The microbiome-gerogene axis: a new frontier in precision geromedicine.

Aging is increasingly recognized as a biologically heterogeneous process arising from dynamic interactions among genetic programs, environmental exposures, and adaptive physiological responses. Within the geroscience framework, conserved hallmarks, including genomic instability, epigenetic alterations, mitochondrial dysfunction(definition), chronic inflammation, cellular senescence(definition), and dysbiosis, capture the systems-level nature of age-related decline. Parallel to this framework, the concept of <i>gerogenes</i> defines coordinated molecular programs that actively drive biological aging when persistently engaged, counterbalanced by gerosuppressive pathways that preserve resilience. Here, we synthesize evidence supporting a unifying microbiome-gerogene axis in which the gut microbiome functions as an upstream, modifiable regulator of molecular aging trajectories. Age-associated microbial remodeling leads to loss of beneficial metabolic functions, including short-chain fatty acid production, bile acid transformation, and mitochondrial-supportive co-metabolism, with downstream effects on epithelial barrier integrity, immune homeostasis, and tissue repair. Integrated multi-omics studies link these microbial changes to host transcriptional, epigenomic, proteomic, and metabolomic signatures of biological aging, enabling mechanistic insights beyond taxonomic associations. Immune aging represents a major convergence point of microbiome-gerogene crosstalk, as dysbiosis driven barrier dysfunction and microbial translocation reinforce inflammaging(definition), immunosenescence, and senescence-associated signaling networks. In parallel, microbial metabolites interface with epigenetic regulation, mitochondrial quality control, circadian biology, and gut-brain-immune communication, extending microbial influence to systemic and neurodegenerative aging processes. Building on this mechanistic foundation, we propose the microbiome-gerogene axis as an integrative framework for precision geromedicine, linking lifestyle exposures to intracellular aging programs and informing biomarker discovery and personalized interventions aimed at extending healthspan(definition) rather than treating late-stage disease.