- Savini, Marzia;
- Folick, Andrew;
- Lee, Yi-Tang;
- Jin, Feng;
- Cuevas, André;
- Tillman, Matthew C;
- Duffy, Jonathon D;
- Zhao, Qian;
- Neve, Isaiah A;
- Hu, Pei-Wen;
- Yu, Yong;
- Zhang, Qinghao;
- Ye, Youqiong;
- Mair, William B;
- Wang, Jin;
- Han, Leng;
- Ortlund, Eric A;
- Wang, Meng C
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.