Inhibition of S6K by resveratrol: In search of the purpose

Mikhail V. Blagosklonny1

• 1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

Received: May 28, 2009       Accepted: June 27, 2009       Published: June 29, 2009

https://doi.org/10.18632/aging.100059
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Mechanisms of the anti-aging effects of resveratrol

Resveratrol, 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 [1-9]. In this issue of Aging, Armour et al demonstrate that resveratrol directly inhibits S6 kinase (S6K) [10].

S6K is a downstream target of mTOR (mammalian Target of Rapamycin). 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 [11]. Rapamycin decelerates mammalian cell senescence [12]. Dephosphorylation of S6 is correlated with suppression of cellular aging by several agents [13-15]. Furthermore, inhibition of the TOR/S6K extends life span in yeast, worms and Drosophila [16-21]. 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- rol may exert its anti-aging effect. But why would plants produce an anti-aging drug?

Purpose of anti-aging effects of resveratrol

As suggested by David Sinclair and co-authors in their elegant xenohormesis hypothesis, by sensingresveratrol, animals can monitor their environment [28,29]. Resveratrol is produced by plants in response to stress. According to the 'xenohormesis hypothesis', organisms have evolved to respond to stress signaling molecules produced by other species. In this way, organisms can prepare in advance for a deteriorating environment and loss of food supply [28,29].

The discovery that resveratrol inhibits S6K further supports this hypothesis, because S6K is a part of the nutrient-sensing pathway. In other words, organisms ‘sense' the lack of nutrients before there is an actual decline in nutrients.

Here I propose an alternative (but not mutually exclusive) model, suggesting that anti-aging effects of resveratrol are ‘side effects' of its cytostatic effect. Given that the nutrient-sensing TOR/S6K pathway promotes cellular growth, plants produce resveratrol to inhibit fungal growth, thus protecting the grape. But the same S6K that drives growth also drives aging. In a recent issue of Aging, Michael Hall and I discussed how growth and aging are hardwired that suppression of growth also suppresses aging [30]. By inhibiting S6K, resveratrol should slow down both growth and aging. Then "the purpose of resveratrol" is to inhibit fungal growth but its ‘side effect' is suppression of aging in a variety of species.https://www.aging-us.com/article/100059/text

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