Min_2026_Mol.Cells__100358

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.