Dihydroceramide desaturases are evolutionarily conserved enzymes that convert dihydroceramide (dhCer) to ceramide (Cer). While elevated Cer levels cause neurodegenerative diseases, the neuronal activity of its direct precursor, dhCer, remains unclear. We show that knockout of the fly dhCer desaturase gene, (), results in larval lethality with increased dhCer and decreased Cer levels. Light stimulation leads to ROS increase and apoptotic cell death in -KO photoreceptors, resulting in activity-dependent neurodegeneration. Lipid-containing Atg8/LC3-positive puncta accumulate in-KO photoreceptors, suggesting lipophagy activation. Further enhancing lipophagy reduces lipid droplet accumulation and rescues -KO defects, indicating that lipophagy plays a protective role. Reducing dhCer synthesis prevents photoreceptor degeneration and rescues-KO lethality, while supplementing downstream sphingolipids does not. These results pinpoint that dhCer accumulation is responsible for -KO defects. Human dhCer desaturase rescues-KO larval lethality, and rapamycin reverses defects caused by dhCer accumulation in human neuroblastoma cells, suggesting evolutionarily conserved functions. This study demonstrates a novel requirement for dhCer desaturase in neuronal maintenance and shows that lipophagy activation prevents activity-dependent degeneration caused by dhCer accumulation.

The desire for lifespan extension is a never-ending quest throughout human history. While extreme lifespans are likely limited genetically, environmental factors and acquired characteristics do affect the speed of degeneration and health span. As a result, lifespan is determined as the collective effect of internal and external factors, including the challenges of oxidative stress, the homeostasis of circulating metabolites, intake of energy and nutrients, and the allocation of resources among major life functions. Restriction of caloric intake is by far the most effective approach to extend lifespan in all species examined from yeast to non-human primates. Although its long-term effect is hard to evaluate in humans, caloric restriction has been shown to induce physiological changes that are similar to those observed in animal models. However, when energy intake is restricted, limited resources need to be relocated from growth and reproduction to maintain life-sustaining functions, resulting in trade-offs between