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.

Organism aging occurs at the multicellular level; however, how pro-longevity mechanisms slow down aging in different cell types remains unclear. We generated single-cell transcriptomic atlases across the lifespan ofCaenorhabditis elegansunder different pro-longevity conditions (http://mengwanglab.org/atlas). We found cell-specific, age-related changes across somatic and germ cell types and developed transcriptomic aging clocks for different tissues. These clocks enabled us to determine tissue-specific aging-slowing effects of different pro-longevity mechanisms, and identify major cell types sensitive to these regulations. Additionally, we provided a systemic view of alternative polyadenylation events in different cell types, as well as their cell-type-specific changes during aging and under different pro-longevity conditions. Together, this study provides molecular insights into how aging occurs in different cell types and how they respond to pro-longevity strategies.One sentence summarySingle-nucleus transcriptome atlas reveals tissue-specific aging patterns and longevity regulation in a multicellular organism

Macroautophagy/autophagy is an evolutionarily conserved intracellular pathway for the degradation of cytoplasmic materials. Under stress conditions, autophagy is upregulated and double-membrane autophagosomes are formed by the expansion of phagophores. The ATG16L1 precursor fusion contributes to development of phagophore structures and is critical for the biogenesis of autophagosomes. Here, we discovered a novel role of the protein tyrosine phosphatase PTPN9 in the regulation of homotypic ATG16L1 vesicle fusion and early autophagosome formation. Depletion of PTPN9 and its Drosophila homolog Ptpmeg2 impaired autophagosome formation and autophagic flux. PTPN9 colocalized with ATG16L1 and was essential for homotypic fusion of ATG16L1 + vesicles during starvation-induced autophagy. We further identified the Q-SNARE VTI1B as a substrate target of PTPN9 phosphatase. Like PTPN9, the VTI1B nonphosphorylatable mutant but not the phosphomimetic mutant enhanced SNARE complex assembly and autophagic flux. Our findings highlight the important role of PTPN9 in the regulation of ATG16L1 + autophagosome precursor fusion and autophagosome biogenesis through modulation of VTI1B phosphorylation status.

No abstract