RESUMEN
Ageing is a major risk factor for vision loss, and inflammation is an important contributor to retinal disease in the elderly. Regenerative medicine based on cell replacement strategies has emerged in recent years as a promising approach to restore vision. However, how the ageing process affects retinal homeostasis and inflammation in the retina and how this may impose a limitation to the success of such interventions remains unknown. Here we report that, in mice and humans, retinal ageing is associated with a reduction in MANF protein levels, specifically in the choroid, where increased densities of activated macrophages can be detected. We further show that the retina of old wild type mice, in the absence of any other genetic alteration, has limited homeostatic capacity after damage imposed by light exposure and reduced engraftment efficiency of exogenously supplied photoreceptors. Finally, we show that supplementation of MANF recombinant protein can improve retinal homeostasis and repair capacity in both settings, correlating with reduced numbers of activated macrophages in the old retina. Our work identifies age-related alterations in retinal homeostasis, independent of genetic alterations, leading to age-related retinal inflammation and damage susceptibility. We suggest that MANF therapy is a potential intervention to maintain retinal homeostasis in the elderly and improve the success of retinal regenerative therapies applied to aged individuals.
RESUMEN
Aging 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 identify 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 decline 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, while hepatocyte-derived MANF prevents hepatosteatosis. Liver rejuvenation by heterochronic parabiosis in mice further depends on MANF, while MANF supplementation ameliorates several hallmarks of liver aging, 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.