Caffeine extends lifespan by enhancing lysosomal lipolysis in Caenorhabditis elegans

Caffeine is a globally consumed stimulant that has beneficial effects on biological processes including metabolism and aging, but its causal role in physiology remains incompletely understood. By using the roundworm Caenorhabditis elegans , here we show that caffeine extends lifespan by enhancing lysosomal lipolysis. Caffeine treatment induced transcriptional responses opposite to age-associated gene expression changes. By comparing with three longevity-promoting regimens, including reduced insulin/insulin-like growth factor 1 (IGF-1) signaling, mild reductions in mitochondrial function, and dietary restriction (DR), we showed that caffeine induced a DR-like transcriptional change. Comparison with eat-2 mutants (a genetic DR model) identified lysosomal lipases lipl-1 and lipl-2 as commonly upregulated genes. Caffeine increased the expression of lipl-1 and lipl-2 , which contributes to lifespan extension and reduced fat storage. Together, these findings indicate that caffeine promotes longevity in a DR-like metabolic alteration by enhancing lysosome-driven lipolysis.