The <scp>NMDA</scp> Receptor Antagonist Memantine Modulates Aging and Stress Resilience

Aging is associated with a progressive decline in physiological resilience, often linked to impaired stress responses and metabolic dysfunction. In Caenorhabditis elegans (C. elegans), caloric restriction (CR) and pharmacological interventions are widely used to dissect conserved longevity pathways. Here, we identify the N-methyl-D-aspartate receptor (NMDAR) antagonist memantine as a novel modulator of lifespan and stress tolerance in C. elegans. Memantine, but not ketamine, extends median lifespan and reproductive lifespan, suggesting that the observed effects are not shared with ketamine at the tested concentration. Transcriptomic analysis revealed significant overlap between memantine-treated animals and CR models, particularly eat-2 mutants, implicating shared metabolic and longevity-associated pathways. Functionally, memantine was found to reduce mitochondrial and oxidative stress, while enhancing β-oxidation of fatty acids, and modifying behavioral responses to food cues, delaying food-seeking behavior and increasing locomotion under starvation, without affecting lipid storage. In summary, these findings suggest that memantine promotes stress resilience and healthy aging via metabolic changes that overlap with CR-associated pathways, highlighting its potential as a longevity-modulating intervention.