Gut microbial communities ferment dietary fiber and amino acids, producing short-chain fatty acids such as butyrate, propionate, and acetate, along with secondary bile acids and other metabolites.

These microbial metabolites enter the bloodstream and reach host tissues, where they modulate immune cell signaling and metabolic pathways, including NF-κB activation, histone deacetylase inhibition, and one-carbon metabolism.

Altered signaling changes the activity of DNA methyltransferases and ten-eleven translocation enzymes, shifting DNA methylation at CpG sites in genes that regulate inflammation, cell-cycle arrest, and cellular senescence.

The shifted methylation pattern at these CpG sites changes the calculated DunedinPACE score, which aggregates methylation marks into a measure of biological aging speed.

Chronological age independently alters both the gut microbiome composition and the DNA methylation landscape, creating strong age-dependent covariance between many taxa and DunedinPACE.

After statistical adjustment for chronological age, the remaining age-independent association for each taxon is small; each taxon contributes a small amount of metabolite or immune signal, so no single taxon has enough signal to survive Benjamini-Hochberg correction at n=123. Bifidobacterium adolescentis, Streptococcus salivarius, and Bacteroides intestinalis carry slightly stronger age-independent effects on the methylation pathway and retain nominal significance.