Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome

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.