Title:
Impact of DNA Damage Response on Cancer and Aging

Noboru Motoyama
Section Chief
Department of Cognitive Brain Science
National Center for Geriatrics and Gerontology

Abstract:
Aging induces the declining of tissue function by affecting at molecular, cellular, and organelle levels, and increases susceptibility to geriatric diseases including diabetes, arteriosclerosis and so on. Premature aging syndromes, such as Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WS), are characterized by accelerated aging with a shortened lifespan and by an early onset of symptoms as well as geriatric diseases related to a normal aging. The responsible genes for premature aging syndromes encode proteins that function in the maintenance of genomic integrity. Moreover, DNA damages are accumulated in cells derived from model mice and patients of premature aging syndromes, and even in that derived from normal elderly, emerging a possibility that DNA damage may link to aging process as well as cancer. Environmental insults such as ionizing radiation (IR), ultraviolet light (UV) and chemicals; aberrant activation of oncogene; oxidative stress such as that attributable to reactive oxygen species derived from oxidative metabolism, induce DNA damage response (DDR), thereby triggering cell cycle arrest, apoptosis and cellular senescence program. In addition, senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP).Here I will present the regulatory mechanisms of apoptosis, cellular senescnece and SASP. I also will present our findings using mice models for HGPS, Zmpste24 ^-/- mice and Chk2 ^-/- mice and discuss how DDR involves in aging process as well as tumor suppression.