Microbiota-derived indole-3-propionic acid extends lifespan in Drosophila and improves muscle and bone health in mice.

Aging is associated with alterations in endogenous tryptophan (TRP) metabolism that contributes to musculoskeletal decline. In this study, we investigated the effects of the microbiota-derived TRP metabolite, indole-3-propionic acid (IPA), on musculoskeletal health in aged mice and lifespan in Drosophila melanogaster. Aged C57BL/6 mice received IPA (20 mg/kg, subcutaneous, three times per week for 12 weeks), while Drosophila were maintained on food supplemented with IPA (100 µM) throughout their lifespan. Our findings revealed that IPA-treated aged mice exhibited enhanced muscle function (grip strength and hang time). Histological and bone microCT analyses revealed no changes in muscle fiber size but enhanced bone microarchitecture. Furthermore, molecular studies have elucidated that IPA treatment prevents oxidative stress and reduces senescence(definition), indicating improved cellular survival. Our Drosophila melanogaster longevity analysis revealed a significant extension of lifespan, but lifespan effects were genotype- and sex-specific. Collectively, our findings identify IPA as a promising microbiota-derived metabolite that improves musculoskeletal health and promotes longevity, highlighting its potential as a therapeutic intervention for age-related decline in function.