Age-Defying Health Benefits: New Research Unravels Secrets of the “Longevity” Gene

Deleting the S6K1 protein in mice reduces inflammation and extends lifespan by suppressing inflammatory proteins, highlighting a new mechanism in aging and potential treatments for age-related diseases.

S6K1 is a protein that plays a role in regulating aging and age-related diseases. Inhibiting this protein in mice has been shown to extend their lifespan and replicate the health benefits of calorie restriction, including lower body fat, stronger bones, and increased resistance to diabetes, although the exact mechanisms behind these effects were previously unclear.

S6K1 is a key target of the mTOR signaling pathway, which regulates growth and metabolism in response to nutrients and stress. The pathway also influences cellular senescence. As we age, senescent cells 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 the SASP will advance our understanding of aging and hold the potential for treating age-related diseases.

In research published today in Nature Aging, scientists at the LMS and the University of Tübingen have shown that deleting the S6K1 gene in aged mouse livers reduces inflammation by suppressing the production of inflammatory proteins released as part of the SASP, rather than by affecting senescence, as originally hypothesized by the research teams. Excitingly, this work now provides a biological mechanism for the beneficial effects of removing S6K1 upon aging and health span in mice first demonstrated by Professor Dominic Withers, Head of the Metabolic Signalling Group, and published in Science in 2009.

Uncovering converging pathways

While initially surprising, the findings corroborate those of other studies published this year, building an emerging picture of the interrelated role that inflammation, metabolism, and senescence play in aging and disease – all of which are strategic areas of research focus for the LMS.

This includes complementary work in fruit flies showing that the S6K protein controls inflammation, a study showing that simulating an excess of nutrients in mice increased inflammation and shortened lifespan, as well as work from 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 deletion have been established in liver tissue, the team plans to carry out follow-up studies to determine whether the same thing is happening in other tissues in the body.

Potential new strategies for treating age-related diseases

While inflammation plays an important role in helping your body respond to injury and infection, it is a significant driver of aging and many diseases. Enriching our knowledge of how inflammation contributes to aging and disease opens up avenues for developing new strategies to treat aging and age-related diseases.

Professor Withers, senior author, commented: “This work was a tour de force exploring the physiological, cellular, and molecular mechanisms that underlie 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 senior author commented: “Enhancing our understanding of the interaction between metabolism, senescence and inflammation is a key first step to designing rational synergistic therapies that could be used to treat diseases of aging.”

Reference: “Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome” by Suchira Gallage, Elaine E. Irvine, Jose Efren Barragan Avila, Virinder Reen, Silvia M. A. Pedroni, Imanol Duran, Vikas Ranvir, Sanjay Khadayate, Joaquim Pombo, Sharon Brookes, Danijela Heide, Gopuraja Dharmalingham, Agharul I. Choudhury, Indrabahadur Singh, Nicolás Herranz, Santiago Vernia, Mathias Heikenwalder, Jesús Gil and Dominic J. Withers, 29 August 2024, Nature Aging.