Streptococcus thermophilus remodels lipid metabolism to extend healthspan in Caenorhabditis elegans through NHR-49-Delta-9 desaturase axis.

Aging is closely associated with dysregulation of lipid metabolism, making the modulation of lipid metabolism a promising strategy for promoting healthspan. Streptococcus thermophilus, a widely utilized probiotic, has shown potential in regulating host metabolism. However, whether and how it can promote healthspan by modulating specific lipid metabolic pathways remains unclear. Using the Caenorhabditis elegans model, this study investigated the effects of Streptococcus thermophilus on healthspan and the underlying molecular mechanisms. We found that Streptococcus thermophilus supplementation significantly extended the healthspan of worms, improving multiple health indicators including enhanced motility and reduced accumulation of age pigments. Furthermore, we found that Streptococcus thermophilus remodeled the host fatty acid profile, markedly increasing the proportion of monounsaturated fatty acids (MUFAs). Mechanistically, Streptococcus thermophilus specifically upregulated the nuclear hormone receptor NHR-49 (a functional ortholog of mammalian PPARα), which in turn activated the expression of downstream delta-9 desaturase genes, including fat-5, fat-6 and fat-7, resulting in increased levels of MUFAs thereby extending healthspan. Intriguingly, exogenous supplementation of 1 mM oleic acid (OA) and palmitoleic acid (POA) restored nhr-49, fat-5, fat-6 and fat-7 mutants-induced shortened lifespan phenotype. In summary, our study demonstrates that Streptococcus thermophilus promotes healthspan by activating the NHR-49/Delta-9 desaturase axis, leading to a systemic reprogramming of lipid metabolism. This finding provides a novel mechanistic basis for developing precise probiotic-based anti-aging strategies targeting the lipid metabolic network.