Critiquing the Sirtuin Model of Calorie Restriction

The science behind the work of groups like Sirtris Pharmaceuticals is based on the study of calorie restriction (CR) and sirtuins - but are sirtuins actually at the root of the biology that drives extended health and longevity through CR? A few contrary positions exist, as is usually the case when research in a field is still dynamic and unfolding. An informative post from Michael Rae can be found in the Methuselah Foundation forums:

"Sirtuin Activation" as the Mechanism of CR and its Putative Mimetics

Kaeberlein is a former grad student of Leonard Guarente's, and collaborated with him on many studies on "long-lived" mutants of the common yeast Saccharomyces cerevisiae. However, he's become an increasingly vocal critic of the thesis -- first advanced by Guarente, and promulgated even more fiercely by another former Guarente protege, David Sinclair -- that the effect of "CR" on "lifespan" in yeast is mediated by activating the histone deacetylase enzyme Sir2 -- the yeast homolog of the mammalian SIRT1.


The literature of gerontology is littered with alleged models of premature aging, in which the deletion of a gene or the imposition of some stressor leads to what is alleged to be an "accelerated aging" phenotype ... Almost anything that interferes with the normal metabolism of an organism but is not immediately fatal will result in a gradual loss of aspects of organismal function that will bear some analogy to "aging;" the question is what if any relationship they bear to "normal" aging. ... Kaeberlein and Powers present evidence that aspects of the CR/sirtuin hypothesis exhibit the same confusion.


Kaeberlein and Powers put forward a nascent alternative hypothesis which needn't concern us here. The strongest rebuttal is that one does not have to offer an alternative mechanism in order to demonstrate that the original is flawed. At this point, if the hypothesis is "reducing glucose concentration in yeast extends replicative lifespan in budding yeast through the activation of Sir2," then that thesis clearly stands on very weak grounds.

And if the hypothesis is, "compounds that activate sirtuins will act as pharmacological mimetics of life-extending Calorie restriction in humans," then I would say that it is outside of the realm of science, and into the realm of science fantasy, until someone shows me the slim, genetically-normal, 45-month-old, fully-fed but sirtuin-activated mouse.

Punchy, but science doesn't have to be weighed down by decorum. There's more than enough money behind sirtuin research and other biochemical pathways relating to calorie restriction for questions to be settled over the next five years, I would imagine. I expect us all to know exactly how calorie restriction works sometime prior to 2012 - a few years to find the root mechanism, and a couple more to validate it.

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