Inhibition of S6K by resveratrol: In search of the purpose

Mechanisms of the anti-aging effects of resveratrolResveratrol, a natural agent found in grape skins, has been proposed to account for the beneficial effects of red wine against heart disease.Resveratrol prevents age-related diseases and extends lifespan in several species [1][2][3][4][5][6][7][8][9].In this issue of Aging, Armour et al demonstrate that resveratrol directly inhibits S6 kinase (S6K) [10].S6K is a downstream target of mTOR(definition) (mammalian Target of Rapamycin(definition)).In response to nutrients, growth factors and hormones, the mTOR/S6K pathway promotes cellular mass growth, which is needed for cell proliferation.In post-mitotic (non-proliferating) cells, mTOR promotes cellular senescence(definition) [11].Rapamycin decelerates mammalian cell senescence [12].Dephosphorylation of S6 is correlated with suppression of cellular aging by several agents [13][14][15].Furthermore, inhibition of the TOR/S6K extends life span in yeast, worms and Drosophila [16][17][18][19][20][21].Also, mice deficient for mTORC1 or S6K are protected against obesity [22,23].Therefore, the discovery made by the David Sinclair laboratory [10] that resveratrol directly inhibits S6K is very important.In addition, resveratrol activates sirtuins [2,[24][25] and AMPK [6,26], which may antagonize the TOR pathway downstream and upstream, respectively (Figure 1).It has been suggested that sirtuins and mTOR may be involved in the same longevity pathway [27].By inhibiting S6K and activating sirtuins, resverat-Review www.impactaging.com