Lysosome lipid signalling from the periphery to neurons regulates longevity

Savini et al. report that lysosomal lipolysis in peripheral adipose depots produces polyunsaturated fatty acids (PUFAs). PUFAs and the lipid chaperone LBP-3 induce a nuclear hormone receptor, neuropeptide-mediated cascade in neurons to extend lifespan. 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-gamma-linolenic acid, and LBP-3 lipid chaperone protein transported from the fat storage tissue to neurons. LBP-3 binds to dihomo-gamma-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.

Automated summary

This study reveals the importance of lysosomes as a signaling hub in coordinating metabolism and aging, as well as the role of lysosomal signaling in promoting longevity through inter-tissue communication. Lysosomal lipolysis in peripheral adipose depots produces polyunsaturated fatty acids (PUFAs) and activates a signaling pathway in neurons that extends lifespan. The polyunsaturated fatty acid dihomo-gamma-linolenic acid and the lipid chaperone LBP-3 play key roles in this fat-to-neuron lipid signaling pathway.