Progressive gut microbiota shifts and functional alterations across aging stages and frailty in mice

The gut microbiota modulates aging through metabolic and immune interactions. To characterize microbial changes during aging, we profiled gut microbiota across four stages in male C57BL/6J mice: young-adult, middle-aged, senescent, and frailty. Using 16S rRNA sequencing and targeted metabolomics, we observed a biphasic diversity pattern, with reduced richness in senescence followed by a rebound in frailty. Frailty-stage microbiota showed increased connectivity and enrichment of Lachnospiraceae, alongside short-chain fatty acid (SCFA) depletion, particularly butanoic acid. Functional predictions revealed elevated immune activity and reduced carbohydrate metabolism, linked to specific microbial taxa. These findings highlight a structured remodeling of the gut microbiota during aging, with frailty representing a distinct dysbiotic state associated with metabolic dysfunction. Modulating gut microbial composition may represent a potential strategy to attenuate frailty and promote healthy aging.