EVIDENCE THAT EPIGENETIC ALTERATIONS DRIVE MAMMALIAN AGING

Aging is associated with epigenetic alterations but what drives these changes and whether they cause aging are not yet known. Each day our bodies experience millions of DNA double-strand breaks (DSBs), which are the most dangerous of all types of DNA damage. Fortunately, almost all DSBs are repaired without mutation. But they are not benign. We have shown that DSBs redistribute chromatin-modifying proteins away from gene regulatory regions to assist with DNA repair, resulting in gene expression changes (Mills et al., 1999; Oberdorffer et al., Cell, 2008). Incomplete restoration of the epigenome after repeated relocalization of chromatin-modifying proteins progressively disrupts transcriptional networks and the 3D organization of nucleus. This “epigenomic noise” is a major upstream cause of aging in yeast cells but whether it is in mammals is not known. To test cause and effect, we generated a transgenic mouse model called the ICE mouse (for Inducible Changes in the Epigenome). The mouse allows us to introduce a few DNA double strand breaks (DSBs) per cell within non-coding regions in cells or in young mice, for a defined time, without causing mutations. If the hypothesis is correct, the DNA methylation clock, epigenetic changes, and aging should all be accelerated. The results of these efforts, which will be presented, indicate that epigenomic changes can drive hallmarks of aging and that they are amenable to reversal.