Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome
Suchira Gallage1,2,3,4, Elaine E Irvine1,2, Jose Efren Barragan Avila3
1Medical Research Council Laboratory of Medical Sciences (LMS), London, UK.
Abstract:
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.
Insights
Deleting S6 kinase 1 (S6K1) reduces liver inflammation in aging mice by suppressing the senescence-associated secretory phenotype (SASP). This finding suggests a mechanism for S6K1 inhibition
Area of Science:
- Cellular and Molecular Biology
- Immunology
- Gerontology
Background:
- Cellular senescence and its associated inflammatory secretory phenotype (SASP) contribute to aging and age-related diseases.
- S6 kinase 1 (S6K1) inhibition is known to extend lifespan and healthspan, but the mechanisms remain unclear.
- The specific role of S6K1 in cellular senescence and inflammation, particularly in the liver, has not been determined.
Purpose of the Study:
- To investigate the role of S6K1 in cellular senescence and inflammation in aged mouse livers.
- To determine if S6K1 deletion affects senescence or the inflammatory SASP.
- To elucidate the liver-intrinsic mechanisms by which S6K1 deletion impacts inflammation and immune responses.
Main Methods:
- Utilized mouse models with S6K1 deletion (whole-body, liver-specific, and myeloid-specific knockouts).
- Analyzed aged mouse livers for cellular senescence markers and inflammatory profiles.
- Investigated key inflammatory signaling pathways, including IRF3 activation and cytokine production (e.g., IL1β), and immune cell infiltration.
Main Results:
- S6K1 deletion did not reduce cellular senescence but significantly ameliorated liver inflammation in aged mice.
- Reduced inflammation was a liver-intrinsic effect, linked to decreased IRF3 activation and impaired IL1β production.
- S6K1 deletion led to reduced immune infiltration and improved clearance of senescent cells, a hepatocyte-intrinsic phenomenon.
Conclusions:
- S6K1 deletion suppresses the inflammatory SASP in hepatocytes, leading to reduced liver inflammation.
- The amelioration of inflammation by S6K1 loss is a hepatocyte-intrinsic effect.
- Suppression of the inflammatory SASP by S6K1 inhibition may underlie its beneficial effects on healthspan and lifespan.
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