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Strategies for targeting senescent cells in human disease
Open accessAbstract
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.
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“Through upregulation of pro-survival and antiapoptotic pathways such as SRC kinases, the PI3K-AKT signaling pathway, heat shock protein (HSP) pathways, serpines, mitochondrial pathways or apoptosis regulator BCL-2-related proteins, those senescent cells with a proapoptotic SASP can survive, despite the cytotoxic microenvironment they create6,7,14,34,35,54–58.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [58]
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In the citing paper
“but also enhance SASP autocrine loop, as found in multiple previous studies,124,125,126,127”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [127]
Experimental — accuracy not yet measuredIn the citing paper
“Persistent senescent cells are known to exert detrimental long-term effects on organ function and can promote tumorigenesis33,96,112,177,178.”
From COVID-19 and cellular senescence (2023) · cites this paper as [96]
In the citing paper
“Senescent cells are highly associated with aging and pathological conditions and could be targeted to slow the aging process.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [3]
In the citing paper
“At the transcript level, p16 and p21 are the two most commonly used markers for senescent cells [3,16].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [3]
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“…of nearby normal cells into SCs, 4,5 which suggests a mechanism by which accumulating a threshold number of SCs can cause disease, including exacerbating cardiovascular, endocrine, hepatic, neurological, muscular, pulmonary, immune-related, and skeletal disorders (reviewed by Gasek et al. 3 ).”
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“Morpho-logically, senescent cells become enlarged and flattened with an increase in the cytoplasm-to-nucleus ratio [3].”
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Background
Metadata
- Authors
- Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M.
- Affiliations
- University of Connecticut (US)
- Mayo Clinic (US)
- Corresponding author
- Xu, Ming
- Venue
- Nature Aging
- Published
- 2021-10-07
- Volume
- 1
- Issue
- 10
- Pages
- 870-879
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC8612694
- OpenAlex
- W3202997660
- Cited by
- 501
- References
- 152
- Citations by year
- 2026: 78 · 2025: 120 · 2024: 141 · 2023: 95 · 2022: 63 · 2021: 4
- FWCI
- 10.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21AG063528,R33AG061456, R37AG013925, R01AG072301, P01AG062413, R21AG063528,R03AG072374,R01AG066679, R01AG068860)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, senolytics, senescence-associated secretory phenotype, senolytic therapy, senotherapeutics, aging, age-related diseases, intracellular signaling, bench-to-bedside translation, chronic disease
- MeSH terms
- Senescence-Associated Secretory Phenotype, Aging, Cell Differentiation, Chronic Disease, Humans, Signal Transduction, Cellular Senescence
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