S6K1 deletion attenuates age-related liver pathology. AExperimental scheme. S6K1 WT and KO mice were aged for 600 days to assess senescence. bImmunoblot images of S6K1, S6K2 and GAPDH protein expression in 600-day whole liver lysates S6K1 WT (left; n = 3) and KO (right; n = 3) mouse. GAPDH served as a loading control for S6K1. S6K2 was run on a separate blot (and therefore GAPDH is a sample preparation control for this blot). cLiver weight (grams) at 600 days from S6K1 Weight (n = 8) and KO (n = 8) mouse. d,AndSirius red coloring (d) and quantification (And) in the liver of young people S6K1 WT (90 d; n = 5), old S6K1 WT (600 d; n = 8) and old S6K1 KO (600 days; n = 8) mouse. f,gKi67 coloring (f) and quantification (g) in the liver of young people S6K1 WT (90 d; n = 6), old S6K1WT (600 d; n = 7) and old S6K1 KO (600 days; n= 7) mouse. h,ICHOP coloring (h) and quantification (I) in the liver of young people S6K1 WT (90 d; n = 5), old S6K1WT (600 d; n= 8) and old S6K1KO (600 days; n= 8) mouse. I,kBiP coloring (I) and quantification (k) in the liver of young people S6K1WT (90 d; n= 5), old S6K1WT (600 d; n= 8) and old S6K1KO (600 days; n= 8) mice. Data are expressed as mean ± standard error. Statistical significance was calculated using a two-tailed Student’s t test t-test (c) or one-way ANOVA with Tukey’s multiple comparison test (And,g). ndenotes individual mice. Scale bar, 100 μm (d,h,I) or 50 μm (f). Credit: Aging of nature(2024). DOI: 10.1038/s43587-024-00695-z
The S6K1 protein is involved in regulating aging and age-related diseases. Blocking this protein in mice allows them to live longer and mimic the health benefits of reduced caloric intake, such as reduced fat mass, stronger bones, and resistance to diabetes, although the underlying mechanisms were not previously understood.
The S6K1 protein is a key target of the mTOR signaling pathway, which regulates growth and metabolism in response to nutrients and stress. This pathway also influences cellular senescence. As senescent cells age, they accumulate and release high levels of inflammatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP).
Elucidating the relationship between S6K1, senescence, and SASP will advance our understanding of aging and offers potential for the treatment of age-related diseases.
In research published in Aging of natureScientists from the LMS and the University of Tübingen have shown that deleting the S6K1 gene in the livers of aged mice reduces inflammation by suppressing the production of inflammatory proteins released as part of the SASP, rather than by affecting senescence, as the research teams had initially hypothesized.
Excitingly, this work now provides a biological mechanism explaining the beneficial effects of S6K1 knockdown on ageing and healthy lifespan in mice, first demonstrated by Professor Dominic Withers, Head of the Metabolic Signalling Group and published in Sciencein 2009.
Discovering converging paths
Although surprising at first, these findings corroborate those of other studies published this year, painting an emerging picture of the interdependent role that inflammation, metabolism and senescence play in aging and disease, all of which are strategic areas of research for the LMS.
This includes further work in fruit flies showing that the S6K protein controls inflammation, a study showing that simulating excess nutrients in mice increased inflammation and shortened lifespan, and work by Professor Stuart Cook, Head of the Cardiovascular Disease Mechanisms Group at the LMS, showing that inhibiting an inflammatory protein, IL-11, led to health benefits and increased lifespan.
Now that the principles of S6K1 suppression have been established in liver tissue, the team plans to conduct follow-up studies to determine whether the same thing happens in other tissues of the body.
Potential new strategies for treating age-related diseases
Although inflammation plays an important role in your body’s response to injury and infection, it is a major contributor to aging and many diseases. Increasing our knowledge of how inflammation contributes to aging and disease opens up opportunities for developing new strategies to treat aging and age-related diseases.
Professor Withers, lead author, commented: “This work has been a tour de force in exploring the physiological, cellular and molecular mechanisms underlying the long-lived phenotype in mice lacking S6K1. It is becoming increasingly clear that inflammatory processes are a key component of age-related diseases and there is great potential for interventions that could modulate this process.”
Professor Jesús Gil, Head of the Senescence Group and lead author, commented: “Improving our understanding of the interplay between metabolism, senescence and inflammation is an essential first step in designing rational synergistic therapies that could be used to treat age-related diseases.”
This work was led by Dr Suchira Gallage, a former PhD student at LMS, under the supervision of Professor Withers and Professor Gil, and in collaboration with Professor Mathias Heikenwälder at the University of Tübingen, where Dr Gallage is now group leader.
More information:
Suchira Gallage et al, Ribosomal S6 kinase 1 regulates inflammation via the senescence secretome, Aging of nature(2024). DOI: 10.1038/s43587-024-00695-z
Provided by the Medical Research Council (MRC) Laboratory of Medical Sciences
Quote:Blocking longevity gene S6K1 extends lifespan in mice by reducing inflammation (2024, August 29) retrieved August 29, 2024 from
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