Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies

An increase in life expectancy in devel-oped countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided evidence of the prominent role of cellular senes-cence in many of these pathologies. Key traits of senes-cent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secre-tory phenotype resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senes-cence is a highly phenotypically heterogeneous pro-cess, hindering the discovery of totally specific and accurate biomarkers. Also, strategies to prevent the pathologic effect of senescent cell accumulation dur-ing aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies, and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiologic functions. In this review, we explore the heterogeneous phenotype of senescent cells and its in-fluence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies. Significance Statement--This paper is an exten-sive review of what is currently known about the com-plex process of cellular senescence and explores its most defining features. The main body of the discussion focuses on how the multifeature fluctuation of the se-nescence phenotype and the physiological role of cellu-lar senescence have both caused a limitation in the search for truly reliable senescence biomarkers and the progression in the development of senotherapies.