PROJECT SUMMARY (See instructions): The accumulation of somatic (non-heritable) DNA mutations over time is a hallmark and potential mechanism of aging. Current theory postulates that un-repaired, stochastic DNA damage results in random DNA mutations that accumulate over time within individual cells, and are passed on as these cells replicate. These mutations are thought to impair cellular function, or to induce cell death or senescence, leading to impaired organ function and aging. Alternately, rare mutations may lead to cellular transformation and cancer. These theories depend upon the extent of mutations accumulated in tissues with age, but we do not have an accurate measurement of the mammalian somatic mutation rate. In the this study, we will utilize high-throughput sequencing and rigorous statistical methods to empirically measure the whole-genome somatic mutation rate in cells of the hematopoietic lineage from genetically identical mice collected at birth, sexual maturity, and old age. Our analyses of these data will determine the extent to which somatic mutations are associated with age, cellular turnover, proliferation, and functional decline. Further, we will explore the potential mechanisms of lifespan extension conferred by treatment with rapamycin by measuring the whole-genome somatic mutation rate in treatment animals and controls. This multi-factorial study of somatic mutations will provide the most accurate measurement of the mammalian somatic mutation rate to date, will begin to define the parameters that control the accumulation of mutations with age, and will begin to empirically test common theories of cancer and aging.

The accumulation of damage to DNA is central to the development of cancer and to the aging process, but the extent and dynamics of mutation accumulation in mammals are poorly understood. The proposed research will characterize the dynamics of mutations accumulated during hematopolesis, which are potentially relevant for a range of blood cancers, hemophilia, and other serious conditions.