Action Mechanisms of Resveratrol in Somatic Longevity and Reproductive System

学术研究促进奖(R15) 白藜芦醇对机体长寿和衰老的作用机制 生殖系统 项目总结 白藜芦醇(RSV)是一种高效、长寿的小分子物质。虽然 多项研究表明，RSV通过Sirtuin(依赖NAD+的家族)延长寿命 脱乙酰酶)依赖的途径，但围绕其潜在机制仍有很大争议 这种延长寿命的效果。 利用线虫秀丽线虫(C.elegans)，我们发现RSV在很大程度上介导了长寿 取决于SIR-2.1(Sirtuin/SIRT1同源物)和MPK-1(ERK/MAPK同源物)。具体来说，RSV 比较缺乏SIR-2.1(SIRT1)或MPK-1(ERK)的单个突变虫体的部分延长寿命 与野生型蠕虫相比。然而，RSV介导的长寿在双突变体中完全取消 同时缺乏SIR-2.1(SIRT1)和MPK-1(ERK)的蠕虫。除了身体的长寿，我们还发现RSV 对生殖系统既有积极的影响也有消极的影响，取决于遗传背景-RSV 通过SIR-2.1(SIRT1)和MPK-1(ERK)相关的形成促进生殖长寿 生殖系肿瘤是一种特定的基因突变。 在这项建议中，我们旨在研究RSV如何与基因协同作用的分子机制 包括SIR-2.1(SIRT1)和MPK-1(ERK)在内的调控因子，控制体细胞寿命和生殖系统 (即生殖长寿和肿瘤发生)。重要的是，SIR-2.1(SIRT1)和MPK-1(ERK)激活DAF- 16(FOXO转录因子家族)和SKN-1(NRF2转录因子家族)， 分别进行了分析。因此，我们将检验RSV控制体细胞寿命的假设(目标1)和 生殖系统(AIM 2)通过SIR-2.1(SIRT1)？DAF16(FOXO)和MPK-1(ERK)？SKN-1(NRF2) 小路。总的来说，拟议的项目将丰富研究和教育的基础设施，以及 增加代表不足的群体的参与，这符合NIH-Area(R15)赠款的目的。 此外，我们在一个简单生物体中的发现将为有争议的 RSV对寿命的影响，但也将对RSV的利用产生重要影响，以提高 脊椎动物衰老相关疾病的预后，如果这种活体方法不可行或 很实用。

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)àDAF16(FOXO) and MPK-1(ERK)àSKN-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.