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

Abstract

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.

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Fig. 1: MANF protein levels decline with age in flies, mice, and humans.
Fig. 2: MANF overexpression extends lifespan in Drosophila.
Fig. 3: Mice with reduced MANF levels develop inflammation and liver damage.
Fig. 4: Immune-cell-derived MANF and hepatocyte-derived MANF contribute to liver homeostasis.
Fig. 5: MANF is required for full liver rejuvenation by heterochronic parabiosis.
Fig. 6: MANF improves liver damage, inflammation, and metabolic dysfunction in old mice.

Data availability

All the data generated or analysed during this study are included in the published article and its Supplementary Information files, and are available from the corresponding author. Analysed RNA-sequencing data are available in Supplementary Table 1 and raw RNA-sequencing data are available under accession numbers GSE123115, GSE123116, and GSE123117 on the NCBI Gene Expression Omnibus database. Correspondence and requests for materials should be addressed to H.J., P.S.-V., and J.N.

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Acknowledgements

We thank M. Konjikusic for technical help with the mouse colony, A. Ireland and M. Ray from Calico Labs for help with library preparation and RNA sequencing, and H. Liu for providing an expert pathologist evaluation of liver sections. Work in H.J.’s laboratory is supported by NIH grant nos. AG052989, AG050104, and AG047497, and some work was supported by Calico Labs. Work in D.A.L.’s laboratory is supported by NIH grant no. EY025779. Work in S.A.V.’s lab is supported by NIH grant no. AG055797. P.S.-V. and J.N. are supported by the Glenn Foundation for Medical Research.

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P.S.-V., J.N., D.A.L., and H.J. conceived the study. P.S.-V. and J.N. designed and analysed all of the experiments. P.S.-V., J.N., and W.C.-C. performed experiments and collected data. P.B.V. and S.A.V. performed and supervised heterochronic parabiosis experiment. R.R.R. and C.Y.L. assisted with in vivo mouse experiments. I.S. performed transcriptomic analysis. G.A.K. and N.V.B. provided human samples, plasmids for HTV experiments and other reagents, provided expertise for experimental design and analysis, and supervised transcriptomic analysis experiments. P.S.-V. and J.N. interpreted the results, prepared the figures, and wrote the manuscript, with input from D.A.L. and H.J. D.A.L. and H.J. supervised the study. All of the authors revised the manuscript.

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Correspondence to Heinrich Jasper.

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Supplementary Information

Supplementary Figures 1–13 and Supplementary Tables 2–5

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Supplementary Table 1

Reads per kilobase of transcript per million values for the RNA sequencing analysis

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Sousa-Victor, P., Neves, J., Cedron-Craft, W. et al. MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage. Nat Metab 1, 276–290 (2019). https://doi.org/10.1038/s42255-018-0023-6

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