The microbiota-epigenome axis in healthy longevity: roles of microbial and gerobiotic metabolites - a narrative exploratory review.

Aging is a dysbiotic and pro-inflammatory process that increases susceptibility to multiple chronic comorbidities. Centenarians and supercentenarians offer a unique biological model for elucidating the molecular determinants of healthy aging and exceptional longevity, as they display distinctive epigenetic signatures and a gut microbiome configuration that diverges from both younger and typically aging individuals, although substantial interindividual variability exists. The gut microbiota constitutes a strategic hub of microorganisms and bioactive metabolites with probiotic and postbiotic potential that modulate host epigenetic circuits through precursors and substrates for epigenetic "writer" and "eraser" enzymes, thereby shaping the aging trajectory. In this review, we examine the interactions between the microbiota and its metabolites, including short-chain fatty acids, lipopolysaccharides, trimethylamine N-oxide (TMAO), p-cresol, and secondary bile acids, and their roles in epigenetic modulation associated with healthy aging. We highlight (i) the attenuation of classical pro-inflammatory pathways through downregulation of NF-κB/COX-2, modulation of the Th17/Treg balance, and also the lower systemic LPS levels of centenarians, which are associated with enhanced SIRT1 activity (↑LPS/↓SIRT1); (ii) the reprogramming of energy metabolism via activation of SIRT1/AMPK and SIRT1/p-53, modulation of mTOR, and attenuation of the IGF-1/insulin axis; (iii) the strengthening of the intestinal barrier through upregulation of tight junction proteins such as ZO-1, occludin, and claudins, resulting in reduced permeability and zonulin levels; and (iv) the optimization of antioxidant defenses. Collectively, these findings suggest translational potential for microbiota-derived metabolites in gerobiotic strategies, although clinical evidence remains limited.