Glucocorticoids suppress selected components of the senescence‐associated secretory phenotype
Open accessAbstract
Summary: Cellular senescence suppresses cancer by arresting the proliferation of cells at risk for malignant transformation. Recently, senescent cells were shown to secrete numerous cytokines, growth factors, and proteases that can alter the tissue microenvironment and may promote age‐related pathology. To identify small molecules that suppress the senescence‐associated secretory phenotype (SASP), we developed a screening protocol using normal human fibroblasts and a library of compounds that are approved for human use. Among the promising library constituents was the glucocorticoid corticosterone. Both corticosterone and the related glucocorticoid cortisol decreased the production and secretion of selected SASP components, including several pro‐inflammatory cytokines. Importantly, the glucocorticoids suppressed the SASP without reverting the tumor suppressive growth arrest and were efficacious whether cells were induced to senesce by ionizing radiation or strong mitogenic signals delivered by oncogenic RAS or MAP kinase kinase 6 overexpression. Suppression of the prototypical SASP component IL‐6 required the glucocorticoid receptor, which, in the presence of ligand, inhibited IL‐1α signaling and NF‐κB transactivation activity. Accordingly, co‐treatments combining glucocorticoids with the glucocorticoid antagonist RU‐486 or recombinant IL‐1α efficiently reestablished NF‐κB transcriptional activity and IL‐6 secretion. Our findings demonstrate feasibility of screening for compounds that inhibit the effects of senescent cells. They further show that glucocorticoids inhibit selected components of the SASP and suggest that corticosterone and cortisol, two FDA‐approved drugs, might exert their effects in part by suppressing senescence‐associated inflammation.
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Glucocorticoid treatment decreases the production of selected components of the SASP, namely, proinflammatory cytokines like IL-6, across different inducers of senescence by inhibiting NF-κB.
“Glucocorticoid treatment decreases the production of selected components of the SASP, namely, proinflammatory cytokines like IL-6, across different inducers of senescence by inhibiting NF-κB (Laberge et al. 2012).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Laberge et al. 2012
Neutralizing antibodies against key SASP components or their receptors, including IL-6, IL-1α, IL-1β, and TNF, have demonstrated senomorphic effects.
“A number of neutralizing antibodies directed against key components of the SASP or their receptors, including IL-6, IL-1α, IL-1β and TNF, also have shown senomorphic properties104,240–248 (TABLE 1).”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [241]
The Results and Discussion report that the glucocorticoids corticosterone and cortisol suppress IL-1α signaling and IL-6 secretion in senescent cells. A search for neutralizing antibodies against the named SASP components or their receptors found no passage showing that such antibodies have senomorphic effects; the antibodies listed in Experimental Procedures are for protein detection. (LLM, conf=0.76)
Experimental — accuracy not yet measuredGlucocorticoids have anti-inflammatory properties by repressing IL-6 secretion via inhibition of NF-κB activity.
“Glucocorticoids are a group of steroid hormones which have anti‐inflammatory properties by repressing IL‐6 secretion via inhibition of NF‐κB activity (Laberge et al, 2012).”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Laberge et al, 2012
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- Authors
- Laberge, R., Zhou, L., Sarantos, M. R., Rodier, F., Freund, A., de Keizer, P. L. J., Liu, S., Demaria, M., Cong, Y., Kapahi, P., Desprez, P., Hughes, R. E., & Campisi, J.
- Affiliations
- Buck Institute for Research on Aging (US)
- Beijing Normal University (CN)
- Corresponding author
- Campisi, Judith
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2012-04-17
- Volume
- 11
- Issue
- 4
- Pages
- 569-578
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3387333
- OpenAlex
- W1898081212
- Cited by
- 229
- References
- 44
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 24 · 2023: 17 · 2022: 24 · 2021: 20 · 2020: 26 · 2019: 15 · 2018: 15 · 2017: 15 · 2016: 12 · 2015: 12 · 2014: 9 · 2013: 9 · 2012: 9
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Buck Institute for Research on Aging
- Ministry of Science and Technology of the People's Republic of China
- KWF Kankerbestrijding
- National Institute on Aging (R01AG038688, R56AG009909, AG017242, AG-09909, P01AG025901, R37AG009909, P01AG017242, AG025901)
- Topics
- Health Sciences › Medicine › Physiology › 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, senescence-associated secretory phenotype, glucocorticoids, corticosterone, cortisol, senescence-associated inflammation, interleukin-6, NF-κB, glucocorticoid receptor, RU486, fibroblasts, drug repurposing, senolytics
- MeSH terms
- Cell Line, Cell Transformation, Neoplastic, Corticosterone, Fibroblasts, Glucocorticoids, Humans, Hydrocortisone, Neoplasm Invasiveness, Phenotype, Receptors, Glucocorticoid, Signal Transduction, Interleukin-6, NF-kappa B, Cellular Senescence, Interleukin-1alpha
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