Strategies for Targeting Senescent Cells in Human Disease

Abstract

Cellular senescence represents a distinct cell fate characterized by replicative arrest in response to a host of extrinsic and intrinsic stresses. Senescence provides programming during development and wound healing, while limiting tumorigenesis. However, pathologic accumulation of senescent cells is implicated in a range of diseases and age-associated morbidities across organ systems. Senescent cells produce distinct paracrine and endocrine signals, causing local tissue dysfunction and exerting deleterious systemic effects. Senescent cell removal by apoptosis-inducing "senolytic" agents or therapies that inhibit the senescence-associated secretory phenotype, SASP inhibitors, have demonstrated benefit in both pre-clinical and clinical models of geriatric decline and chronic diseases, suggesting senescent cells represent a pharmacologic target for alleviating effects of fundamental aging processes. However, senescent cell populations are heterogeneous in form, function, tissue distribution, and even differ among species, possibly explaining issues of bench-to-bedside translation in current clinical trials. Here, we review features of senescent cells and strategies for targeting them, including immunologic approaches, as well as key intracellular signaling pathways. Additionally, we survey current senolytic therapies in human trials. Collectively, there is demand for research to develop targeted senotherapeutics that address the needs of the aging and chronically-ill.

Figure 1.. Senescent Cell Accumulation Positive Feedback Loop.

Cellular senescence is induced following exposure to an initial stress. The resulting senescent cells produce a SASP that can potentiate further senescence cell accumulation and impair clearance. In turn, the SASP can be amplified eliciting an environment of chronic inflammation and additional senescence inducing stressors that drive a feed-forward cycle of senescent cell accumulation.

Figure 2.. Senescent Cell Features Targeted by Senolytics.

Select features of senescent cells have been leveraged to specifically reduce their abundance. Broadly, these targets include unique surface markers, SCAP and other survival networks, biochemical adaptations, and changes in organelle characteristics.

Figure 3.. Layers of Heterogeneity in Cellular Senescence.

Senescent cells exhibit context dependent phenotypic diversity. Numerous stimuli can induce a stress response sufficient to induce cellular senescence. Furthermore, susceptibility to these stressors and senescent cell characteristics can depend on cell type, tissue, disease state, and other context. The resulting senescent cells display a spectrum of convergent and divergent phenotypes in their secretome and consequent functionality. (ROS, Reactive Oxygen Species).