Senescence and the SASP: many therapeutic avenues

Jodie Birch, Jesús Gil, Jodie Birch, Jesús Gil

Abstract

Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells to delay aging and limit dysfunction, known as "senotherapy," is gaining momentum. While drugs that selectively kill senescent cells, termed "senolytics" are a major focus, SASP-centered approaches are emerging as alternatives to target senescence-associated diseases. Here, we summarize the regulation and functions of the SASP and highlight the therapeutic potential of SASP modulation as complimentary or an alternative to current senolytic approaches.

Keywords: SASP; aging; cancer; disease; inflammation; senescence; senolytics; senomorphics; therapeutics.

© 2020 Birch and Gil; Published by Cold Spring Harbor Laboratory Press.

Figures

Figure 1.
Figure 1.
The pleiotropic functions of the SASP. Shown here is a summary of the effects exerted by senescent cells (in the middle) that are mediated by the SASP. The effects above the senescent cell (in green) represent those that are considered beneficial, whereas those at the bottom (in red) reflect some of the detrimental consequences of the SASP.
Figure 2.
Figure 2.
Regulation of the senescence-associated secretory phenotype (SASP). Scheme showing the different factors contributing to SASP induction. Transcription factors are shown in yellow. Intracellular signaling components are shown in orange. Sensors and receptors and ligands are shown in red. (DSB) Double-strand breaks, (CCF) chromatin cytoplasmic foci.
Figure 3.
Figure 3.
Mechanism by which senescent cells contribute to disease. Both SASP-independent (top) and SASP-dependent (bottom) effects of senescent cells likely explain how senescence promotes tissue and organ dysfunction. The build-up of senescent cells can deplete stem and progenitor pools and could lead to dysfunctions associated with senescent cell accumulation, such as the case in atherosclerosis. Alternatively, paracrine functions of senescent cells, such as the ability of SASP factors to contribute to chronic systemic inflammation and tissue inflammation and remodeling are also at play. Specific SASP components, such as hemostatic factors including SERPINs and PAI-1, promote platelet activation and increased thrombosis following chemotherapy. Similarly, liver injury, induced by acetaminophen, is driven by macrophage-dependent TGF-β signaling that favors hepatocyte paracrine senescence limiting regeneration.
Figure 4.
Figure 4.
Targeting senescent cells and the SASP in age-related disease. Different strategies to target senescent cells in age-related pathologies have been proposed with the two main approaches being cell death induction via senolytics (A) and modulation of the SASP by interfering with its regulatory pathways (B).
Figure 5.
Figure 5.
Targeting senescence in cancer. Engaging senescence using “prosenescence therapies” in cancer can be followed up by strategies that then exploit vulnerabilities of senescent cancer cells. Inducing senescent cell death by senolytic treatment or through the development of senolytic CAR T cells that recognize factors expressed on the surface of senescent cancer cells is one approach. An alternative method is to use drugs that potentiate the SASP. Drugs that induce or reinforce the SASP have been found to promote immune cell surveillance and senescent cell clearance. SASP inducers can also remodel the tumor microenvironment, favoring access by immune cells and chemotherapeutic drugs used as part of anticancer treatments. TME, tumor microenvironment.

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