by external factors or genetic predisposition. Early-onset diseases, such as sickle cell anaemia, caused by a heritable beta-globin gene mutation, can result at young ages in vascular constriction and increased risk of infection, also common in older people. But because these phenotypes occur within the realm of natural selection, sickle cell anaemia is not an ageing-related disease as its causes have little to do with ageing. Such a mechanistic distinction is much more difficult for late-onset diseases. Many would distinguish potentially fatal vascular degeneration from benign greying of hair. However, both phenotypes could have the same cause: intrinsic ageing. On the other hand, different mechanisms might produce the same disease-related phenotype at old age. For example, intrinsic endothelial cell ageing might contribute to atherosclerosis, as do mutations or polymorphisms in genes encoding the low-density lipoprotein receptor or ApoB. Statins can lower cholesterol and suppress atherosclerosis in individuals with high-risk low-density lipoprotein receptor or ApoB alleles, but cannot prevent intrinsic endothelial cell ageing. (Emphasis mine.)

All in all, this a very good review that I recommend reading in its entirety. They strike a note of cautious optimism that I think is right on: we are learning more about this field but there is no justification for irrational exuberance. (And certainly no justification for heading down to the Natural medicine store for resveratrol in a pill...)

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Anti aging Resveratrol is one of the most sought after studies today. Since ancient times, we have been obsessed with keeping our youthful appearance and health. This is why anti aging Resveratrol researches are on the watch list of almost everyone in the medical and beauty industry.

Some studies were conducted on laboratory animals and believed to have similar benefits with humans. The only real proof is from personal testimonials of people taking these Resveratrol Supplements.

These types of Anti-Aging Supplements will only truly be proven years from now when people are living to be 130. Doctors are comfortable that taking Resveratrol Supplements now will slow down the aging process and prolong life expectancy.

Doesn't it work in fish too? Not that it has anything to do with your argument, but the response does seem conserved across a heck of a lot of organisms. rb

Resveratrol can help you to lead a long and healthy life so says Dr. Oz.
Red wine alone does not supply enough resveratrol to achieve the
full range of benefits. You need to take high potency resveratrol
supplements to achieve the results documented in scientific studies.
Resveratrol Supplements can also help you control your weight naturally
by increasing energy, reducing cravings, and limiting your appetite.
According to Wikipedia, Consumer Lab, an independent dietary
supplement and over the counter products evaluation organization,
published a report on 13 November 2007 on the popular resveratrol
supplements. The organization reported that there exists a wide range
in quality, dose, and price among the 13 resveratrol products
evaluated. The actual amount of resveratrol contained in the
different brands range from 2.2mg for Revatrol, which claimed to have
400mg of "Red Wine Grape Complex", to 500mg for Biotivia.com Transmax,
which is consistent with the amount claimed on the product's label.
Prices per 100mg of resveratrol ranged from less than $.30 for
products made by Biotivia.com, jarrow, and country life, to a high of
$45.27 for the Revatrol brand.

By Jim Hagan (not verified) on 28 Aug 2008 #permalink

Should we distinguish between ageing and disease? The answer to this question, which is still debated, depends on the disease and how its mechanism relates to 'intrinsic ageing'; that is, ageing-related changes that are not determined primarily by external factors or genetic predisposition. Early-onset diseases, such as sickle cell anaemia, caused by a heritable beta-globin gene mutation, can result at young ages in vascular constriction and increased risk of infection, also common in older people.

I suppose that there is really a lot more that may be put into this piece of writing. Wishing for a subsequent post for the very same subject.

Finally a well thought out article on this emerging subjects. I can't wait to see what future research will reveal.