Abstract
Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions.
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Acknowledgements
We thank the Demaria laboratory for continuous and fruitful discussions. M.D. is funded by the Dutch Research Council (NWO) Talent Program, the Dutch Organization for Health Research and Development (ZonMw), the Dutch Cancer Foundation (KWF), the American Federation for Aging Research (AFAR) and the Hevolution Foundation.
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All authors researched data for the article, contributed substantially to the discussion of content and wrote the article. J.H.E. and M.D. reviewed and/or edited the manuscript before submission.
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M.D. is co-inventor of patents held by the Buck Institute for Research on Aging and by Cleara Biotech. M.D. is the scientific cofounder of Cleara Biotech and consultant for Oisin Biotechnologies. The M.D. laboratory currently receives research funding from Ono Pharmaceuticals. J.H.E. holds equity in Unity Biotechnology and Aegeria Soft Tissue and is an adviser for Tessera Therapeutics, HapInScience, and Font Bio.
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Glossary
- α-Klotho
-
An enzyme that can suppress oxidative stresses; its plasma level is used to evaluate health span.
- Cyclic GMP–AMP synthase–stimulator of interferon genes
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(cGAS–STING). A complex that senses the presence of DNA in the cytosol and activates an inflammatory response.
- Foreign body response
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An immune and stromal cell response to a foreign material, such as a biomaterial implant, that results in encapsulating fibrosis and abnormal vasculature that resembles fibrosis in other disease processes.
- Inflammageing
-
Chronic low-grade inflammation that can be discovered during ageing and can contribute to age-related diseases.
- Inflammatory cells
-
Immune cells that exhibit a pro-inflammatory phenotype and contribute to acute and chronic inflammation; the subset includes innate immunity cells, such as neutrophils and macrophages, and select lymphocyte populations, such as cytotoxic CD8+ T cells, varying depending on context.
- JAK–STAT pathway
-
A signalling pathway that regulates cell proliferation and differentiation as well as inflammatory responses.
- Leukotrienes
-
Fatty acid eicosanoid inflammatory factors with detrimental roles in allergy and asthma.
- Minority mitochondrial outer membrane permeabilization
-
(miMOMP). A phenomenon occurring in a subset of mitochondria of senescent cells that contributes to the release of mitochondrial DNA to the cytosol.
- mTOR
-
A kinase that senses nutrient stimuli and coordinates cell growth and metabolism.
- NF-κB
-
A transcription factor that regulates inflammation factors in activated B cells.
- p38 MAPK
-
Stress-activated protein kinases of the MAPK family that mediate cellular responses to inflammatory signals. p38 and other MAPKs are central regulators of cell proliferation, differentiation and stress responses.
- Pro-resolving phenotype
-
Immune cell subtypes that resolve inflammation and promote tissue repair; generally include M2 macrophages, T helper 2 cells and regulatory T cells, varying depending on context.
- Prostaglandins
-
Fatty acid eicosanoid factors that can be both pro-inflammatory and anti-inflammatory.
- Senolytic therapy
-
A therapy aimed to selectively kill senescent cells in physiological and pathological contexts.
- Senomorphic therapy
-
A therapy aimed to selectively target certain phenotypes of senescence (for example, the senescence-associated secretory phenotype) without killing the cells.
- Theca and interstitial cells
-
Cells that are part of the ovarian follicles and are important for hormone secretion in the ovary.
- Topoisomerase 1 cleavage complexes
-
(TOP1cc). Topoisomerase 1–DNA catalytic intermediates.
- Type 3 immune response
-
An immune response centred around T helper 17 cells and the production of IL-17 and IL-22; characterized by the recruitment of inflammatory neutrophils and macrophages.
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Wang, B., Han, J., Elisseeff, J.H. et al. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00727-x
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DOI: https://doi.org/10.1038/s41580-024-00727-x
