Role of a SIRT3, a Sir2-related Mitochondrial Protein Deacetylase, in Aging

2003 senior Scholar Award in aging

The aging process is increasingly considered to be a programmed event regulated by individual gene products, like other developmental processes. One major implication of this working model is that several diseases associated with aging might actually be linked by a common set of aging genes. This model also implies that therapeutic intervention targeting these aging genes could slow the aging process and its associated pathologies. From studies in simple organisms, and more recently in mammals, we have learned that calorie restriction increases life span, an observation that links aging and metabolism. The histone deacetylase proteins related to sir2 represent a critical link between calorie restriction and the slowing of aging. Overexpression of sir2 proteins is associated with delayed aging in yeast and in C. elegans. Sir2 proteins participate in transcriptional silencing in yeast and exhibit nicotinamide dinucleotide phosphate (NAD+)-dependent histone deacetylase activity. These proteins are conserved from bacteria to humans and seven human sir2 homologues, designated hSIRT1ñ7, have been identified. We recently reported that hSIRT3 is expressed as an active NAD+-dependent protein deacetylase in the matrix of mitochondria. The presence of a NAD+-dependent enzyme in the mitochondria is compatible with the model that hSIRT3 represents a link between aging, calorie restriction, and sir2 proteins in mammals. Our work is focused on determining the contribution of hSIRT3 to the aging process in mammals and on determining the role of protein acetylation in mitochondria.

Eric Verdin M.D.
J. David Gladstone Institutes