David Sinclair, PhD

DNA Damage Drives SIRT1 Relocation, Sparking Epigenetic Aging

Good question. Back in the 2000s, Phillip Oberdoerffer, a postdoc in our lab, published that DNA breaks cause epigenetic drift in mammals, not just yeast, consistent with the Information Theory of Aging Summary of the 2009 study ICYMI: One of the hallmarks of aging is the gradual loss of genome stability and control of gene activity. In yeast, a protein called Sir2 (the original Sirtuin) helps keep certain genes turned off and protects repetitive regions of DNA. As yeast age, or when their DNA is damaged, Sir2 leaves its normal locations and moves to sites of DNA damage to help with repair. This causes previously silent genes to become active, leading to changes associated with aging We found that the mammalian version of Sir2, called SIRT1, behaves in a similar way. In mouse cells, SIRT1 normally helps silence repetitive DNA and regulates many genes throughout the genome. When DNA damage occurs, SIRT1 moves away from these regions and relocates to DNA breaks to assist in repair. As a result, gene expression patterns change in ways that closely resemble those seen in aging mouse brains Increasing SIRT1 levels improves survival in mice with unstable genomes and reduces many of the gene expression changes that occur with age. These findings suggest that aging may result, at least in part, from the repeated redistribution of SIRT1 and other chromatin-regulating proteins as they respond to DNA damage, gradually disrupting the youthful organization of the genome https://t.co/F6IuGkRRbe