Inhibition of IL11 signalling extends mammalian healthspan and lifespan

Ageing is associated with metabolic dysfunction, sarcopenia and frailty that taken together reduce healthspan. For age-associated diseases, ERK and mTORC1 are critical pathways and sterile inflammation and senescence represent key pathologies, from worms to humans. Here we examined the role of IL11 in mammalian healthspan. As mice age, IL11 is progressively upregulated in liver, skeletal muscle and visceral fat to stimulate an ERK/LKB1/AMPK/mTORC1 axis of senescence, inflammation, adiposity, hepatosteatosis, hyperlipidaemia and impaired glucose metabolism. Two-year old mice deleted for Il11 exhibit reduced senescence, inflammation and fibrosis and are protected from metabolic multi-morbidity, sarcopenia and frailty. Genetic inhibition of IL11 signalling reduces epigenetic clock markers of ageing, prevents telomere attrition and maintains mitochondria number and function in old age. Administration of a neutralising IL11 antibody to old mice reverses metabolic dysfunction and sarcopenia while reducing ageing biomarkers and frailty. In human fibroblasts, anti-IL11RA prevents replicative senescence, telomere attrition and mitochondrial dysfunction. In old mice, anti-IL11 reactivates a program of white fat beiging. To translate our findings, we developed and tested an anti-IL11 antibody specifically engineered for clinical trials in ageing humans. These studies identify IL11 as a new inflammaging factor and therapeutic target for extending mammalian healthspan.