Longevity-promoting human gut Bifidobacteria strains require distinct cytoprotective pathways and share dependence on host lipid regulation

Human gut Bifidobacteria are abundant during infancy and have been reported to be enriched in some exceptionally long-lived populations, yet whether their beneficial effects on lifespan and healthspan are broadly shared across the genus or restricted to specific strains remains unclear. Using an anaerobic bacteria-Caenorhabditis elegans platform with heat-killed diets, we systematically compared 11 human gut Bifidobacteria strains representing nine species. B. infantis ATCC 15697, B. longum NCC 2705, and B. breve DSMZ 20213 produced the largest lifespan extensions and improved multiple measures of physiological resilience, whereas the other strains produced smaller, neutral, or detrimental effects. Genetic analyses showed that these three strains required different combinations of conserved cytoprotective regulators, yet all depended on NHR-49, a lipid-regulating nuclear receptor functionally related to mammalian PPAR, for full lifespan extension. Consistent with this shared requirement, further analyses showed that B. infantis and B. longum also required FAT-7, an NHR-49-regulated delta-9 fatty acid desaturase, for lifespan extension and oxidative stress protection. Untargeted lipidomics identified distinct but partially overlapping phosphatidylethanolamine, diacylglycerol, and triacylglycerol species that were enriched by these diets and reduced by fat-7 RNAi. Bulk lipid extracts from either strain enhanced oxidative stress resistance when added to a standard E. coli diet, providing functional evidence that bacterial lipids contribute to protection. Together, these findings support a strain-selective model. Related commensal strains differ in their physiological effects and cytoprotective pathway requirements but share dependence on host lipid regulation. The findings also identify gut bacteria-host lipid interactions as a mechanistic axis linking microbial products to stress resilience and longevity.