The Coffee–Gut–Redox Axis in Healthy Aging: Microbial Metabolism, Redox Signaling, and Implications for Coffee-Derived Nutraceuticals

Coffee is a chemically heterogeneous dietary exposure whose association with healthy aging is epidemiologically consistent but mechanistically unresolved. This critical hypothesis review proposes the Coffee–Gut–Redox Axis (CGRA), a branched, falsifiable model that has not yet been causally validated in humans. In this model, roast-, brew-, and processing-dependent delivery of chlorogenic acids, melanoidins/fiber, caffeine and trigonelline engages a microbiome-dependent arm (colonic phenolic catabolism and short-chain fatty acid production) and microbiome-independent arms (proximal chlorogenic acid absorption, caffeine–adenosine signaling and trigonelline-supported nicotinamide adenine dinucleotide synthesis), which converge on context-dependent redox and inflammatory signaling. Each linkage is graded separately for association, human target engagement, preclinical plausibility and mediation, and experimental concentrations are compared with exposures achievable from brewed coffee. The most reproducible human microbial signal is enrichment of Lawsonibacter asaccharolyticus; small interventions show partly caffeine-independent microbial remodeling but have not tested mediation. Prospective cohorts report concordant associations with mortality, type 2 diabetes, liver fibrosis, Parkinson disease, and frailty, which are treated as concordance rather than validation. We specify refutation criteria, safety, intolerance and allergen considerations, requirements for coffee-derived nutraceuticals, and a standardized, multi-arm, multi-omic trial architecture.