PROJECT SUMMARY A critical level at which aging is regulated is the cellular responses to molecular events, which in turn alter the tissue and systemic milieu. Understanding cell fate decisions that occur in response to endogenous and exogenous insults that cause aging offers opportunities to develop novel therapies for age-related phenotypes and pathologies. One important cell fate that drives aging is cellular senescence: an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). Senescent cells increases with age in most tissues. These cells can drive a surprisingly diverse array of aging phenotypes and diseases, largely through the SASP. Moreover, eliminating senescent cells, using either transgenic mouse models or a new class of drugs termed senolytics, can help maintain homeostasis in aged or damaged tissues, and postpone or ameliorate many age-related pathologies. In this proposal, we will characterize a novel aspect of cellular senescence, cell competition, to determine how it contributes to aging. Cell competition is a process by which neighboring (winner) cells detect and remove suboptimal (loser) cells by killing and engulfing them. Our preliminary data show that several senescence-inducing stimuli allow a subset of senescent cells to acquire winner status, allowing them to actively kill and engulf a subset of neighboring non-senescent cells. This killing is transient and coincides with the onset of the pro-inflammatory SASP. We propose that this early transient killing of non-senescent neighbors is required for the long-term survival of pro- inflammatory senescent cells during aging. It is possible that a subset of senescent cells acquires winner status to avoid elimination and/or acquire nutrients (by engulfment) for survival. Deciphering the mechanisms of cell competition in the context of cellular senescence is essential to understand many processes in biology, ranging from embryogenesis to cancer. Using unbiased high throughput techniques such as proteomics and single cell transcriptomics, we plan to determine the molecular events that regulate cell competition by early senescent cells. Further, investigating these processes will open new opportunities for eliminating pro- inflammatory senescent cells before they can drive pathology.

PROJECT NARRATIVE This proposal will investigate the mechanisms of cell competition acquired by early senescent cells. We propose that the transient killing of non-senescent neighbors is required for the long-term survival of pro- inflammatory senescent cells during aging. Selective elimination of these senescent cells could open new possibilities for alleviating age-related pathologies.