Cellular senescence: a key therapeutic target in aging and diseases

Abstract

Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.

Figure 1. Diverse stress stimuli can induce cellular senescence and lead to generation of senescent cells, which play pleiotropic roles in both physiology and pathology.

CCF, cytoplasmic chromatin fragment; DNA-SCARS, DNA segments with chromatin alterations reinforcing senescence; mtDNA, mitochondrial DNA; SADF, senescence-associated DNA damage foci; SAHF, senescence-associated heterochromatin foci; SAMD, senescence-associated mitochondrial dysfunction; SASP, senescence-associated secretory phenotype; TAF, telomere-associated foci.

Figure 2. Current strategies to target senescent cells.

Figure 3. Drug screening and drug design can facilitate the discovery and development of senotherapeutics to treat aging and age-related diseases.