Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

Aging is the predominant cause of morbidity and mortality in industrialized countries, yet the molecular mechanisms driving aging and especially the contribution by the microbiome remain unclear. We combined multi-omics with metabolic modeling to comprehensively characterize host–microbiome interactions during aging in mice. Our findings reveal a complex dependency of host metabolism on known and novel microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These microbial changes coincided with increased inflammaging as well as a corresponding downregulation of key host pathways, predicted by our model to be microbiome-dependent, that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate microbiome–host interactions that potentially influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.