Dihydromyricetin Is Associated with Healthspan-Related Phenotypes and Neuroprotection in Caenorhabditis elegans, Alongside Redox and Mitochondrial Quality-Control Changes

Dihydromyricetin (DHM), a dietary flavanonol known for its antioxidant and neuroprotective properties, has been connected to mitochondrial homeostasis, yet how it engages mitochondrial quality control during aging has not been resolved. This study examined DHM’s effects on lifespan, neuronal integrity, resistance to oxidative stress, mitochondrial status, and lipid handling in Caenorhabditis elegans. DHM (50–200 μM) extended mean lifespan by 9.1–15.0%, reduced age-related degeneration of ALM (anterior lateral microtubule) and PLM (posterior lateral microtubule) touch-receptor neurons, and preserved locomotor and anterior touch-response performance into later adulthood. Survival after juglone challenge improved with DHM treatment, and the compound showed robust 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging activity. DHM modestly lowered tetramethylrhodamine ethyl ester (TMRE) fluorescence. In a separate cohort assessed under a different exposure schedule, the mtDNA copy number did not differ significantly from that of the vehicle. DHM also increased GFP-negative/mCherry-positive mitochondrial puncta in ALM neurons, patterns consistent with a shifted mitochondrial energetic state and greater mitochondrial trafficking to acidic degradative compartments. The neuroprotective effect persisted in ucp-4(ok195) mutants but was not statistically detected in pink-1(tm1779); pdr-1(gk448) double mutants; since a formal cross-genotype interaction test was not performed, this pattern is treated as hypothesis-generating rather than definitive evidence of pathway dependency. DHM lowered intestinal lipid stores, suppressed fat-5, fat-6, and fat-7 expression, and modestly upregulated atfs-1. Neither the SOD-3 nor GST-4 canonical reporters showed significant induction, and DHM’s lifespan-extending effect was retained in daf-16(mu86) mutants, with an exploratory Cox model providing no evidence of a genotype × dose interaction. Together, these findings indicate that DHM is associated with healthspan-related phenotypes alongside a coordinated pattern of redox regulation, mitochondrial quality-control responses, and metabolic adjustment.