Dyskeratosis Congenita Links Telomere Attrition to 
Age-Related Systemic Energetics

Abstract

Underlying 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, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence associated metabolites in fibroblast conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/ mass spectrometry and liquid chromatography/ mass spectrometry. We showed extracellular citrate was 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, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species (1-3). Additionally, our data are 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 role of telomere dysfunction in human ageing in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.

Investigating the association between blood metabolites and telomere length: A mendelian randomization study

“…Based on relevant research, levulinate might influence telomere length through several potential pathways. Firstly, it might participate in energy metabolism processes, such as the citric acid cycle (TCA cycle) [61] and oxidative phosphorylation [62], generating the cellular energy (ATP) required for telomere maintenance. Secondly, levulinate might be involved in biosynthetic pathways, such as nucleotide and amino acid synthesis, which were closely related to telomere biogenesis and maintenance [37,63].…”