3-HK SUPPLEMENTATION INCREASES NICOTINATE PHOSPHORIBOSYLTRANSFERASE (NAPRT) EXPRESSION IN DROSOPHILA

Abstract The increasing prevalence of physical frailty and aging related diseases in older adults necessitates the development of novel biological strategies to slow age-related declines. In humans, tryptophan metabolism through the kynurenine pathway (KP), which produces the energy metabolite and cellular cofactor nicotinamide adenine dinucleotide (NAD+), has been linked to various aging-related diseases including metabolic syndrome, neurodegenerative diseases, and physical frailty. Elevated levels of KP metabolites, such as 3-hydroxykinurenine (3-HK), correlate negatively with lifespan and physical function. A profile of downstream KP metabolites in the serum of older adults showed that 3-HK was increased in frail compared to both non-frail and young subjects, and liver kynurenine/tryptophan ratio correlates negatively with maximum lifespan in twenty-six mammalian species. To comprehensively explore the effects of elevated cytotoxic KP metabolites, we fed DGRP_229 Drosophila males diet infused with 3-HK. We found that treatment with 3-HK reduced average lifespan by 17% (P< 0.0001) compared against control. To elucidate the biological mechanisms of 3-HK treatment, we performed qRT-PCR on 11 genes involved in tryptophan metabolism. We found that treatment with 3-HK significantly decreased the expression of nicotinate phosphoribosyltransferase (Naprt) (P=0.0022), which plays an important role in NAD+ biosynthesis and protects against oxidative stress. Our findings indicate that some of the detrimental effects observed after 3-HK supplementation may be mediated by changes in NAD+ biosynthesis and highlight the potential feasibility of using NAD+ supplementation as an intervention method.