Lysosome lipid signalling from the periphery to neurons regulates longevity
Marzia Savini, Andrew Folick, Yi-Tang Lee, Feng Jin, André Cuevas, Matthew C. Tillman, Jonathon Duffy, Qian Zhao, Isaiah A.A. Neve, Pei-Wen Hu, Yong Yu, Qinghao Zhang, Youqiong Ye, William B. Mair, Jin Wang, Leng Han, Eric A. Ortlund, Meng C. Wang
Abstract
Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in ageing-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate ageing remains unclear. Here we report a fat-to-neuron lipid signalling pathway induced by lysosomal metabolism and its longevity-promoting role in Caenorhabditis elegans. We discovered that induced lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signalling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation is mediated by a specific polyunsaturated fatty acid, dihomo-γ-linolenic acid, and LBP-3 lipid chaperone protein transported from the fat storage tissue to neurons. LBP-3 binds to dihomo-γ-linolenic acid, and acts through NHR-49 nuclear receptor and NLP-11 neuropeptide in neurons to extend lifespan. These results reveal lysosomes as a signalling hub to coordinate metabolism and ageing, and lysosomal signalling mediated inter-tissue communication in promoting longevity.