MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage

Ageing is accompanied by altered intercellular communication, deregulated metabolic function, and inflammation. Interventions that restore a youthful state delay or reverse these processes, prompting the search for systemic regulators of metabolic and immune homeostasis. Here, we identified mesencephalic-astrocyte-derived neurotrophic factor (MANF), a secreted stress-response protein with immune modulatory properties, as an evolutionarily conserved regulator of systemic and, in particular, liver metabolic homeostasis. We show that MANF levels declined with age in flies, mice, and humans, and MANF overexpression extends lifespan in flies. MANF-deficient flies exhibit enhanced inflammation and shorter lifespans, and MANF heterozygous mice exhibit inflammatory phenotypes in various tissues, as well as progressive liver damage, fibrosis, and steatosis. We show that immune-cell-derived MANF protects against liver inflammation and fibrosis, whereas hepatocyte-derived MANF prevents hepatosteatosis. Liver rejuvenation by heterochronic parabiosis in mice further depends on MANF, whereas MANF supplementation ameliorates several hallmarks of liver ageing, prevents hepatosteatosis induced by diet, and improves age-related metabolic dysfunction. Our findings identify MANF as a systemic regulator of homeostasis in young animals, suggesting a therapeutic application for MANF in age-related metabolic diseases.