Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA.
Oklahoma City VA, Oklahoma City, OK, USA; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
Redox Biol. 2024 Jul;73:103189. doi: 10.1016/j.redox.2024.103189. Epub 2024 May 15.
Age-related endothelial dysfunction is a pivotal factor in the development of cardiovascular diseases, stemming, at least in part, from mitochondrial dysfunction and a consequential increase in oxidative stress. These alterations are central to the decline in vascular health seen with aging, underscoring the urgent need for interventions capable of restoring endothelial function for preventing cardiovascular diseases. Dietary interventions, notably time-restricted feeding (TRF), have been identified for their anti-aging effects on mitochondria, offering protection against age-associated declines in skeletal muscle and other organs. Motivated by these findings, our study aimed to investigate whether TRF could similarly exert protective effects on endothelial health in the vasculature, enhancing mitochondrial function and reducing oxidative stress. To explore this, 12-month-old C57BL/6 mice were placed on a TRF diet, with food access limited to a 6-h window daily for 12 months. For comparison, we included groups of young mice and age-matched controls with unrestricted feeding. We evaluated the impact of TRF on endothelial function by measuring acetylcholine-induced vasorelaxation of the aorta. Mitochondrial health was assessed using fluororespirometry, and vascular reactive oxygen species (ROS) production was quantified with the redox-sensitive dye dihydroethidium. We also quantified 4-hydroxynonenal (4-HNE) levels, a stable marker of lipid peroxidation, in the aorta using ELISA. Our findings demonstrated that aged mice on a standard diet exhibited significant impairments in aortic endothelial relaxation and mitochondrial function, associated with elevated vascular oxidative stress. Remarkably, the TRF regimen led to substantial improvements in these parameters, indicating enhanced endothelial vasorelaxation, better mitochondrial function, and reduced oxidative stress in the aortas of aged mice. This investigation establishes a vital foundation, paving the way for subsequent clinical research aimed at exploring the cardiovascular protective benefits of intermittent fasting.
年龄相关性内皮功能障碍是心血管疾病发展的关键因素，至少部分源于线粒体功能障碍和随之而来的氧化应激增加。这些改变是与衰老相关的血管健康下降的核心，强调了迫切需要能够恢复内皮功能以预防心血管疾病的干预措施。饮食干预，特别是限时喂养 (TRF)，因其对线粒体的抗衰老作用而被确定，为防止与年龄相关的骨骼肌和其他器官下降提供了保护。受这些发现的启发，我们的研究旨在探讨 TRF 是否也可以对血管内皮健康产生保护作用，增强线粒体功能并减少氧化应激。为此，我们将 12 个月大的 C57BL/6 小鼠置于 TRF 饮食中，每天的食物摄入量限制在 6 小时内，持续 12 个月。为了进行比较，我们还包括了年轻小鼠组和具有无限制喂养的年龄匹配对照组。我们通过测量主动脉对乙酰胆碱诱导的血管舒张来评估 TRF 对内皮功能的影响。使用荧光呼吸计评估线粒体健康，并用氧化敏感染料二氢乙啶定量测量血管活性氧 (ROS) 产生。我们还使用 ELISA 定量测量主动脉中 4-羟基壬烯醛 (4-HNE) 水平，这是脂质过氧化的稳定标志物。我们的研究结果表明，标准饮食的老年小鼠表现出主动脉内皮松弛和线粒体功能显著受损，与血管氧化应激升高相关。值得注意的是，TRF 方案导致这些参数的显著改善，表明增强的内皮血管舒张、更好的线粒体功能和衰老小鼠主动脉中的氧化应激减少。这项研究为后续旨在探索间歇性禁食对心血管保护作用的临床研究奠定了重要基础。
