Longtine Abigail G, Greenberg Nathan T, Gonzalez Antonio, Lindquist Alexandra, VanDongen Nicholas S, Mahoney Sophia A, Rahman Gibraan, Clayton Zachary S, Ziemba Brian P, Ludwig Katelyn R, Widlansky Michael E, Knight Rob, Seals Douglas R, Brunt Vienna E
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Aging Biol. 2024;2. doi: 10.59368/agingbio.20240033. Epub 2024 Aug 27.
Adverse changes in the gut microbiome with aging are an emerging mediator of arterial dysfunction, which contributes to cardiovascular disease (CVD) development. We investigated the therapeutic potential of enhancing the bioavailability of gut-derived short-chain fatty acids (SCFAs; produced from dietary fiber) for improving age-related arterial dysfunction. We performed gut microbial whole-genome sequencing in young (3 months) versus old (24 months) male C57BL/6N mice to explore changes in bacterial taxonomic abundance and functional pathways with aging and relations to arterial function. We then supplemented young and old mice with the SCFA acetate in drinking water versus controls and versus a high-fiber diet for 8-10 weeks to test the effects of these interventions on vascular function and explore potential mechanisms. Of the various differences in the gut microbiomes of old mice, lower SCFA-producing capacity (taxonomic abundance and functional pathways) stood out as a key feature related to worse arterial function after adjusting for age. Acetate supplementation and a high-fiber diet reversed ~30% of the age-related increase in aortic pulse wave velocity (stiffness) and fully restored carotid artery endothelium-dependent dilation (endothelial function) to young levels. Acetate and a high-fiber diet reduced age-related increases in systemic inflammation. We also found that improvements in endothelial function were likely mediated by suppressed early growth response-1 signaling using innovative siRNA-based knockdown in isolated arteries. There were no effects of the interventions in young mice. Acetate supplementation was comparably effective for ameliorating arterial dysfunction with aging as a high-fiber diet and thus shows promise for reducing CVD risk in older adults.
肠道微生物群随衰老而发生的不良变化是动脉功能障碍的一个新出现的介导因素，这会促进心血管疾病（CVD）的发展。我们研究了提高肠道来源的短链脂肪酸（SCFAs；由膳食纤维产生）的生物利用度对改善与年龄相关的动脉功能障碍的治疗潜力。我们对年轻（3个月）和年老（24个月）的雄性C57BL/6N小鼠进行了肠道微生物全基因组测序，以探索细菌分类丰度和功能途径随衰老的变化以及与动脉功能的关系。然后，我们给年轻和年老的小鼠在饮用水中补充SCFA乙酸盐，并与对照组和高纤维饮食组进行比较，持续8 - 10周，以测试这些干预措施对血管功能的影响并探索潜在机制。在年老小鼠肠道微生物群的各种差异中，较低的SCFA产生能力（分类丰度和功能途径）在调整年龄后作为与较差动脉功能相关的关键特征凸显出来。补充乙酸盐和高纤维饮食可逆转约30%与年龄相关的主动脉脉搏波速度（僵硬程度）增加，并使颈动脉内皮依赖性舒张（内皮功能）完全恢复到年轻水平。乙酸盐和高纤维饮食可降低与年龄相关的全身炎症增加。我们还发现，内皮功能的改善可能是通过在分离的动脉中使用基于创新的小干扰RNA敲低来抑制早期生长反应-1信号传导介导的。这些干预措施对年轻小鼠没有影响。补充乙酸盐在改善衰老引起的动脉功能障碍方面与高纤维饮食具有同等效果，因此有望降低老年人患CVD的风险。
