Cellular senescence and senolytics: the path to the clinic

Abstract

Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies-including recent and ongoing clinical trials-for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.

Fig. 1 |. Senescence-associated secretory phenotype.

The SASP is a key feature of cellular senescence. Cellular stressors induce DNA damage response signaling, which activates key transcription factors and pathways including NF-κB, CCAAT/enhancer binding protein-β (C/EBPβ), GATA binding protein 4 (GATA4), p38 and JAK-STAT, which can drive and modulate the SASP^,,,,,,,–. The various forms of the SASP can comprise chemokines, extracellular matrix proteases, remodeling factors, bioactive lipids, noncoding nucleotides and reactive metabolites^,,–. IL-6, interleukin-6; ROS, reactive oxygen species; TGF-β, transforming growth factor beta; TIMPs, tissue inhibitors of metalloproteinases; TNF, tumor necrosis factor.

Fig. 2 |. The threshold theory of senescent cell accumulation.

This theory postulates that once senescent cell burden exceeds a threshold, self-amplifying paracrine and endocrine spread of senescence through the SASP outpaces clearance of senescent cells by the immune system^,. Additionally, increased abundance of SASP factors may impede immune system function^,, further amplifying accumulation of senescent cells. Senescent cell accumulation may also accelerate other fundamental aging mechanisms. In studies of effects of transplanting senescent versus non-senescent cells into middle-aged mice, a minimum number of transplanted senescent cells was necessary to cause accelerated aging-like phenotypes. In conditions in which senescent cell burden is already high, such as obesity, fewer senescent cells need to be transplanted to induce the same effect as in lean mice of the same age^,,. Consistent with this, in human childhood cancer survivors who have had DNA-damaging anticancer therapy, a subsequent accelerated aging-like phenotype can occur at a considerably earlier age than in older individuals who do not have a history of childhood cancer treatment. Hence, senescent cells with a proapoptotic, inflammatory SASP may need to exceed a threshold to exert detrimental effects. Systemic clearance of senescent cells by genetic or pharmacologic means tends to attenuate the other pillars of aging and can delay, prevent or alleviate multiple age-related disorders and diseases^,,,.

Fig. 3 |. First and second-generation senolytic strategies.

First-generation senolytics target different SCAPs, including tyrosine kinase receptors (TKRs), growth factor receptors (GFRs), ephrin receptor B1 (EFNB1), SRC kinases, PI3K-AKT, HSP90, BCL-2 family members, caspase inhibition and p53 modulation^,,,–. High-throughput library screens and other approaches have informed second-generation senolytic strategies, including lysosomal and SA-β-gal-activated prodrugs and nanoparticles^,,,, sodium–potassium pump (Na⁺/K⁺-ATPase)-dependent apoptosis^,, SASP inhibition^– and immune-mediated clearance by CAR T cells, antibody–drug conjugates or vaccines^,–.