Selenocysteine mimics the effect of dietary restriction on lifespan via SKN-1 and retards age-associated pathophysiological changes in Caenorhabditis elegans

Selenocysteine, a sulfur-containing amino acid, can modulate cellular oxidative stress defense systems by incorporating into anti-oxidant enzymes such as glutathione peroxidase and thioredoxin reductase. Selenocysteine can also prevent cancer, neurodegenerative diseases and cardiovascular diseases. A recent study revealed that dietary supplementation with selenocysteine can increase the resistance of Caenorhabditis elegans to environmental stressors and its lifespan. The objective of the present study was to identify the underlying mechanism involved in the lifespan-extending effect of selenocysteine and the effect of selenocysteine on age-associated pathophysiological changes. Lifespan assays with known long-lived mutants of age-1 (the ortholog of the phosphoinositide 3-kinase), clk-1 (the ortholog of demethoxyubiquinone hydroxylase) and eat-2 (a ligand-gated ion channel subunit) revealed that the effect of selenocysteine on lifespan specifically overlapped with that of the eat-2 mutation, a genetic model of dietary restriction (DR). Selenocysteine mimicked the effect of DR on the bacterial dilution method. It required SKN-1 (the ortholog of mammalian nuclear factor-erythroid-related factor) for lifespan extension. In addition, selenocysteine significantly delayed the paralysis induced by human amyloid-β gene, positively correlated with the incidence of Alzheimer's disease. The effect of selenocysteine on amyloid-β-induced toxicity was dependent on the nuclear localization of DAF-16. Reduced survival caused by high-glucose-diet was recovered by selenocysteine. Selenocysteine also reduced the cellular level of reactive oxygen species known to be increased by high-glucose-diet. The results of the present study suggested that selenocysteine can mimic the effect of DR on lifespan and age-associated pathophysiological alterations, providing scientific evidence for the development of DR mimetics using selenocysteine.