SIRT1 Phosphorylation and Cell Proliferation

SIRT1, the mammalian ortholog of Sir2, is an NAD + -dependent deacetylase, and its gene expression can affect the lifespan of multiple organisms, as can compounds that pharmacologically activate it. It possesses a large and growing list of substrates, such as p53, NFκB, and FoxO, and influences cell survival, stress resistance, cell differentiation, glucose and fat metabolism. Importantly, SIRT1 may regulate longevity and has proved to be a significant factor in aging research. However several key questions have not been addressed, namely: 1) are SIRT1 levels regulated in the context of aging and senescence, and 2) is SIRT1 regulated post-translationally. In order to address the first question, I investigated the changes in the level of SIRT1 with aging and senescence, and showed that levels of the SIRT1 protein decline as cells lose mitotic activity with age and that the decline is due to a post-transcriptional mechanism. These results are described in chapter 2.

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