Loss of Ceramide Synthases Elicits a PHA-4/FoxA-, SKN-1-, and Autophagy-Dependent Lifespan Extension in C. elegans

Sphingolipids, and in particular ceramide and sphingosine-1-phosphate, have emerged as major players in cell physiology and implement their actions in almost every aspect of cell regulation. Besides playing structural roles, important for cellular membrane integrity as well as signal transduction, these lipid species are recognized as bioactive signalling molecules involved in regulation of cell growth, differentiation, senescence(definition), and apoptosis, and thus a delicate equilibrium between the levels of these interconvertible lipid species underlies the balance between cell survival and death. The C. elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2, and lagr-1. Here we show that functional loss of HYL-1 and LAGR-1 depletes 43:1;3 sphingolipids and extends lifespan in a PHA-4-, SKN-1-, and ATG-12-dependent manner. The transcription factors PHA-4 and SKN-1 as well as ATG-12, which is part of the autophagic response, are all associated with dietary restriction-induced longevity and in consistence with this, the observed lifespan extension is accompanied by reduced feeding and an increased level of autophagy(definition). The lifespan extension is also accompanied by reduced reproduction and an increased resistance to heat-stress, which are traits generally associated with long-lived animals. We suggest that the altered sphingolipid profile leads to signaling events which, at least in part, mimics those of dietary restriction-induced longevity.