Microbial keystone taxa and metabolic signatures in centenarians regulate intestinal homeostasis during aging

Abstract Microbial networks and keystone taxa play pivotal roles in maintaining gut microecological stability and host homeostasis, irrespective of their abundance. However, most previous studies of aging‐associated gut microbiota have relied on abundance‐based analyses, largely overlooking microbial networks and microbe‐host interactions. Here, we employed a co‐occurrence network approach to identify keystone taxa during aging in humans and mice. We found that centenarians harbor distinctive keystone taxa dominated by members of Clostridium , of which Clostridium scindens ( C. scindens ) can significantly enhance microbial network stability, probably contributing to longevity and reduced susceptibility to age‐related diseases. Mechanistically, C. scindens produces indole‐3‐acetic acid (IAA) from tryptophan via the enzymes amidase (AMIE) and aldehyde dehydrogenase (ALDH). Oral administration of either C. scindens or IAA effectively mitigates intestinal aging by restoring gut barrier dysfunction in aged mice. Further analysis revealed that C. scindens ‐derived IAA restores intestinal dysfunction through activation of aryl hydrocarbon receptor (AHR) signaling, leading to upregulation of intestinal CLDN10, a key tight junction protein. Structurally, IAA enhances Claudin ‐ 10 transcription by promoting AHR binding to its promoter region. Our findings provide new insights into the characterization of microbial networks in centenarians and highlight that C. scindens and IAA may contribute to healthy longevity by promoting gut microecological stability and host homeostasis.