Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans

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Science  02 Jan 2015:
Vol. 347, Issue 6217, pp. 83-86
DOI: 10.1126/science.1258857

Lysosomes signal the nucleus to control aging

Folick et al. propose a mechanism by which a lysosomal enzyme influences nuclear events that control longevity in the worm (see the Perspective by Shuo and Brunet). Increased expression of the lysosomal acid lipase LIPL-4 increased longevity, and this effect depended on the presence of the lysosomal lipid-binding protein LBP-8. LBP-8 acts as a chaperone that helps carry lipds to the nucleus. The authors identified the fatty acid oleoylethanolamide (OEA) as a potential signaling molecule whose transport to the nucleus could activate nuclear hormone receptors and transcription factors NHR-49 and NHR-80. The transcriptional targets of NHR-49 and NHR-80 in turn regulate longevity.

Science, this issue p. 83


Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.

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