Cellular senescence in aging: Molecular basis, implications and therapeutic interventions

Cellular senescence is an irreversible proliferation arrest in response to cellular damage and stress. Although cellular senescence is a highly stable cell cycle arrest, it can influence many physiological, pathological, and aging processes. Cellular senescence can be triggered by various intrinsic and extrinsic stimuli such as oxidative stress, mitochondrial dysfunction, genotoxic stress, oncogenic activation, irradiation and chemotherapeutic agents. Senescence is associated with several molecular and phenotypic alterations, such as senescence-associated secretory phenotype (SASP), cell cycle arrest, DNA damage response (DDR), senescence-associated β-galactosidase, morphogenesis, and chromatin remodeling. Cellular senescence is a regular physiological event involved in tissue homeostasis, embryonic development, tissue remodeling, wound healing, and inhibition of tumor progression. Mitochondria are one of the organelles that undergo significant morphological and metabolic changes associated with senescence. Recent evidence unraveled that inter-organelle communication regulates cellular senescence, where mitochondria form a highly complex and dynamic network throughout the cytoplasm with other organelles, like the endoplasmic reticulum. An imbalance in organelle interactions may result in faulty cellular homeostasis, which contributes to cellular senescence and is associated with organ aging. Since mitochondrial dysfunction is a common characteristic of cellular senescence and age-related diseases, mitochondria-targeted senolytic or redox modulator senomorphic strategies help solve the complex problems with the detrimental consequences of cellular senescence. Understanding the regulation of mitochondrial metabolism would provide knowledge on effective therapeutic interventions for aging and age-related pathologies. This chapter focuses on the biochemical and molecular mechanisms of senescence and targeting senescence as a potential strategy to alleviate age-related pathologies and support healthy aging.