Molecular mechanisms underlying the maximal lifespans of animal species

虽然不同动物物种的寿命差异很大，但我们对这种情况的理解是有限的。 然而，一个有趣的观察结果是，寿命与“细胞应激抵抗力”有关，即组成动物的单个细胞耐受暴露于潜在致命应激源的能力。 有趣的是，同样的对压力的耐受性，赋予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使细胞抗应激的实际机制变得特别重要，因为这些知识可能用于改善老年人的寿命和/或整体健康。 我建议的研究，将与一个相对适度的资金投资，有助于推动我们沿着一条道路，积极影响衰老过程，通过提高对细胞抵抗压力和疾病的理解。 我建议在3个领域进行研究：（1）研究现有动物物种的细胞抗应激能力，这些动物物种的寿命自然不同，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抵抗力，该基因突变使它们的寿命延长约50%。 我将特别感兴趣的是，在这两种情况下（物种之间和单一物种内），是否有相同的机制参与推断寿命。(3)研究白藜芦醇如何增强细胞的抗应激能力。 我们已经证明，这种在红酒和其他饮食来源中发现的物质能够增加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。 我们将继续推进这项工作，目标是充分了解白藜芦醇促进这种反应的机制。 这种三管齐下的方法将使我们能够更好地了解动物如何获得长寿和抗病能力。 反过来，这将继续增加知识的基础，这些知识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.