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bioRxiv · 10.1101/2021.06.10.447794

Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity

Savini, M.·Duffy, J. D.·Folick, A.·Lee, Y.-T.·Hu, P.-W.·Neve, I.·Jin, F.·Zhang, Q.·Tillman, M.·Ye, Y.·Mair, W.·Wang, J.·Han, L.·Ortlund, E.·Wang, M. C.
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Abstract

Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in aging-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate aging remains unclear. Here, we report a fat-to-neuron lipid signaling pathway induced by lysosomal metabolism and its longevity promoting role in Caenorhabditis elegans. We discovered that lysosomal lipolysis in peripheral fat storage tissue up-regulates the neuropeptide signaling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation requires the secretion from the fat storage tissue of a lipid chaperone protein LBP-3 and polyunsaturated fatty acids (PUFAs). LBP-3 binds to specific PUFAs, and acts through a nuclear hormone receptor NHR-49 and neuropeptide NLP-11 in neurons to extend lifespan. Together, these results reveal lysosomes as a signaling hub to coordinate metabolism and aging, and a lysosomal signaling mechanism that mediates intertissue communication to promote longevity.

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Savini, M., Duffy, J. D., Folick, A., Lee, Y.-T., Hu, P.-W., Neve, I., Jin, F., Zhang, Q., Tillman, M., Ye, Y., Mair, W., Wang, J., Han, L., Ortlund, E., Wang, M. C.. 2021-06-10. Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity. https://doi.org/10.1101/2021.06.10.447794

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