Potential Probiotic Lacticaseibacillus rhamnosus NKU FL1-11 Prevents Aging-Related Oxidative Stress and Inflammation via mTOR and FoxO Signaling Pathways in Zebrafish

Aging, a complex physiological process characterized by multi-organ involvement and closely associated with oxidative stress and chronic inflammation, has prompted growing scientific interest in natural antioxidant probiotics due to their dual health-promoting properties and anti-oxidative capabilities. However, the effectiveness and mechanisms of multiple emerging Lacticaseibacillus rhamnosus (L. rhamnosus) strains extracted from the fecal microbiota of breastfed infants on zebrafish models remain unclear. In this study, the anti-aging potential of L. rhamnosus NKU FL1-11, selected for its potent inhibition of senescence-associated β-galactosidase activity, was systematically investigated using H₂O₂-induced senescent zebrafish through a comprehensive assessment of protective effects and mechanistic analysis. Our findings demonstrated that L. rhamnosus NKU FL1-11 exhibits probiotic attributes, including biosafety, acid tolerance, bile salt tolerance, and anti-oxidative capacity. The pre-treatment of L. rhamnosus NKU FL1-11 could preserve locomotor behavior. Additionally, L. rhamnosus NKU FL1-11 supplementation significantly increased the activities of CAT, GSH-Px, and GSH (p < 0.01) and reduced the levels of TNF-α, IL-1β, and IL-6 (p < 0.05). RNA-seq analysis showed that differential genes were closely linked to oxidative stress and inflammation, specially enriched to FoxO signaling pathway and mTOR signaling pathway. Furthermore, we validated the FoxO/mTOR signaling pathway by qPCR and western blotting analyses. Collectively, our findings suggest that L. rhamnosus NKU FL1-11 emerges as a probiotic strain exhibiting remarkable anti-oxidative and anti-inflammatory capacities. The strain demonstrates significant efficacy in preventing H₂O₂-induced aging, positioning its potential application as an anti-aging functional ingredient. However, comprehensive pre-clinical evaluations and mechanistic investigations are warranted to validate these preliminary observations.