Rationale: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. Objective: To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. Methods and Results: We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Conclusions: Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.

中文翻译：

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与年龄相关的线粒体功能障碍加速动脉粥样硬化形成。

理由：衰老是动脉粥样硬化的最强危险因素之一。然而，衰老是否会独立于慢性高脂血症而增加动脉粥样硬化的风险尚不清楚。目的：确定诱导高脂血症前的血管老化是否会促进动脉粥样硬化形成。方法和结果：我们分析了年轻和年老的血脂正常的野生型无病小鼠的主动脉，发现衰老导致 IL（白细胞介素）-6 水平升高和线粒体功能障碍，与线粒体自噬和相关蛋白 Parkin 增加有关。在主动脉组织培养中，我们发现有证据表明，随着年龄的增长，线粒体功能障碍和 IL-6 存在正反馈回路。我们通过诱导 LDL（低密度脂蛋白）受体的肝脏特异性降解并结合 10 周的西方饮食，在老年和年轻小鼠中引发急性高脂血症，并发现老年野生型小鼠的动脉粥样硬化形成增强。高脂血症进一步降低了线粒体功能，并增加了老年小鼠主动脉中帕金蛋白的水平，但对年轻小鼠没有影响。暴露于高脂血症的年轻小鼠平滑肌细胞自噬的遗传破坏导致主动脉帕金蛋白和 IL-6 水平升高、线粒体功能受损和动脉粥样硬化形成增强。重要的是，通过口服亚精胺增强老年高脂血症小鼠的线粒体自噬可防止主动脉 IL-6 和 Parkin 的增加，减轻线粒体功能障碍，并减少动脉粥样硬化形成。结论：高脂血症前，衰老会升高 IL-6 并损害主动脉内的线粒体功能，这与线粒体自噬增强和 Parkin 水平升高有关。这些与年龄相关的变化使脉管系统在急性高脂血症时加剧动脉粥样硬化形成。我们的工作表明，旨在改善血管线粒体生物能量学或在高脂血症发生前减少炎症的新型疗法可能会减少与年龄相关的动脉粥样硬化。