Caffeine-Induced Upregulation of and Enhances Intestinal Integrity by Reducing Vitellogenin in Aged Model.

Intestinal aging is characterized by declining protein homeostasis via reduced proteasome activity, which are hallmarks of age-related diseases. Our previous study showed that caffeine intake improved intestinal integrity with age by reducing vitellogenin (VIT, yolk protein) in . In this study, we investigated the regulatory mechanisms by which caffeine intake improves intestinal integrity and reduces vitellogenin (VIT) production in aged . We performed RNA-seq analysis, and qRT-PCR to validate and confirm the RNA-seq results. Transgenic worms with VIT-2::GFP and VIT-6::GFP were used for measuring VIT production. dsRNAi was conducted to elucidate the roles of and genes. and , a ortholog of human , was upregulated by caffeine intake. They reduced VIT production by repressing , a transcriptional activator of expression. Interestingly, was required for and expression, and RNAi of and promoted intestinal atrophy and colonization, suggesting a balancing mechanism for VIT levels in intestinal health. Additionally, lifespan was extended by caffeine intake (2 ± 0.05 days), however, this effect was not observed by but not RNAi, suggesting that the mode of action for an anti-aging effect of caffeine through and is distinctive. The lifespan extended by was mediated by SKN-1 activation. Caffeine intake enhances intestinal health through proteasome activity and extends lifespan in aged by upregulating and . These findings suggest that caffeine consumption mitigates age-related proteasome impairment and maintains intestinal integrity during aging.