Academic Research Enhancement Award (R15) Action Mechanisms of Resveratrol in Somatic Longevity and Reproductive System PROJECT SUMMARY Resveratrol (RSV) has emerged as a highly effective, longevity-promoting small molecule. Although several studies have shown that RSV extends lifespan through Sirtuin (a family of NAD+-dependent deacetylases)-dependent pathways, there is still much controversy surrounding the underlying mechanisms of this lifespan extension effect. Using the nematode Caenorhabditis elegans (C. elegans), we found that RSV-mediated longevity largely depends on both SIR-2.1 (a Sirtuin/SIRT1 homolog) and MPK-1 (an ERK/MAPK homolog). Specifically, RSV partially extended lifespan in single mutant worms lacking either SIR-2.1(SIRT1) or MPK-1(ERK), compared to that of wild-type worms. However, RSV-mediated longevity was completely abolished in double mutant worms lacking both SIR-2.1(SIRT1) and MPK-1(ERK). In addition to somatic longevity, we found that RSV has both positive and negative effects on the reproductive system depending on the genetic context ? RSV promotes both reproductive longevity via SIR-2.1(SIRT1) and the formation of MPK-1(ERK)-associated germline tumors in a specific genetic mutant. In this proposal, we aim to investigate the molecular mechanism of how RSV cooperates with genetic regulators, including SIR-2.1(SIRT1) and MPK-1(ERK), to control somatic longevity and reproductive system (i.e., reproductive longevity and tumorigenesis). Importantly, SIR-2.1(SIRT1) and MPK-1(ERK) activate DAF- 16 (a family of the FOXO transcription factor) and SKN-1 (a family of the NRF2 transcription factor), respectively. Therefore, we will test the hypothesis that RSV controls somatic longevity (Aim 1) and the reproductive system (Aim 2) through both SIR-2.1(SIRT1)DAF16(FOXO) and MPK-1(ERK)SKN-1(NRF2) pathways. Overall, the proposed project will enrich the infrastructure for research and education as well as increase the participation of underrepresented groups, which fulfills the purpose of the NIH-AREA (R15) grant. In addition, our findings in a simple organism will provide new mechanistic insights into the controversial effects of RSV on longevity, but will also have important implications regarding RSV utilization to enhance the prognosis of aging-associated diseases in vertebrates, where such in vivo methods are not feasible or practical.
Resveratrol (RSV) was originally identified as an activator of Sirtuin (a family of NAD+-dependent deacetylases) and has been shown to extend lifespan in both invertebrates and vertebrates. However, subsequent studies have also demonstrated that the effects of RSV on longevity have been quite controversial. Therefore, in this proposal, we will investigate the underlying mechanism of RSV-mediated effects on somatic longevity, reproductive longevity, and tumorigenesis, using the nematode Caenorhabditis elegans as a model system.
