Action Mechanisms of Resveratrol in Somatic Longevity and Reproductive System

学术研究提升奖（R15） 白藜芦醇在体细胞长寿和抗衰老中的作用机制 生殖系统 项目摘要 白藜芦醇（RSV）已成为一种高效，长寿促进小分子。虽然 几项研究表明，RSV通过Sirtuin（NAD+依赖性 脱乙酰酶）依赖的途径，仍然有很多争议周围的潜在机制 寿命延长的效果。 利用秀丽隐杆线虫（Causophabditis elegans，C. elegans），我们发现RSV介导的长寿主要是 依赖于SIR-2.1（Sirtuin/SIRT 1同源物）和MPK-1（ERK/MAPK同源物）。具体而言，RSV 在缺乏SIR-2.1（SIRT 1）或MPK-1（ERK）的单一突变蠕虫中， 与野生型蠕虫相比。然而，RSV介导的寿命在双突变体中被完全消除， 缺乏SIR-2.1（SIRT 1）和MPK-1（ERK）的蠕虫。除了体细胞寿命，我们发现RSV 对生殖系统有积极和消极的影响，这取决于遗传背景- RSV 通过SIR-2.1（SIRT 1）和MPK-1（ERK）相关蛋白的形成促进生殖寿命 一种特定的基因突变体的生殖系肿瘤。 在这个建议中，我们的目标是研究RSV如何与遗传学合作的分子机制， 调节因子，包括SIR-2.1（SIRT 1）和MPK-1（ERK），以控制体细胞寿命和生殖系统 (i.e.,生殖寿命和肿瘤发生）。重要的是，SIR-2.1（SIRT 1）和MPK-1（ERK）激活了ERK-1。 16（FOXO转录因子家族）和SKN-1（NRF 2转录因子家族）， 分别因此，我们将检验RSV控制体细胞寿命（目标1）和RSV抑制体细胞寿命（目标2）的假设。 通过SIR-2.1（SIRT 1）<$DAF16（FOXO）和MPK-1（ERK）<$SKN-1（NRF 2）对生殖系统（目标2）进行调节 途径。总体而言，拟议项目将丰富研究和教育的基础设施， 增加代表性不足的群体的参与，这符合NIH-AREA（R15）赠款的目的。 此外，我们在一个简单的有机体中的发现将为有争议的 RSV对寿命的影响，但也将有重要的影响，关于RSV的利用，以提高 脊椎动物衰老相关疾病的预后，其中这种体内方法不可行，或 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.