Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome
Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.
Authors
- Indrabahadur Singh (ORCID: https://orcid.org/0000-0002-1474-7928)
- Dominic J. Withers (ORCID: https://orcid.org/0000-0002-8009-7521)
- Agharul I. Choudhury
- Elaine E. Irvine (ORCID: https://orcid.org/0000-0001-5508-8140)
- Jesús Gil (ORCID: https://orcid.org/0000-0002-4303-6260)
- Virinder Reen (ORCID: https://orcid.org/0009-0008-8903-9636)
- Sharon Brookes
- Mathias Heikenwälder (ORCID: https://orcid.org/0000-0002-3135-2274)
- Gopuraja Dharmalingham
- Imanol Durán (ORCID: https://orcid.org/0000-0001-6615-3788)
- Sanjay Khadayate (ORCID: https://orcid.org/0000-0003-4278-6403)
- Silvia M.A. Pedroni (ORCID: https://orcid.org/0000-0002-3626-891X)
- Jose Efren Barragan Avila (ORCID: https://orcid.org/0000-0002-9348-909X)
- Santiago Vernia (ORCID: https://orcid.org/0000-0001-6728-5555)
- Suchira Gallage (ORCID: https://orcid.org/0000-0002-1956-3597)
- Nicolás Herranz (ORCID: https://orcid.org/0000-0003-1351-7300)
- Danijela Heide
- Vikas Ranvir (ORCID: https://orcid.org/0000-0002-0437-6908)
- Joaquim Pombo
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- General Medical Council (GB)
- NIHR Imperial Biomedical Research Centre (GB)
- Commonwealth Education Trust (GB)
- Imperial College London (GB)
- University of Tübingen (DE)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Aging
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1038/s43587-024-00695-z
- Citations
- 22
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 7.18