The lipidomes of C. elegans with mutations in asm-3/acid sphingomyelinase and hyl-2/ceramide synthase show distinct lipid profiles during aging

Lipid metabolism affects cell and physiological functions that mediate animal healthspan and lifespan. Lipidomics approaches in model organisms have allowed us to better understand changes in lipid composition related to age and lifespan. Here, using the model C. elegans, we examine the lipidomes of mutants lacking enzymes critical for sphingolipid metabolism; specifically, we examine acid sphingomyelinase (asm-3), which breaks down sphingomyelin to ceramide, and ceramide synthase (hyl-2), which synthesizes ceramide from sphingosine. Worm asm-3 and hyl-2 mutants have been previously found to be long- and short-lived, respectively. We analyzed longitudinal lipid changes in wild type animals compared to mutants at 1-, 5-, and 10-days of age. We detected over 700 different lipids in several lipid classes. Results indicate that wildtype animals exhibit increased triacylglycerols (TAG) at 10-days compared to 1-day, and decreased lysophoshatidylcholines (LPC). We find that 10-day hyl-2 mutants have elevated total polyunsaturated fatty acids (PUFA) and increased LPCs compared to 10-day wildtype animals. These changes mirror another short-lived model, the daf-16/FOXO transcription factor that is downstream of the insulin-like signaling pathway. In addition, we find that hyl-2 mutants have poor oxidative stress response, supporting a model where mutants with elevated PUFAs may accumulate more oxidative damage. On the other hand, 10-day asm-3 mutants have fewer TAGs. Intriguingly, asm-3 mutants have a similar lipid composition as the long-lived, caloric restriction model eat-2/mAChR mutant. Together, these analyses highlight the utility of lipidomic analyses to characterize metabolic changes during aging in C. elegans.