Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

• 成果类型: Article
• 署名作者: Widjaja, Anissa A.; Lim, Wei-Wen; Viswanathan, Sivakumar; Chothani, Sonia; Ben Corden; Dasan, Cibi Mary; Goh, Joyce Wei Ting; Lim, Radiance; Singh, Brijesh K.; Tan, Jessie; Pua, Chee Jian; Lim, Sze Yun; Adami, Eleonora; Schafer, Sebastian; George, Benjamin L.; Sweeney, Mark; Xie, Chen; Tripathi, Madhulika; Sims, Natalie A.; Huebner, Norbert; Petretto, Enrico; Withers, Dominic J.; Ho, Lena; Gil, Jesus; Carling, David; Cook, Stuart A.
• 署名单位: National University of Singapore; National Heart Centre Singapore; Barts Health NHS Trust; Helmholtz Association; Max Delbruck Center for Molecular Medicine; St. Vincent's Institute of Medical Research; St Vincent's Health; St Vincent's Hospital Melbourne; NSW Health; St Vincents Hospital Sydney; University of Melbourne; German Centre for Cardiovascular Research; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; China Pharmaceutical University; Imperial College London
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5037
• DOI: 10.1038/s41586-024-07701-9
• 发表日期: 2024-08-01
• 页码: 157-+
• 关键词: senescence; mice; interleukin-11; adipocytes; distinct; disease; mouse

摘要

For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark(1-7). 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.