Cellular senescence is a central biological mechanism for cancer prevention in mammals. Cells enter senescence when tumor-inducing genes are aberrantly activated, and in response undergo an arrest in proliferation accompanied by dramatic changes in metabolism and morphology, thus preventing their further development into tumors. Various types of physiologic stresses can also induce senescence, and this process is thought to play a central role in promoting aging, possibly by limiting the proliferative potential of stem-cell pools. While much is known about senescence in cultured cells, basic questions regarding the roles of this process in the living organism are still unanswered. In this proposal we describe the development of systems for the study of senescence in the living organism. We utilize the two central molecular activators of senescence: the p16INK4a and p19ARF genes. These genes are specifically induced during cellular senescence, and their expression is sufficient to induce this state. We will develop and characterize mice in which the expression of p16INK4a or p19ARF can be induced in multiple tissues through tetracycline administration, in order to induce cellular senescence in these tissues. This will allow us to experimentally generate senescent cells in the adult mouse and characterize their molecular and functional traits. We will study the effects of cellular senescence on tissue and organism physiology, and assess whether induction of senescence induces aging-like phenotypes. This system will provide the first genetic system to study this central biological program in its proper physiologic context, shedding light on aging processes and cancer prevention mechanisms.
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