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

Abstract

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.

Regulation of inflammation as an anti‐aging intervention

“…Interestingly, we found that heterozygous carriers of the MANF null allele develop signs of chronic inflammation, characterized by increased levels of pro‐inflammatory cytokines and accumulation of activated macrophages in different organs. This inflammatory state is accompanied by liver disease at middle age, resembling phenotypes observed at old age .…”

“…Indeed, proof of principle studies have emerged in recent years that support the application of immune modulatory interventions to improve regenerative success in aging: In the retina, we showed that MANF, an immune modulator with the ability to promote pro-repair activity of macrophages, can be used as a co-adjuvant in retinal transplants and promote functional integration of replacement cells, accelerating and enhancing vision recovery [35]. Interestingly, systemic administration of MANF can improve immune and metabolic homeostasis in older organisms [23]. Thus, it is likely that such systemic intervention applied in older organisms could also be used to improve regenerative success [71,72].…”

Mesencephalic Astrocyte‐Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin‐Related Modifier (SUMO)ylation‐Related Suppression of NF‐κB/Snail Signaling Pathway and Epithelial‐Mesenchymal Transition

“…Meanwhile, MANF promotes the survival and proliferation of pancreatic β cells . Furthermore, MANF as an immune modulator mediates tissue repair in the mammalian retina and maintains liver metabolic homeostasis . Additionally, MANF plays key roles in facilitating the survival of cardiac cells from ischemic injury, modulating myocardial hypertrophy and heart failure as well .…”

“…Meanwhile, our studies have indicated that inflammation triggers ER stress and promotes MANF nuclear translocation, which facilitates the interaction of MANF and nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) p65 and inhibits the transcriptional activity of NF‐κB . As a result, MANF inhibits inflammatory response …”

“…(13,14) As a result, MANF inhibits inflammatory response. (15) In chronic hepatitis B, a persistent inflammation with impaired antiviral immune response promotes the initiation and progression of HCC. The inflammatory tumor microenvironment also induces ER stress in tumor cells.…”