Potential Regulators of the Senescence-Associated Secretory Phenotype During Senescence and Aging

Senescent cells express and secrete a variety of extracellular modulators that include cytokines, chemokines, proteases, growth factors, and some enzymes associated with extracellular matrix remodeling, defined as the senescence-associated secretory phenotype (SASP). SASP reinforces senescent cell cycle arrest, stimulates and recruits immune cells for immune-mediated clearance of potentially tumorigenic cells, limits or induces fibrosis, and promotes wound healing and tissue regeneration. On the other hand, SASP mediates chronic inflammation leading to the destruction of tissue structure and function and stimulating the growth and survival of tumor cells. SASP is highly heterogeneous and the role of SASP depends on the context. The regulation of SASP occurs at multiple levels including chromatin remodeling, transcription, mRNA translation, intracellular trafficking, and secretion. Several SASP modulators have already been identified setting the stage for future research on their clinical applications. In this review, we summarize in detail the potential signaling pathways that trigger and regulate SASP production during aging and senescence.