Molecular Patterns and Signatures of Longevity
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CitationMa, Siming. 2016. Molecular Patterns and Signatures of Longevity. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractSince their divergence from a common ancestor some 200 million years ago, mammals have undergone significant diversification in physiology, morphology, habitat, size, and longevity. The maximum lifespan of mammalian species ranges from under 3 to over 200 years, but the molecular basis of such variation is poorly understood. While many genes, pathways, dietary interventions, and pharmacological compounds have been shown to influence the lifespan of model organisms, it is not known whether the same mechanisms are responsible for the longevity variation across different species. This thesis presents the analyses of gene expression and the levels of metabolites, chemical elements, and/or proteins, across multiple organs and tissues of up to 42 species of mammals, as well as the analyses of 5 long-lived mouse models, 22 natural isolates of yeast, and 16 species of fruit flies, to identify the molecular patterns and signatures associated with species longevity. The results show that longer-lived mammals up-regulate ribosomal proteins and genes involved in DNA repair, and down-regulate ubiquitin-mediated proteolysis and apoptotic functions. Some of the metabolic changes in long-lived mammals, such as higher levels of sphingomyelins and glycerophospholipids but lower levels of polyunsaturated triacylglycerols, were also observed in long-lived mouse models. Yeast strains of varying replicative lifespan differed in their aerobic respiration capacity, attributable to different protein composition in mitochondria. Long-lived fruit flies overexpressed the genes involved in lipid metabolism but suppressed the genes involved in neuronal development. Many genes previously implicated in lifespan control in model organisms also showed the expected correlation with the longevity traits across species. This thesis presents the snapshots of the complex changes associated with species natural lifespan variation and offers new insights into the mechanisms of longevity control and potential lifespan extension strategies.
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