Parishin B, a phenolic constituent of Gastrodia elata Blume, extends lifespan and improves stress resistance in Caenorhabditis elegans.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodia elata Blume (Tianma) is a traditional Chinese medicinal herb widely used for the management of dizziness, headache, convulsions, limb numbness, and neurological disorders. Modern pharmacological studies have demonstrated that G. elata possesses neuroprotective, antioxidant, and anti-inflammatory activities that may be relevant to aging-associated functional decline. Parishin B, a representative phenolic constituent of G. elata, exhibits neuroprotective properties and diverse biological activities; however, its contribution to the traditional medicinal functions of Tianma and its potential anti-aging effects remain unclear. AIM OF THE STUDY: This study aimed to evaluate the effects of parishin B on healthspan, lifespan, proteotoxic stress, and cellular senescence and to elucidate the conserved molecular mechanisms underlying its protective activities. MATERIALS AND METHODS: The geroprotective activity of parishin B was investigated using Caenorhabditis elegans (C. elegans) as an in vivo model. Lifespan assays, lifespan-related phenotypic analyses, stress resistance assays, and transgenic models of neurodegenerative diseases were employed to assess the effects of parishin B on aging-associated functional decline and proteotoxicity. Transcriptomic profiling, quantitative RT-PCR, fluorescent reporter analyses, and genetic approaches were used to identify the signaling pathways involved. The effects of parishin B on cellular senescence and neurotoxicity were further evaluated in mammalian cell models. RESULTS: Parishin B significantly extended the lifespan of wild-type C. elegans, with 200 μM producing a 23.88% increase in mean lifespan. Parishin B improved multiple lifespan parameters, including locomotor activity, muscle integrity, mitochondrial morphology, lipid homeostasis, and lipofuscin accumulation. Moreover, parishin B alleviated proteotoxicity-associated phenotypes in multiple nematode models of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Transcriptomic analysis revealed coordinated regulation of immune-, stress-response-, lysosomal-, and longevity-associated pathways. Mechanistically, parishin B requires DAF-16/FOXO-, SKN-1/Nrf2-, HSF-1-, and HLH-30 to enhance cytoprotective responses, including antioxidant defense, autophagy-lysosome-associated reporter signals, and the resistance to oxidative and thermal stress. In mammalian systems, parishin B protected PC12 cells against Aβ1-42-induced cytotoxicity and attenuated senescence-associated phenotypes in mouse embryonic fibroblasts. CONCLUSIONS: The present study identifies parishin B as a bioactive constituent contributing to the pharmacological basis of Gastrodia elata. By activating conserved stress-response and proteostasis-regulating pathways, parishin B promotes longevity, enhances stress resilience, preserves protein homeostasis, and alleviates cellular senescence. These findings provide mechanistic evidence supporting the traditional use of Tianma and highlight parishin B as a promising natural product for mitigating aging-associated functional decline and proteotoxic disorders.