Birth and death of cellular senescence

Cellular senescence is a stress response of stable growth arrest mediated by the CDK inhibitors p16 and p21 which acts as a potent barrier to tumorigenesis. Senescent cells are characterized by a persistent DNA damage response and by an hypersecretory phenotypes (SASP). The SASP covers beneficial tissue repair and tumor suppressive functions, but can drive pathology, including cancer, when senescent cells are aberrantly induced and become chronic. For example, senescent cells accumulate as a consequence of cancer therapy and natural aging, and their genetic or pharmacological clearance is sufficient to extend reduce dysfunctions and extend healthy lifespan. Chapter 1 of this thesis reflects on the various contexts where senescent cells act detrimentally. Chapter 2 focuses on cancer therapy and provides detailed information on the cellular and organismal consequence of chemotherapy, radiotherapy and CDK4/6 inhibitors. Chapter 3 investigates the pro-senescence effect of CDK4/6 inhibitors and emphasizes the existence of heterogeneous senescence programs with differential consequences on health. Chapter 4 concentrates on natural aging and analyze the accumulation of p16+ senescent cells in mice and humans. Chapter 5 studies potential mechanisms regulating premature or natural accumulation of senescent cells, and also analyzes the potential influence of various intrinsic and extrinsic factors. Finally, chapter 6 represents a reflection on how the finding and knowledge developed during my PhD can contribute to the field of senescence, and how they can be used for future research efforts aimed at defining the multifactorial and heterogeneous biological roles of cellular senescence.