Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

  • Nature. 2024 Aug;632(8023):157-165. doi: 10.1038/s41586-024-07701-9.
Anissa A Widjaja  #  1 ,  Wei-Wen Lim  #  2  3 ,  Sivakumar Viswanathan  2 ,  Sonia Chothani  2 ,  Ben Corden  3  4 ,  Cibi Mary Dasan  2 ,  Joyce Wei Ting Goh  2 ,  Radiance Lim  2 ,  Brijesh K Singh  2 ,  Jessie Tan  3 ,  Chee Jian Pua  3 ,  Sze Yun Lim  2 ,  Eleonora Adami  5 ,  Sebastian Schafer  2 ,  Benjamin L George  2 ,  Mark Sweeney  6 ,  Chen Xie  3 ,  Madhulika Tripathi  2 ,  Natalie A Sims  7  8 ,  Norbert Hübner  5  9  10 ,  Enrico Petretto  2  11 ,  Dominic J Withers  6  12 ,  Lena Ho  2 ,  Jesus Gil  6  12 ,  David Carling  6  12 ,  Stuart A Cook  13  14  15
Affiliations
  • 1. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore. [email protected].
  • 2. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
  • 3. National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
  • 4. Barts Heart Centre, Barts Health NHS Trust, London, UK.
  • 5. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
  • 6. MRC Laboratory of Medical Sciences, London, UK.
  • 7. Bone Biology and Disease Unit, St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
  • 8. Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
  • 9. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
  • 10. Charité-Universitätsmedizin, Berlin, Germany.
  • 11. Institute for Big Data and Artificial Intelligence in Medicine, School of Science, China Pharmaceutical University, Nanjing, China.
  • 12. Institute of Clinical Sciences, Faculty of Medicine, Imperial College, London, UK.
  • 13. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore. [email protected].
  • 14. National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore. [email protected].
  • 15. MRC Laboratory of Medical Sciences, London, UK. [email protected].
  • # Contributed equally.
PMID: 39020175 DOI: 10.1038/s41586-024-07701-9
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.

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