New Scholar Award in Aging
Shin-ichiro Imai, M.D., Ph.D.
Washington University School of Medicine

The Function of Mammalian NAD-dependent deacetylase Sir2a and NAD Biosynthesis Enzymes in Aging-associated Epigenetic Gene Regulation

Epigenetic alteration in gene expression is one of the postulated mechanisms underlying aging, as well as oxidative lesions by reactive oxygen species, genomic instability by accumulated DNA damages, telomere shortening in proliferating cells, and accumulation of glycation end products of proteins. Histone deacetylases are essential regulators in the epigenetic regulation of chromatin structure and suggested to have important roles for aging in lower eukaryotes. Among them, the Sir2 (silent information regulator 2) protein family recently receives particular attention. Sir2 proteins are novel nicotinamide adenine dinucleotide (NAD)-dependent histone/protein deacetylases, and this enzymatic activity is critical to regulate aging and longevity in lower eukaryotes. Our ultimate goal is to elucidate the function of mammalian Sir2a in mammalian aging and longevity. We hypothesize that mammalian Sir2a and NAD biosynthesis enzymes play important roles in epigenetic changes of gene expression in mammalian aging. We will address this hypothesis at cellular and organismal levels by using mouse as a model.

Understanding a previously unrecognized feature of gene regulation, that is, the NAD-dependent gene regulation by Sir2 in mammalian aging will provide new insights to the fundamental connection between epigenetic gene regulation, energy metabolism and aging. This study will also open a new field in aging research, that is, the role of NAD biosynthesis in mammalian aging. Identifying mammalian Sir2a and NAD biosynthesis as critical regulatory elements in mammalian aging will lead us to possible intervention to prevent detrimental effects of aging and, hopefully, slow down the pace of aging in mammals.

Contact Dr. Imai.