Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP‐ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere‐driven diseases.

中文翻译：

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NAD代谢失衡的重新平衡可改善端粒功能障碍的影响。

端粒短是端粒生物学疾病（例如先天性角化病）的主要定义特征，目前尚无有效的治疗方法。在这里，我们报道了来自DC患者和晚期端粒酶敲除小鼠的原代成纤维细胞显示出较低的烟酰胺腺嘌呤二核苷酸（NAD）水平，以及NAD代谢组中的失衡，包括CD38 NADase升高和聚（ADP-核糖）聚合酶和SIRT1活性降低。分别影响许多相关的生物学途径。补充NAD前体，烟酰胺核糖和CD38抑制作用可改善NAD稳态，从而减轻端粒损伤，线粒体生物合成和清除缺陷，细胞生长迟缓和DC成纤维细胞衰老。这些发现揭示了直接的，