Ribosomal S6 kinase 1 regulates ‘inflammaging’ via the senescence secretome
Open accessPreprint — published as 10.1038/s43587-024-00695-z
Abstract
Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream effector S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. However, the underlying mechanisms contributing to the broad range of age-related benefits observed with loss of S6K1 signalling are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory phenotype (termed the senescence-associated secretory phenotype, or SASP). While both cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, the specific role of S6K1 signalling in these processes has not been determined. Here, focussing on mouse liver, a key target tissue for the beneficial metabolic effects of loss of S6K1 signalling, we show that S6K1 deletion does not reduce senescence but ameliorates inflammation and immune cell infiltration in aged livers. Using human and mouse models of senescence, we demonstrated that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Furthermore, gene expression analysis suggested that downregulated cGAS/STING and IRF3 activation might mediate the impaired SASP observed upon S6K deletion. Using a hepatic oncogene induced senescence model, we showed in viv o that S6K1 deletion results in reduced IRF3 activation, impaired production of cytokines such as IL1ý and reduced immune infiltration. Overall, deletion of S6K reduces inflammation in the liver suggesting that suppression of the inflammatory SASP by loss of S6K could contribute to explain the beneficial effects of inhibiting this pathway on healthspan and lifespan.
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Effects of miR-128-3p on Renal Inflammation in a Rat Periodontitis Model
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Curcumin attenuates PM2.5-triggered pulmonary senescence via the mTOR/S6K1 signaling pathway
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- Authors
- Gallage, S., Irvine, E. E., Pedroni, S. M. A., Barragan Avila, J. E., Khadayate, S., Pombo, J., Brookes, S., Heide, D., Dharmalingham, G., Choudhury, A. I., Herranz, N., Vernia, S., Heikenwalder, M., Gil, J., & Withers, D. J.
- Affiliations
- German Cancer Research Center (DE)
- Imperial College London (GB)
- Corresponding author
- Gil, Jesús
- Withers, Dominic J.
- ORCID
- Venue
- Nature Aging
- Publisher
- openRxiv
- Published
- 2023-10-20
- Volume
- 4
- Issue
- 11
- Pages
- 1544-1561
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC11564105
- OpenAlex
- W4402027652
- Cited by
- 31
- References
- 61
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 2
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Nature Aging (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc)
- Funders
- Wellcome Trust (098565/Z/12/Z)
- Cancer Research UK (C15075/A28647)
- Research Councils UK (MC-A654-5QB40)
- Fonds Wetenschappelijk Onderzoek (30826052)
- Vlaamse regering
- Medical Research Council (MC-A654-5QB40, MC-U120085810)
- 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
- S6 kinase 1, inflammaging, senescence-associated secretory phenotype, cellular senescence, liver aging, IRF3 activation, IL-1β, immune cell infiltration, myeloid cells, hepatocytes, healthspan, lifespan extension
- MeSH terms
- Senescence-Associated Secretory Phenotype, Aging, Animals, Humans, Inflammation, Liver, Male, Cellular Senescence, Mice, Knockout, Hepatocytes, Ribosomal Protein S6 Kinases, 90-kDa, Interferon Regulatory Factor-3, Mice, Interleukin-1beta
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