Gastrodia elata Polysaccharide Attenuates Aging by Modulating Oxidative Stress, Inflammation, and Gut Microbiota

ABSTRACT Aging is a natural, progressive physiological process accompanied by systemic multi‐organ dysfunction, for which effective intervention strategies remain limited. Gastrodia elata is a well‐known food and medicine homologous resource with extensive bioactive properties. Gastrodia elata polysaccharide (GEP), a bioactive macromolecule isolated from G. elata , is a promising candidate for the development of anti‐aging functional products. In this study, we first verified the preliminary anti‐aging effects of GEP in vitro and in Caenorhabditis elegans , and further administered GEP to natural aging mice to explore its anti‐aging effects and underlying mechanisms. The results showed that GEP significantly alleviated d ‐galactose ( d ‐gal)‐induced senescence of BV2 microglia, prolonged the lifespan of nematodes, and in aging mice, it markedly ameliorated cognitive impairment, muscle dysfunction, and hippocampal neuronal damage, while upregulating the expression of neuroprotective BDNF. Moreover, GEP reduced the level of malondialdehyde (MDA) and increased the activities of superoxide dismutase (SOD) and catalase (CAT), and activated the Nrf2/Keap1 signaling pathway by downregulating Keap1 and upregulating HO‐1 and NQO1, suggesting that GEP may ameliorate aging by reversing oxidative stress imbalance. GEP also significantly decreased the levels of pro‐inflammatory factors tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and interleukin‐6 (IL‐6) in both serum and brain tissue, which may be the result of the alleviation of chronic inflammation by the inactivation of the TLR4/NF‐κB pathway. Furthermore, our results revealed a significant association between GEP‐mediated gut microbial remodeling and its neuroprotective phenotypes. GEP normalized aging‐induced gut dysbiosis, recovered microbial diversity, restored the abundance of beneficial genera including Akkermansia and Lactobacillus , and elevated intestinal tight junction proteins ZO‐1 and occludin. Such intestinal improvements may partially contribute to GEP's anti‐aging capacity through the gut–brain axis, though definitive causal evidence such as fecal microbiota transplantation is lacking in the present study. Collectively, these findings provide a theoretical foundation for the development and application of GEP‐based functional products targeting aging intervention.