Caffeine extends lifespan by enhancing lysosomal lipolysis in Caenorhabditis elegans

Abstract 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 eliciting transcriptional remodeling that enhances lysosomal lipolysis. We found that transcriptomes of aged, caffeine-fed animals shifted toward youthful states. 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 program. Comparison with eat-2 mutants (a genetic DR model) identified lysosomal lipases lipl-1 and lipl-2 as commonly upregulated genes. The induction of lipl-1 and lipl-2 was required for increased lifespan and reduced neutral lipid accumulation by caffeine intake. Together, these findings indicate that caffeine promotes longevity in a DR-like metabolic reprogramming by enhancing lysosome-driven lipolysis.