Nutrition · Nov 2026
Gut microbial metabolites mediate the effects of nutrition on aging: molecular pathways linking diet, microbiome, and host longevity
By Adam SY, Sayed H, Ahmed AA et al.
The gut microbiome transforms dietary components into bioactive metabolites with the potential to influence aging. However, the field remains dominated by descriptive and correlational studies, and causal mechanisms in humans remain uncertain. In this review, we critically discuss how major microbial metabolites, short-chain fatty acids (SCFAs), tryptophan-derived indoles, and secondary bile acids, signal through conserved receptors such as FFAR2 (GPR43), FFAR3 (GPR41), AhR, and GPBAR1 (TGR5), as well as through receptor-independent pathways, to modulate longevity pathways including AMPK/mTOR nutrient sensing, autophagy, epigenetic regulation, and age-associated inflammation. Three key challenges complicate translation to humans: substantial inter-individual variability in metabolite production, age-related polypharmacy and microbial imbalance that confound results, and the scarcity of long-term, standardized microbiome–metabolite–host studies in older adults. We emphasize that secondary bile acids exert context-dependent effects during aging, and that TMAO has been associated with vascular aging and adverse cognitive outcomes, including cognitive decline, rather than improved cognitive function. We further discuss how polypharmacy alters microbiome composition and metabolite production through antimicrobial effects, changes in gut transit, and drug–microbe metabolic interactions. We propose that precision nutrition, rather than one-size-fits-all probiotic supplementation, is the most practical pathway forward, integrating multi-omics approaches to identify actionable dietary strategies that consistently shape the longevity-associated metabolome. Finally, we offer a paradigm for future mechanistic human trials that record systemic metabolite flow and host cellular responses alongside fecal composition.