Human gut Bifidobacteria strains regulate host longevity via shared and divergent mechanisms in C. elegans

The human gut microbiome influences many aspects of host aging physiology. However, it is not clear how distinct bacterial strains interact with host aging pathways and different healthspan metrics. To investigate this question, we chose Bifidobacteria as our bacterial model. The Bifidobacteria genus contains diverse species that are enriched in both human infants and centenarians, suggesting that they may confer "youthful" effects in aging adults. We selected eleven strains from nine Bifidobacteria species that are commonly detected in human fecal samples. Using our human anaerobic gut bacteria-C. elegans aging platform, we examined 1) individual Bifidobacteria strains' contribution to lifespan and healthspan and 2) their genetic interactions with the conserved, longevity-associated transcriptional regulators. We identified two B. longum and B. infantis strains that most strongly increased lifespan and stress resistance. Notably, these two strains act through shared (e.g., ATFS-1/ATF5, HSF-1/HFS1, and SKN-1/NRF2) and yet strain-specific pathways (e.g., NHR-49/PPARα for B. infantis) to enhance both lifespan and oxidative stress protection. Lastly, both strains activate a panel of genes involved in molecular chaperone, antioxidant, and lipid remodeling activities, serving as candidate cytoprotective mechanisms for further investigations. In summary, this study establishes a framework of dissecting the mechanistic links between human anaerobic gut bacteria and conserved host aging pathways that can be applicable beyond Bifidobacteria. While the connections between gut microbiome and aging in humans are complex, our approach provides the beginning steps to uncover strain-level interactions that may ultimately inform targeted probiotic strategies for promoting healthy aging.