Telomerase deficiency in humans is associated with systemic age-related changes in energy metabolism

Abstract

SUMMARYUnderlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, DKC1) and progressive telomere attrition. We show extracellular citrate is repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, citrate and senescence factors only weakly distinguished DC patients from controls, whereas other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance, consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the early diagnosis of telomere dysfunction and anti-senescence therapeutics.HighlightsExtracellular citrate is regulated by telomere function in vitro and in vivo.Dyskeratosis Congenita (DC) is a human disease characterized by systemic telomere attrition, which showed an age-related plasma energetic profile, distinct from age-related disease and that of centenarians.The DC profile strikingly out-performed senescence factors in discriminating DC from controls, and pyruvate associated with a low lactate:pyruvate ratio is potentially a useful and cheap minimally invasive diagnostic aid for DC and telomere dysfunction.Mechanistically DC systemic metabolism is indicative of a shift to reduced pyruvate dehydrogenase activity, glycolysis and/or increased citrate and lactate production followed by further metabolism in the kidneys and liver.