Autophagy-dependent longevity models in C. elegans display altered lipid metabolism, including a decrease in the intestinal production and secretion of the yolk lipoprotein vitellogenin and increased neutral lipid storage, but the contribution of intracellular lipid distribution in lifespan extension is not fully understood.
Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked and modulate lifespan in a conserved fashion. We find that over-expression of vitellogenin reduces the lifespan of long-lived animals by impairing the induction of autophagic and lipophagic genes necessary for longevity. Increased vitellogenesis also results in intestinal lipid depletion in long-lived animals, demonstrating that elevated intestinal lipid storage found in long-lived animals is primarily due to reduced vitellogenesis. Indeed, we find that silencing vitellogenin genes is sufficient to increase lifespan via autophagic and lipophagic gene induction and by redistributing lipid bound for secretion toward neutral lipid droplet storage, thereby increasing the amount of lipids available for lipophagy.
Lifespan extension from reduced vitellogenesis requires transcription factors DAF-16/FOXO and HLH-30/TFEB, suggesting that the transcriptional regulation of autophagy is coordinated with lipoprotein biogenesis. Nuclear hormone receptors (NHR) NHR-49/PPARa and NHR-80/HNF4 are also required to extend lifespan under reduced vitellogenesis and enhanced lysosomal lipolysis, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, the expression of vitellogenin and hepatic apolipoprotein B, respectively, are significantly reduced, suggesting a conserved link in lifespan modulation. Altogether, our study suggests that lipoprotein biogenesis is an important mechanism in aging by impairing the transcriptional induction of autophagy. .
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