Science of Aging  
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David A. Sinclair et al. Discover Three Classes of Molecules that Activate Sirtuins (Including Resveratrol)

Who:David A. Sinclair, Konrad T. Howitz, Kevin J. Bitterman, Haim y. Cohen, Dudley W. Lamming, Siva Lavu, Jason G. Wood, Robert E. Zipkin, Phuong Chung, Anne Kisielewski
When:August 24, 2003
Methods: By screening small molecule libraries for molecules which could modulate sirtuin activity
Institution: Harvard Medical School
Where: Boston, Massachusetts, U.S.A

Working off a model of calorie restriction via sirtuins David Sinclair et al. worked to find molecules which could modulate sitruins activity, and thus longevity.

They accomplished this by screening a number of small molecule libraries, which included analogues of epsilon-acetyl lysine, NAD+, NAD+ precursors, nucleotides and purinergic ligands. Results from the screening where assayed against human SIRT1 to identify potential inhibitors, and the following molecules where found: Resveratrol, Butein, Piceatannol, Isoliquiritigenin, Fisetin, and Quercetin. Of all of these, resveratrol proved to be the most potent, increasing the replicative lifespan of yeast by 70%. It was not the only compound which extended yeast lifespan however, as butein increased it by 31%, and fisetin by 55%.

Citing work which suggests SIR2 may extend lifespan by stabilizing repetitive DNA, the authors hypothesize that resveratrol works in the same way.

"Homologous recombination between ribosomal DNA (rDNA) repeats can generate an extrachromosomal circular DNA molecule that is replicated until it reaches toxic levels in old cells. Consistent with this, resveratrol reduced the frequency of rDNA recombination by about 60% in a SIR2-dependent manner."

The authors conclude the paper suggesting that their findings create new avenues of research for the effects of polyphenols on human aging and age related diseases.


References

  1. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. 2003, Nature 425 (6954): 191?196.

<- Coleen Murphy et al. find genes downstream of daf-16 which regulate aging in C.elegans nematodes  || Timeline ||  Norman E. Sharpless finds that expression of the Ink4a/Arf locus is a biomarker of aging ->