Targeting phospholipase PLAG-15 promotes healthy aging in C. elegans via lysosomal-related genes

Complex lipid metabolism plays a crucial role in regulating aging. We recently discovered that the phospholipid bis(monoacylglycero)phosphate (BMP) increases in aged human muscles and many mouse tissues. The phospholipase PLA2G15 is reportedly involved in BMP synthesis, however, its specific role in aging remains unknown. To elucidate the role of PLA2G15 in aging, we used <i>Caenorhabditis elegans</i> as a model. When silencing <i>plag-15</i>, the predicted worm orthologue of <i>PLA2G15,</i> we observed improved healthspan and lifespan extension. Semi-targeted lipidomics highlighted that instead of changes related to BMP, <i>plag-15</i> RNAi led to lower levels of lysophosphatidic acid, lysophosphatidylcholine, and lysophosphatidylethanolamine. Transcriptome-guided epistasis experiments identified that the lifespan extension of <i>plag-15</i> RNAi worms is regulated by transcription factors <i>hlh-30</i> and <i>elt-3</i>, and lysosomal vitamin B12 transporter <i>pmp-5</i> (human <i>TFEB</i>, <i>GATA</i>, and <i>ABCD4</i> respectively). Overall, we conclude that targeting phospholipid remodeling through <i>plag-15</i> could be a promising strategy to promote healthy aging.