Dendrobium officinale extends lifespan in yeast and Drosophila via context-dependent PI3K-AKT modulation.

<h4>Ethnopharmacological relevance</h4>Dendrobium officinale Kimura et Migo (Tiepi Shihu), a yin-nourishing tonic in traditional Chinese medicine, has been historically used for health maintenance and longevity promotion.<h4>Aim of the study</h4>We evaluated the anti-aging effects of D. officinale whole powder (DOP) and a non-polysaccharide fraction (DOE) and explored underlying mechanisms focusing on conserved PI3K-AKT signaling.<h4>Materials and methods</h4>Network pharmacology was applied to predict aging-related targets and enriched pathways. Anti-aging activity was assessed in yeast (Saccharomyces cerevisiae) and female flies (Drosophila melanogaster) using lifespan and healthspan(definition) assays, a high-sugar diet challenge, and pathway readouts via qRT-PCR and Western blotting. In RAW264.7 macrophages, the PI3K inhibitor LY294002 and the AKT inhibitor MK-2206 were used to evaluate pathway dependence.<h4>Results</h4>Network pharmacology identified 355 overlapping targets, enriched in PI3K-AKT, MAPK, Ras, and HIF-1 pathways. We found that dihydroconiferyl alcohol, homovanillyl alcohol, and taxifolin extended yeast lifespan, and these effects were abolished in yeast mutants defective in key aging-related genes. In flies, DOP extended female lifespan, improved climbing performance, and mitigated high-sugar diet-induced lifespan loss and hyperglycemia, accompanied by reduced AKT phosphorylation under dietary stress and enhanced FOXO-associated responses. DOE also extended lifespan, increased AKT/S6K phosphorylation and reduced FOXO in flies. D. officinale was associated with context-dependent modulation of innate immune-related gene expression. However, DOE suppressed AKT activity and increased FOXO in RAW264.7 cells; co-treatment with MK-2206 abolished DOE-induced changes.<h4>Conclusions</h4>D. officinale exerts anti-aging effects in yeast and Drosophila models, while mammalian macrophages support a mechanistic role for context-dependent PI3K-AKT signaling regulation. Its distinct fractions act in a context-dependent manner, with AKT serving as a central regulatory node and FOXO-associated responses, supporting its ethnopharmacological use as a longevity-promoting herb.