Context-Dependent Roles of p53 in Cellular Senescence and Fibrosis

Cellular senescence(definition) is an irreversible growth arrest state and a hallmark of organismal aging. While induction of cellular senescence in healthy organs is undesirable, senescence of specific cell types can be beneficial in certain pathological milieus. For instance, the senescence of activated myofibroblasts helps to limit excessive collagen deposition and preserving tissue homeostasis. Senescent cells express signature gene products, including cell cycle regulators and senescence-associated secretory phenotype (SASP), which includes proinflammatory cytokines, growth factors, and protease inhibitors. Among the senescence regulators, the tumor suppressor p53 plays a pivotal role in suppression of fibrogenesis by dual action: through transcriptional repression of matrix protein genes, and through activation of the cellular senescence pathway in matrix-producing myofibroblasts. Because p53 activation suppresses collagen synthesis, it offers a promising treatment for most fibrotic diseases. However, sustained activation of p53 stress-response in healthy cells may accelerate cellular senescence and aging by promoting the release of SASP. Therefore, the magnitude and timing of p53 activation are critical factors that determine whether its effects are beneficial or detrimental in a given pathological milieu. Here, we discuss the fascinating dual trajectory of p53: its role in driving cellular senescence that contributes to aging, and its capacity to limit the progression of fibrogenesis, a major driver of age-related morbidity and mortality worldwide.