Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

Anissa A. Widjaja (), Wei-Wen Lim, Sivakumar Viswanathan, Sonia Chothani, Ben Corden, Cibi Mary Dasan, Joyce Wei Ting Goh, Radiance Lim, Brijesh K. Singh, Jessie Tan, Chee Jian Pua, Sze Yun Lim, Eleonora Adami, Sebastian Schafer, Benjamin L. George, Mark Sweeney, Chen Xie, Madhulika Tripathi, Natalie A. Sims, Norbert Hübner, Enrico Petretto, Dominic J. Withers, Lena Ho, Jesus Gil, David Carling and Stuart A. Cook ()
Additional contact information
Anissa A. Widjaja: Duke–National University of Singapore Medical School
Wei-Wen Lim: Duke–National University of Singapore Medical School
Sivakumar Viswanathan: Duke–National University of Singapore Medical School
Sonia Chothani: Duke–National University of Singapore Medical School
Ben Corden: National Heart Centre Singapore
Cibi Mary Dasan: Duke–National University of Singapore Medical School
Joyce Wei Ting Goh: Duke–National University of Singapore Medical School
Radiance Lim: Duke–National University of Singapore Medical School
Brijesh K. Singh: Duke–National University of Singapore Medical School
Jessie Tan: National Heart Centre Singapore
Chee Jian Pua: National Heart Centre Singapore
Sze Yun Lim: Duke–National University of Singapore Medical School
Eleonora Adami: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Sebastian Schafer: Duke–National University of Singapore Medical School
Benjamin L. George: Duke–National University of Singapore Medical School
Mark Sweeney: MRC Laboratory of Medical Sciences
Chen Xie: National Heart Centre Singapore
Madhulika Tripathi: Duke–National University of Singapore Medical School
Natalie A. Sims: St Vincent’s Institute of Medical Research
Norbert Hübner: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Enrico Petretto: Duke–National University of Singapore Medical School
Dominic J. Withers: MRC Laboratory of Medical Sciences
Lena Ho: Duke–National University of Singapore Medical School
Jesus Gil: MRC Laboratory of Medical Sciences
David Carling: MRC Laboratory of Medical Sciences
Stuart A. Cook: Duke–National University of Singapore Medical School

Nature, 2024, vol. 632, issue 8023, 157-165

Abstract: Abstract For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1–7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK–AMPK–mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.

Date: 2024
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DOI: 10.1038/s41586-024-07701-9

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