Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.
Department of Medical Physics and Informatics / Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary.
Geroscience. 2019 Aug;41(4):419-439. doi: 10.1007/s11357-019-00095-x. Epub 2019 Aug 28.
Understanding molecular mechanisms involved in vascular aging is essential to develop novel interventional strategies for treatment and prevention of age-related vascular pathologies. Recent studies provide critical evidence that vascular aging is characterized by NAD+ depletion. Importantly, in aged mice, restoration of cellular NAD+ levels by treatment with the NAD+ booster nicotinamide mononucleotide (NMN) exerts significant vasoprotective effects, improving endothelium-dependent vasodilation, attenuating oxidative stress, and rescuing age-related changes in gene expression. Strong experimental evidence shows that dysregulation of microRNAs (miRNAs) has a role in vascular aging. The present study was designed to test the hypothesis that age-related NAD+ depletion is causally linked to dysregulation of vascular miRNA expression. A corollary hypothesis is that functional vascular rejuvenation in NMN-treated aged mice is also associated with restoration of a youthful vascular miRNA expression profile. To test these hypotheses, aged (24-month-old) mice were treated with NMN for 2 weeks and miRNA signatures in the aortas were compared to those in aortas obtained from untreated young and aged control mice. We found that protective effects of NMN treatment on vascular function are associated with anti-aging changes in the miRNA expression profile in the aged mouse aorta. The predicted regulatory effects of NMN-induced differentially expressed miRNAs in aged vessels include anti-atherogenic effects and epigenetic rejuvenation. Future studies will uncover the mechanistic role of miRNA gene expression regulatory networks in the anti-aging effects of NAD+ booster treatments and determine the links between miRNAs regulated by NMN and sirtuin activators and miRNAs known to act in the conserved pathways of aging and major aging-related vascular diseases.
了解血管衰老涉及的分子机制对于开发治疗和预防与年龄相关的血管病变的新介入策略至关重要。最近的研究提供了重要证据，表明血管衰老的特征是 NAD+耗竭。重要的是，在老年小鼠中，用 NAD+增强剂烟酰胺单核苷酸（NMN）治疗恢复细胞 NAD+水平可发挥显著的血管保护作用，改善内皮依赖性血管舒张，减弱氧化应激，并挽救与年龄相关的基因表达变化。强有力的实验证据表明，miRNA（miRNA）的失调在血管衰老中起作用。本研究旨在检验以下假设：与年龄相关的 NAD+耗竭与血管 miRNA 表达的失调有关。一个推论假设是，在 NMN 治疗的老年小鼠中进行功能性血管年轻化也与恢复年轻的血管 miRNA 表达谱有关。为了检验这些假设，用 NMN 处理 24 个月大的老年（24 个月大）小鼠 2 周，并将其主动脉中的 miRNA 特征与未经处理的年轻和老年对照小鼠的主动脉中的 miRNA 特征进行比较。我们发现，NMN 治疗对血管功能的保护作用与 miRNA 表达谱在老年小鼠主动脉中的抗衰老变化有关。NMN 诱导的差异表达 miRNA 在老年血管中的预测调节作用包括抗动脉粥样硬化作用和表观遗传年轻化。未来的研究将揭示 miRNA 基因表达调控网络在 NAD+增强剂治疗抗衰老作用中的机制作用，并确定受 NMN 调节的 miRNA 与 Sirtuin 激活剂之间的联系，以及已知在衰老和与年龄相关的主要血管疾病的保守途径中起作用的 miRNA。
