Cellular and molecular determinants of vertebrate lifespans

该提案概述了一项研究计划，将导致更好地了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应激能力的增强有关。更大的细胞应激抵抗力促进细胞和组织功能在更长时间内的维持。在特别长寿物种的高度氧化组织（例如大脑和心脏）中，单个细胞可以持续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。在这项研究计划中，我描述了一种策略，用于识别与哺乳动物和鸟类物种的长寿共同进化的细胞应激抗性的组成部分。这种方法利用了广泛的物种，包括一些寿命特别长的物种（如蝙蝠和鸟类）。将分析在维持细胞机制处于功能状态、消除致突变DNA损伤和调节线粒体功能方面发挥作用的蛋白质。除了采取多物种的方法外，我还将在一种具有单一基因突变的小鼠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%（斯内尔侏儒）。生理压力导致细胞死亡，这是衰老的组织退化的基础。长寿的动物可以通过在成年动物的组织中维持干细胞群来对抗这种情况，这些干细胞可以复制和分化以取代丢失的细胞。我将确定长寿动物的心脏组织中是否有更多或更健壮的成体干细胞。最后，这种性质的研究产生的信息对人们有益。我最近发现了一个潜在的重要的相互作用之间的饮食多酚白藜芦醇和线粒体抗氧化酶锰超氧化物歧化酶。用白藜芦醇处理人类细胞或活小鼠会诱导这种酶的产生增加，这与抗应激能力的增加一致。在这个建议中，我概述了实验，将阐明白藜芦醇与细胞的相互作用，导致锰超氧化物歧化酶的诱导，以及实验，将导致改善白藜芦醇传递到细胞，以促进这种效果。

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.