Resveratrol and rapamycin as therapeutics vs. aging and cancer

A review I should have cited yesterday addresses the promise and challenges of the two most prominent natural-product candidates for longevity-enhancing therapeutics. The author is prominent biogerontologist and all-around bright feller Matt Kaeberlein (see here for earlier posts on his group’s work).

Resveratrol and rapamycin: are they anti-aging drugs?

Studies of the basic biology of aging have advanced to the point where anti-aging interventions, identified from experiments in model organisms, are beginning to be tested in people. Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age-associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti-cancer treatment, and rapamycin is already approved for use in human patients. Compounds such as these, identified from longevity studies in model organisms, hold great promise as therapies to target multiple age-related diseases by modulating the molecular causes of aging.

Note that resveratrol has been taking a bit of a thrashing of late, with recently released studies calling into question its ability to directly activate sirtuins. Briefly, the critics posit that the early data may have been misinterpreted due to artifacts in a fluorescence-based system used to detect protein-drug interactions — but check comment #32 on that post for David Sinclair’s personal response on this issue.

ResearchBlogging.orgKaeberlein, M. (2010). Resveratrol and rapamycin: are they anti-aging drugs? BioEssays, 32 (2), 96-99 DOI: 10.1002/bies.200900171

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3 comments

  1. The real objection to resveratrol is not that it does or does not modulate some putative effector in the ‘right’ direction, but that when it comes right down to it resveratrol doesn’t actually extend life in normal, healthy animals (see also more evidence that resveratrol doesn’t work:

    We have no evidence of extension of life in any mammal — just the near-normalization of premature mortality in animals rendered obese and diabetic because of a life gorging on a high-sucrose, high-saturated-fat diet. Of note, (8) found (similarly to Auwerx and de Cabo) that resveratrol gave significant protection to obese, high-fat-diet fed Wistar rats (not mice, let alone C57Bl/6) against “hyperglycaemia, dyslipidemia, increased serum oxidized-LDL (ox-LDL) and hepatic oxidative stress,” it gave no such benefits to normal-weight, normal-diet rats: in fact, resveratrol supplementation of “standard-fed-rats reduced glutathione-antioxidant defense system and enhanced hepatic lipid hydroperoxide [my emphasis].” Above, remember, just such a diabetic, obese, junkfood-died rodent model study (Auwerx) was favorably referenced as evidence of the safety of resveratrol!

    In mice, resveratrol doesn’t fully replicate CR-induced gene expression changes (6) nor induce some demonstrably important CR-induced metabolic changes (7). Heck, it’s not even clear that the stuff does any good in yeast (where the whole hype got started) (3); nor in Drosophila elegans (note that Partridge’s group is possibly the most experienced lab in the world in doing lifespan studies in Drosophila) (4); nor in another (tephritid) species of fruit flies ((5): there may have been a marginal effect in flies fed 1 of the 24 different diet combinations, but I’m skeptical of that result, and IAC there was no effect in the other 23 diets); nor in C. elegans (4) — and in mammals, again, the evidence to date is against it

  2. The real objection to resveratrol is not that it does or does not modulate some putative effector in the ‘right’ direction, but that when it comes right down to it resveratrol doesn’t actually extend life in normal, healthy animals (see also more evidence that resveratrol doesn’t work:

    We have no evidence of extension of life in any mammal — just the near-normalization of premature mortality in animals rendered obese and diabetic because of a life gorging on a high-sucrose, high-saturated-fat diet. Of note, (8) found (similarly to Auwerx and de Cabo) that resveratrol gave significant protection to obese, high-fat-diet fed Wistar rats (not mice, let alone C57Bl/6) against “hyperglycaemia, dyslipidemia, increased serum oxidized-LDL (ox-LDL) and hepatic oxidative stress,” it gave no such benefits to normal-weight, normal-diet rats: in fact, resveratrol supplementation of “standard-fed-rats reduced glutathione-antioxidant defense system and enhanced hepatic lipid hydroperoxide [my emphasis].” Above, remember, just such a diabetic, obese, junkfood-died rodent model study (Auwerx) was favorably referenced as evidence of the safety of resveratrol!

    In mice, resveratrol doesn’t fully replicate CR-induced gene expression changes (6) nor induce some demonstrably important CR-induced metabolic changes (7). Heck, it’s not even clear that the stuff does any good in yeast (where the whole hype got started) (3); nor in Drosophila elegans (note that Partridge’s group is possibly the most experienced lab in the world in doing lifespan studies in Drosophila) (4); nor in another (tephritid) species of fruit flies ((5): there may have been a marginal effect in flies fed 1 of the 24 different diet combinations, but I’m skeptical of that result, and IAC there was no effect in the other 23 diets); nor in C. elegans (4) — and in mammals, again, the evidence to date is against it

  3. Point very well taken.

    That said, I’m not sure that mice rendered obese and diabetic by high sucrose and fat aren’t a better model for most Western humans than “normal, healthy” animals fed optimized chow. 🙂 I.e., if resveratrol can normalize premature mortality in overfed couch potatoes, it might still find some clinical use in our society – though, granted, not as a true anti-aging therapeutic.

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