d-Allulose, a stereoisomer of d-fructose, extends Caenorhabditis elegans lifespan through a dietary restriction mechanism: A new candidate dietary restriction mimetic

Abstract Dietary restriction (DR) is an effective intervention known to increase lifespan in a wide variety of organisms. DR also delays the onset of aging-associated diseases. DR mimetics, compounds that can mimic the effects of DR, have been intensively explored. d- Allulose ( d- Alu), the C3-epimer of d- fructose, is a rare sugar that has various health benefits, including anti-hyperglycemia and anti-obesity effects. Here, we report that d- Alu increased the lifespan of Caenorhabditis elegans both under monoxenic and axenic culture conditions. d- Alu did not further extend the lifespan of the long-lived DR model eat-2 mutant, strongly indicating that the effect is related to DR. However, d- Alu did not reduce the food intake of wild-type C. elegans . To explore the mechanisms of the d- Alu longevity effect, we examined the lifespan of d -Alu-treated mutants deficient for nutrient sensing pathway-related genes daf-16 , sir-2.1 , aak-2 , and skn-1 . As a result, d- Alu increased the lifespan of the daf-16 , sir-2.1 , and skn-1 mutants, but not the aak-2 mutant, indicating that the lifespan extension was dependent on the energy sensor, AMP-activated protein kinase (AMPK). d -Alu also enhanced the mRNA expression and enzyme activities of superoxide dismutase (SOD) and catalase. From these findings, we conclude that d- Alu extends lifespan by increasing oxidative stress resistance through a DR mechanism, making it a candidate DR mimetic.