Cellular and molecular determinants of vertebrate lifespans

该提案概述了一个研究计划，该计划将有助于更好地理解动物寿命的生物学。过去二十年的实验表明，寿命的延长或自然延长与细胞抗逆性的增强有关。更大的细胞抗逆性促进细胞和组织功能在更长时间内的维持。在特别长寿的物种的高氧化组织（如大脑和心脏）中，单个细胞可以存活80多年。然而，令人惊讶的是，我们对这是如何实现的知之甚少。在本研究计划中，我描述了一种识别与哺乳动物和鸟类物种寿命共同进化的细胞抗逆性成分的策略。这种方法利用了广泛的物种，包括一些特别长寿的物种（如蝙蝠和鸟类）。将分析在维持细胞机制处于功能状态、去除诱变DNA损伤和调节线粒体功能方面起作用的蛋白质。除了采用多物种方法外，我还将在一种具有单一基因突变的小鼠（Snell dwarf）中研究这些相同的细胞功能。这种突变使它们的寿命延长了50%。生理压力导致细胞死亡，这是组织老化退化的基础。长寿的动物可能会通过在成年动物的组织中维持干细胞的数量来应对这种情况，这些干细胞可以复制和分化以取代失去的细胞。我将确定长寿动物的心脏组织中是否有更多或更强健的成体干细胞。最后，在这种性质的研究中产生的信息是有益于人们的。我最近发现了膳食多酚白藜芦醇和线粒体抗氧化酶mn -超氧化物歧化酶之间潜在的重要相互作用。用白藜芦醇处理人类细胞或活小鼠诱导这种酶的产生增加，这与增强的抗逆性是一致的。在本提案中，我概述了将阐明白藜芦醇与导致mn超氧化物歧化酶诱导的细胞相互作用的实验，以及将导致改善白藜芦醇向细胞递送以促进这种作用的实验。

This proposal outlines a research program that will lead to a better understanding of the biology of animal lifespan. Experiments over the last two decades have shown us that increased or naturally long lifespans are associated with increased cellular stress resistance. Greater cellular stress resistance promotes the maintenance of cell and tissue functions over longer periods of time. In highly oxidative tissues (e.g. brain and heart) of particularly long-lived species, individual cells may persist for 80+ years. However, we know surprisingly little about how this is achieved. In this research proposal, I describe a strategy for identifying components of cellular stress resistance that have co-evolved with longevity in mammalian and avian species. This approach makes use of a wide range of species, including some that are exceptionally long-lived (e.g. bats and birds). Proteins that function in maintaining cellular machinery in a functional state, removing mutagenic DNA damage, and regulating mitochondrial function will be assayed. In addition to the multi-species approach taken, I will also investigate these same cellular functions in a strain of mice possessing a single gene mutation that extends their lifespan by 50% (the Snell dwarf). Physiological stressors cause cell death, which underlies the tissue degeneration of aging. Long-lived animals may counter this by maintaining populations of stem cells within tissues of adults that can replicate and differentiate to replace lost cells. I will determine whether longer-lived animals have more or more robust adult stem cells in heart tissue. Finally, the information generated in studies of this nature is of benefit to people. I recently discovered a potentially important interaction between the dietary polyphenol resveratrol and the mitochondrial antioxidant enzyme Mn-superoxide dismutase. Treatment of human cells or live mice with resveratrol induces increased production of this enzyme that is coincident with increased stress resistance. In this proposal, I outline experiments that will elucidate the interaction of resveratrol with cells that lead to Mn-superoxide dismutase induction, as well as experiments that will lead to improved delivery of resveratrol to cells to facilitate this effect.