Dimethyl fumarate ameliorates quinolinic acid-induced ageing and neurodegeneration in Caenorhabditis elegans.
Sun Yi, Zhou Ke, Cui Jiaorong, Ding Haoxuan, Shareef Iqra, Du Liuliang, Shi Zhen, Fu Linlin, Sun Fenfen, Zhu Zuobin, Pan Wei
Abstract
The ageing population and the increasing prevalence of age-related diseases underscore the urgent need for targeted therapeutic strategies. Accumulating evidence indicates that quinolinic acid (QA), a neuroinflammatory neurotoxin, contributes to the pathogenesis of neurodegenerative disorders. In this study, using Caenorhabditis elegans as a model organism, we demonstrate that chronic QA exposure acts as a robust driver of accelerated aging, significantly reducing overall healthspan. This pro-aging effect is accompanied by the premature onset of decreased locomotor function, enhanced lipofuscin accumulation, and decreased thermotolerance. Beyond these systemic aging phenotypes, QA induced pronounced cognitive deficits, including impaired short- and long-term associative memory and structural damage to dopaminergic neurons. Using this QA-induced injury model, we investigated the therapeutic potential of the clinical compound dimethyl fumarate (DMF), a derivative of a tricarboxylic acid cycle intermediate, and revealed that DMF's protective effects are partially dependent on the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In summary, our results demonstrate the therapeutic efficacy of DMF as a highly effective geroprotector and neuroprotector against QA-induced toxicity and define the Nrf2 pathway as a crucial mediator of the cognitive benefits of DMF, thus establishing its therapeutic repurposing potential for age-related neurodegenerative diseases.
Key Findings
- Chronic quinolinic acid exposure accelerates aging and reduces healthspan in Caenorhabditis elegans.
- Quinolinic acid induces cognitive deficits and dopaminergic neuron damage in the model organism.
- Dimethyl fumarate provides neuroprotection and geroprotection against quinolinic acid toxicity via partial activation of the Nrf2 pathway.
Clinical Significance
Dimethyl fumarate shows potential as a therapeutic agent to protect against age-related neurodegenerative diseases by activating the Nrf2 pathway, suggesting its repurposing for clinical use in managing neuroinflammation and cognitive decline.
Citation
Sun Yi, Zhou Ke, Cui Jiaoronget al.. Dimethyl fumarate ameliorates quinolinic acid-induced ageing and neurodegeneration in Caenorhabditis elegans. Biogerontology. 2026-Jun-06.