RUI: Testing the network hypothesis of Cellular Aging in Saccharomyces Cerevisiae

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Intellectual merit. What is aging? This question remains elusive despite over 150 years of research. In this project, the novel hypothesis is proposed that cellular aging is an emergent property of gene/protein networks. This hypothesis argues that the plasticity of cellular aging, 70~80% of natural variation in life span, is attributed mainly to the stochasticity of detrimental changes that can propagate through the networks. Polymorphic variations can alter stochastic processes of aging by influencing the strength and dynamics of interactions in the networks and can contribute to 20~30% of natural variation in life span. This hypothesis predicts that the rate of cellular aging is proportional to the robustness of the network, a prediction that will be tested in this project both computationally and experimentally. The first aim is to examine the statistical associations of the effects of genes on aging and their effects in robustness and to predict new genes associated with aging. The second aim is to test experimentally the link between network robustness and the rate of cellular aging. Several proxies of network robustness will be measured in a collection of wild isolates of yeast. The associations between these proxies of robustness and the rate of cellular aging will then be evaluated. By recognizing cellular aging as an emergent property, this novel network model of aging can provide a mechanistic foundation for other theories of aging. Because cellular aging is a system-level property, it cannot be pinpointed to specific genes. This explains the paradox in the field that not gene with a direct functional link to aging has yet to be found, even though over 80 genes are known to influence the aging process in yeast alone. The general principle of emergent properties of gene/protein networks will also offer new insights into the relationship between the genotype and phenotype of an organism.Broader impacts. The project will benefits to the institutional research and teaching programs at an historically black women's college. This project will largely be carried out by undergraduate students from a minority background. By engaging these students in hypothesis-driven research and intense interdisciplinary training, it will cultivate a love of research and encourage their pursuits of science-related careers. This project will also invigorate the research program and enhance the research capacity at this college.