Human gut Bifidobacteria strains promote longevity via shared and divergent mechanisms
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 full 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. Author summaryGut bacteria are increasingly linked to healthy aging, but which strains are beneficial and how they act on the host remain poorly understood. Human gut Bifidobacteria are common members of the infant gut microbiome and have been reported to be enriched in some exceptionally long-lived populations. Using Caenorhabditis elegans and controlled, heat-killed bacterial diets, we compared 11 human gut Bifidobacteria strains representing nine species. B. infantis, B. longum, and B. breve produced the largest lifespan benefits and improved physiological resilience, whereas the remaining strains produced smaller, neutral, or detrimental effects, showing that these benefits are highly strain-selective. Genetic experiments revealed that the three selected strains required different combinations of conserved stress response regulators. Despite these differences, all depended on NHR-49, a regulator of host lipid metabolism functionally related to mammalian PPAR, for full lifespan extension. Consistent with this shared requirement, B. infantis and B. longum also required FAT-7, an NHR-49-regulated fatty acid desaturase, for lifespan extension and protection from oxidative stress. Lipidomic profiling showed that the two strains reshaped host complex lipid composition in partially overlapping ways, with many changes reduced when fat-7 expression was lowered. Lipid extracts from either strain were also sufficient to improve oxidative stress resistance when added to a standard diet, providing functional evidence that bacterial lipids contribute to protection. Together, these findings identify gut bacteria-host lipid interactions as a mechanistic axis linking strain-specific bacterial effects to stress resilience and longevity.