Molecular mechanisms underlying the maximal lifespans of animal species

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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.