Abstract
Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of C. elegans and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of eat-2 (ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span–extending activity of MDHB is completely abolished in daf-2 (e1370) mutations, which suggests that daf-2 is crucial for a MDHB-induced pro-longevity effect in C. elegans. Moreover, MDHB enhances the nuclear localization of daf-16/FoxO, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in C. elegans. Therefore, our results indicate that MDHB at least partially acts as a modulator of the daf-2/daf-16 pathway to extend the lifespan of C. elegans, and MDHB might be a promising therapeutic agent for age-related diseases.
Highlights
“Every man desires to live long but no man wishes to be old,” Jonathan Swift said in the 17th century
MDHB inhibits the expression of daf-2/insulin/IGF-1 signaling (IIS), while it upregulates the expression of the daf-16 gene
Our genetic analysis shows that MDHB promotes daf-16/forkhead box O (FoxO) nuclear localization, thereby modulating the expression of daf-2/daf-16 target genes that are positively associated with stress tolerance and lifespan regulation, including the upregulation of genes encoding the antioxidant enzymes
Summary
“Every man desires to live long but no man wishes to be old,” Jonathan Swift said in the 17th century. The observation that C. elegans has only 35% homology to human genes has long been seen as one of its chief deficits in anti-aging research [7,8] It has not prevented nematodes from becoming a classical model organism in biogerontological studies [8]. Our genetic analysis shows that MDHB promotes daf-16/FoxO nuclear localization, thereby modulating the expression of daf-2/daf-16 target genes that are positively associated with stress tolerance and lifespan regulation, including the upregulation of genes encoding the antioxidant enzymes. Putting all this together, we conclude that MDHB acts as a modulator of the daf-2/daf-16 pathway to enhance resistance to oxidative stressors, prolonging the adult lifespan of C. elegans
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