[PDF][PDF] Does resveratrol activate yeast Sir2 in vivo?
M Kaeberlein, BK Kennedy - Aging Cell, 2007 - Citeseer
Aging Cell, 2007•Citeseer
In the February issue of Aging Cell, Yang et al.(2007) describe resveratrol derivatives with
improved stability and report that they increase yeast replicative lifespan. The authors refer
to these drugs as 'sirtuin activating compounds', implying that lifespan is increased due to
activation of the Sir2 histone deacetylase. We applaud the development of more stable and
potent resveratrol analogs. We wish to point out, however, that whether resveratrol and
related compounds activate Sir2 in vivo remains unknown and further experimental …
improved stability and report that they increase yeast replicative lifespan. The authors refer
to these drugs as 'sirtuin activating compounds', implying that lifespan is increased due to
activation of the Sir2 histone deacetylase. We applaud the development of more stable and
potent resveratrol analogs. We wish to point out, however, that whether resveratrol and
related compounds activate Sir2 in vivo remains unknown and further experimental …
In the February issue of Aging Cell, Yang et al.(2007) describe resveratrol derivatives with improved stability and report that they increase yeast replicative lifespan. The authors refer to these drugs as ‘sirtuin activating compounds’, implying that lifespan is increased due to activation of the Sir2 histone deacetylase. We applaud the development of more stable and potent resveratrol analogs. We wish to point out, however, that whether resveratrol and related compounds activate Sir2 in vivo remains unknown and further experimental validation is necessary.
The Yang et al.(2007) study as well as a prior report (Howitz et al., 2003) are complicated by the use of the PSY316AT yeast strain background. Among the strains commonly used in yeast aging research, PSY316AT is the only known case where overexpression of Sir2 fails to increase lifespan (Kaeberlein et al., 2004, 2005b). While it is possible that a sirtuin agonist could increase Sir2 activity in a manner not achieved by overexpression of the enzyme, it also needs to be considered that resveratrol (and its analogs) could affect longevity in a Sir2-independent manner. Resveratrol is known to interact with a variety of proteins that have yeast homologs, such adenosine monophosphate (AMP) kinase, protein kinase C and mitochondrial adenosine triphosphate (ATP) synthase, among others (Kaeberlein & Rabinovitch, 2006). Any of these proteins could potentially mediate effects of resveratrol on yeast cells or in other organisms. Another complicating factor is the use of replicative lifespan as the sole measure of drug activity. While longevity is of clear interest, increased lifespan does not imply increased Sir2 activity, as several single-gene mutations are known to increase lifespan in a Sir2-independent manner (Kaeberlein et al., 2004, 2005c). Sir2 activity can be measured more directly, for example, by monitoring transcription of marker genes at telomeres, silent mating loci and rDNA (Smith & Boeke, 1997; Roy & Runge, 2000; Sandmeier et al., 2002; Kaeberlein et al., 2005a). In fact, the PSY316AT strain used by Yang et al. was engineered for
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