The role of sphingolipid metabolism in lifespan and healthspan extension in C. elegans

Multiple advancements in research have led to a better understanding of the aging process. However, many metabolic pathways that promote healthy aging are still unknown. Here, we investigate the bioactive sphingolipid metabolism pathway and its roles in regulating lifespan and healthspan, which is the average period of one's life in good health. Sphingolipids are involved in cellular signaling and known to promote cell proliferation, secretion, stress response and survival. The sphingolipid pathway is composed of sphingomyelin, ceramide, sphingosine and sphingosine‐1‐phosphate (S1P). Ceramide synthases (CER synthases) mediate the conversion of ceramide to sphingosine while sphingosine kinase (SPHK) converts sphingosine to S1P. Using C. elegans , we previously found that mutations in sphk‐1/SPHK and hyl‐2/CER synthase result in decreased lifespan, suggesting that sphingolipids play a role in lifespan extension. However, it is unknown whether the sphingolipid genes act in known cellular pathways that mediate aging. Therefore, we tested the genetic interactions between sphingolipid enzymes and known models of aging, including the insulin like signaling (ILS) pathway that has been linked to lifespan extension. For this, lifespan analyses were performed on daf‐ 16/FOXO, which has a shortened lifespan phenotype, coupled with knockdown of sphingolipid metabolism genes. DAF‐16 is a downstream transcription factor target of DAF‐2 /insulin‐like growth factor receptor and has important roles in mediating the gene expression of stress response. We observed that daf‐16 is epistatic to sphingolipid mutants for lifespan phenotypes, as indicated by similar short lifespan phenotypes of double knockout of daf‐16;hyl‐2 and daf‐16;sphk‐1 compared to mutants with a single knockout of daf‐16 . Thus, sphingolipids may act upstream of DAF‐16 to mediate stress response genes and lifespan. Future experiments will analyze transcriptional reporters for DAF‐16, and known stress response genes SOD‐3/superoxide dismutase, to determine whether cellular stress response mechanisms occurs normally in hyl‐2 and sphk‐1 mutants under induced oxidative stress. An analysis of stress response will further enhance our understanding of the interaction between sphingolipids and known pathways that promote lifespan and healthspan. Support or Funding Information Research reported in this publication was supported by the National Institute On Aging of the National Institutes of Health under Award Number R15AG052933. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .