Senescence as a pivotal point of healthy aging – SENAGE

Cellular senescence attracted a lot of attention as a key player contributing to organismal aging. The accumulation of senescent cells is dramatically increased with aging, however their precise contribution to aging-related phenotypes remains largely unclear. The unknown extent of aging-induced senescence and the exact role of different senescent subtypes in functional decline with aging represent a prominent gap in current scientific knowledge. This project will address this by comprehensive analysis of senescent cells with 2 novel knock-in mouse models, which will constitute a unique and invaluable resource for scientists in all fields of senescence and aging. Through additional functional and interaction analyses, it will also provide key insights into how senescent cells contribute to functional decline with aging. Thus, this project directly addresses a fundamental role of senescence in the aging process, about which currently very little is known; thus, it has the strong potential to advance the field and establish new paradigms. The latter is further supported by our extensive preliminary data to show that physiological senescence could play a major role in protecting from an aging-induced functional decline in defined tissues and organs. Our experiments will definitively resolve many of these questions, and will reveal for the first time the comprehensive distribution of senescent cells in the aging organism. Moreover, the experiments with selective ablation of senescent cells will provide a direct answer to their functional roles. Using our unique mouse models, we will establish comprehensive transcriptional profiles in different senescent cell types. This knowledge would help to better understand the common molecular mechanism responsible for aging-induced activation of senescence but also to identify potential targets to manipulate senescence through reprogramming and/or selective elimination. This in turn could have a significant impact on the treatment of many aging-induced pathological conditions. As such, this project will directly address the extent to which senescent cells can contribute to different age-related diseases and the benefits of their removal.