Fight Aging!

A little science coverage relating to calorie restriction mimetics today for those of you who like to keep a close eye on such things; this post was made by Pete Estrep on the Gerontology Research Group list:

I'm not sure how tuned in to the Sirtuin/resveratrol controversy GRG members are (I know some eavesdroppers/lurkers know the scoop) but this is turning into the biggest head scratcher in aging research. Here are the basics. While in Lenny Guarente's lab at MIT, Longenity co-founder Matt Kaeberlein discovered the life extension effects in yeast of a protein called Sir2. Guarente's lab showed that Sir2 is a NAD-dependent deacetylase and Guarente and Heidi Tissenbaum showed lifespan extension of nematodes overexpressing Sir2. Several labs, including Guarente's and Dave Sinclair's at Harvard went on to show that Sir2 has several interesting properties. Some of the most interesting research has come from a collaboration between Sinclair's lab and BIOMOL Research Laboratories in Pennsylvania, the makers of in vitro assay products for Sirtuin activity. Using the BIOMOL assay several Sirtuin Activating Compounds (STACs) have been identified, one of which is resveratrol. Sinclair showed that resveratrol increases yeast replicative lifespan, and then together with Marc Tatar and Steve Helfand, they showed that resveratrol extends lifespan in nematodes and fruitflies. Resveratrol looks very exciting, right? Well, things have gotten interesting in the past few months.

Matt Kaeberlein, who is now back in academia at the University of Washington, recently published two papers with Brian Kennedy and Stan Fields. One shows that the lifespan-extending effects of Sir2 in yeast are strain dependent, that calorie restriction of yeast extends lifespan more than Sir2 overexpression, and that this effect is Sir2 independent.

The more recent publication shows that the in vitro assay used to assay Sir2 function is faulty, that resveratrol activation of Sir2 is an artifact, and that resveratrol has no effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and replicative lifespan (Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell S, Napper A, Curtis R, Distefano PS, Fields S, Bedalov A, Kennedy BK. Substrate specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Jan 31; [Epub ahead of print] PMID: 15684413. The in vitro artifact has been confirmed by another group at the University of Wisconsin ( Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol .J .Biol Chem. 2005 Mar 4.). So, at least three groups have shown lifespan extension by resveratrol in yeast, worms, and flies, and it is claimed that resveratrol is acting by binding to and directly activating Sir2; and now two groups have shown that this binding is an artifact and Kaeberlein and colleagues have shown that the lifespan extension also appears to be an artifact.

Now, to further complicate things, Parker and colleagues (Parker, J. et al. Nat. Genet. 37, 349-350 (2005) have presented data suggesting that resveratrol moderates the symptoms and is neuroprotective in two models of Huntington's disease, and this effect is Sir2 dependent. Are you confused yet? Me too, along with everyone else in the field. Stay tuned for new developments.

While I'm not voting this "biggest head scratcher" (that would be reserved for why serious longevity research is so underfunded), it is certainly interesting. It seems that research groups are on the verge of pulling the various threads together - this sort of confusion and contradiction is very indicative of progress in science. A more accurate picture of this facet of our metabolic processes and its interaction with healthy life span can only be beneficial. It is plausible that we could obtain an extra decade or two of additional healthy life span from the application of modern biotechnology to improving our metabolism. This may not be radical life extension, but it is certainly better than nothing.