Kynurenine pathway dysregulation via loss of QPRT drives declines in activity and altered metabolism in mice

Abstract Chronic inflammatory pathway activation increases with age and is epidemiologically linked to multiple aging-related pathophysiological processes, phenotypes such as physical frailty and sarcopenia and early healthspan(definition) declines in aging organisms. Despite this, molecular mechanisms that directly connect chronic inflammation to these conditions remain poorly characterized. We hypothesize that chronic inflammation contributes to the development of age-related phenotypes by increasing the degradation of dietary tryptophan into multiple metabolites with unique physiological properties, called kynurenines, via the ‘kynurenine pathway’ (KP). To understand the impact of elevated KP metabolites on mammalian healthspan we utilized the quinolinate phosphoribosyltransferase knock-out (QPRT −/− ) mouse which lacks the terminal enzyme of the KP and thus develops increased levels of downstream kynurenines. We tested the effects of this mutation on glucose handling, spontaneous motor activity, body composition and metabolism using indirect calorimetry, in male and female, young, middle aged and older mice. QPRT − / − mice had significantly altered levels of numerous KP metabolites and nicotinamide. Phenotypic characteristics varied in a sex-specific manner with decreased activity, lean mass and VO 2 , and impaired glucose clearance as early as 12 months seen in female QPRT −/− compared to age and sex-matched mice. Male QPRT −/− mice developed reduced lean mass by middle age and had altered respiration and food intake. This data indicates that KP dysregulation can drive declines in activity and alter metabolism in mammals and is a potential target to intervene on frailty and functional decline.