Genomic instability and alterations in gene expression are hallmarks of eukaryotic
aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive
DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to
sites of genomic instability, resulting in the desilencing of genes that cause sterility,
a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian
Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across
the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and
relocalizes to DNA breaks to promote repair, resulting in transcriptional changes
that parallel those in the aging mouse brain. Increased SIRT1 expression promotes
survival in a mouse model of genomic instability and suppresses age-dependent transcriptional
changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying
proteins may be a conserved mechanism of aging in eukaryotes.