Molecular mechanisms underlying the maximal lifespans of animal species

虽然不同动物物种的寿命差异很大，但我们对这种情况发生的原因的理解有限。然而，一个有趣的观察是，长寿与“细胞抗逆性”有关，也就是说，构成动物的单个细胞耐受潜在致命压力源的能力。有趣的是，对压力的耐受性赋予了长寿，似乎也提供了对各种疾病的抵抗力，包括与衰老相关的常见神经退行性疾病。这些公认的关系使我们了解细胞抗压力的实际机制变得尤为重要，因为这些知识可能用于延长寿命和/或老年人的整体健康。我正在提议的研究，将在相对适度的资金投入下，帮助我们通过更好地理解细胞对压力和疾病的抵抗力，走上一条积极影响衰老过程的道路。我建议在三个方面进行研究：(1)研究现有动物物种的细胞抗逆性，这些物种自然具有完全不同的寿命，并了解它们的不同之处。(2)研究具有特定基因突变的小鼠的细胞应激抗性，该基因突变使其寿命延长约50%。我将特别感兴趣的是发现在两种情况下（物种之间和单一物种内）是否涉及相同的机制来延长寿命。(3)探讨白藜芦醇增强细胞抗逆性的作用机制。我们已经证明，在红酒和其他饮食来源中发现的这种物质，能够增强细胞对压力源的抵抗力，可能是通过使细胞产生更多的天然抗氧化酶来实现的。我们将继续推进这项工作，以充分了解白藜芦醇引发这种反应的机制。这种三管齐下的方法将使我们更好地了解动物是如何实现长寿和抗病的。反过来，这将继续增加知识的基础，可以转化为与衰老相关的疾病的新疗法。

While the lifespans of different animal species vary widely, our understanding of why this occurs is limited. An interesting observation, however, is that longevity is associated with 'cellular stress resistance', that is, the ability of the individual cells comprising an animal to tolerate exposure to potentially lethal stressors. Interestingly, the same tolerance to stress that confers longevity seems also to provide resistance to various diseases, including common neurodegerative diseases associated with aging. These recognized relationships make it particularly important for us to understand the actual mechanisms that make cells stress resistant, because such knowledge might be used to improve longevity and/or the overall health of older individuals. I am proposing research that will, with a relatively modest investment of funds, help to move us along a path to positively affecting the aging process through an improved understanding of cellular resistance to stress and disease. I am proposing research in 3 areas: (1) To investigate cellular stress resistance in existing animal species that naturally have quite different lifespans and understand what they do differently. (2) To investigate cellular stress resistance in mice with a specific gene mutation that makes them live about 50% longer. I will be particularly interested in discovering whether the same mechanisms are involved in coferring longevity in both contexts (between species and within a single species). (3) To investigate how resveratrol works to enhance cellular stress resistance. We have shown that this substance, found in red wine and other dietary sources, is able to increase cellular resistance to stressors, possibly by causing cells to produce more of their natural antioxidant enzymes. We will continue to move forward with this work, with the goal of fully understanding the mechanisms by which resveratrol elicits this response. This three-pronged approach will allow us to develop a much better understanding of how animals achieve longevity and disease resistance. In turn, this will continue to increase the foundation of knowledge that can be translated into novel remedies for disorders associated with aging.