Intrinsic capacity (IC) decline is inherently correlated with aging, yet distinguishing specific IC-related biomarkers from general physiological aging markers remains a significant challenge. We aimed to identify multi-omics signatures associated with IC decline after adjustment for relevant covariates and to explore the functional pathways potentially involved in IC decline.

We analyzed 110 fecal (metagenomics) and 121 serum (untargeted metabolomics) samples from older adults at Beijing Hospital. Multivariable models were applied adjusting for age, sex, Charlson Comorbidity Index (CCI), fish intake, and fruit intake frequency. Differential analyses and network-based mediation approaches were used to assess microbiome–metabolome–IC associations.

After multivariable adjustment, 57 bacterial species and 56 serum metabolites were associated with IC status. The normal IC group showed enrichment of multiple taxa, including Lactobacillus zeae and Paenibacillus glucanolyticus . IC decline was associated with concurrent alterations in amino acid and carnitine-related metabolic pathways, including changes in L-serine, Cysteine, N6,N6,N6-trimethyl-L-lysine, and carnitine C5-OH. Network-based mediation analysis identified overlapping associations among senescence-related metabolites (N1,N8-diacetylspermidine), dietary-derived microbial products (3-(3-hydroxyphenyl)-3-hydroxypropanoic acid), and secondary bile acids (3-epideoxycholic acid), suggesting a structured microbiome–metabolome architecture linked to IC variation.

This study identifies a multi-omics signature associated with IC decline after adjustment for major demographic, clinical, and dietary factors. The findings reveal concurrent alterations in circulating metabolites related to nutrient and carnitine metabolism, alongside compositional and functional differences in the gut microbiome. Together, these parallel findings characterize a multi-omics profile associated with functional decline. These results provide hypotheses for future validation in longitudinal studies.