The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.Biomolecules 2020, 10, 420 2 of 16 focus on the p53-dependent senescence signaling pathways involved with different stages of senescence and with a consideration for the associated key biomarkers. We also provide an overview on the regulation of p53-mediated cellular senescence in the context of different pathophysiological conditions. Senescence as Cellular Response to StressCellular senescence is defined as a cell state characterized by prolonged and generally irreversible cell-cycle arrest [14] and the acquisition of different phenotypic alterations, including morphological changes, chromatin remodeling, metabolic reprogramming, and secretion of pro-inflammatory factors or SASP (senescence associated secretory phenotypes). These latter count cytokines, growth factors, proteases, and non-soluble extracellular matrix proteins [15]. All these features ultimately limit the replication of both old and damaged cells. Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.Stressors include both intrinsic factors, such as oxidative damage, telomere attrition, hyperproliferation, oncogene activation, and environmental sources, including UV-light, γ-irradiation, and chemotherapeutic drugs [18,19]. Regardless of their origin, the stress factors trigger DNA damage responses (DDR) in the affected cells, which can result in different outcomes, depending on the cell type and the extent of the damage [20]. Mild DNA damage normally induces cell cycle arrest, while severe injury can activate the senescence program or the death programs; the latter includes apoptosis, mitotic catastrophe, autophagy, and necrosis [21].p53 plays a pivotal role in determining the fate of th...