Role of cellular senescence in cardiovascular aging

项目摘要/摘要 衰老是心血管疾病(CVD)的主要危险因素。随年龄增长而增加的心血管疾病风险是中介因素 主要由动脉功能障碍引起，包括血管内皮细胞受损和大弹性增加 动脉(例如，大动脉)变硬。这些血管功能的改变在很大程度上是由于过多的活性氧造成的。 降低血管扩张分子一氧化氮(NO)的生物利用度，并诱导 动脉的结构性变化。然而，调控这些过程的上游事件并不完全 明白了。一种被认为是年龄相关性动脉功能障碍的机制是细胞衰老，这在很大程度上是 导致促炎分子分泌的永久性细胞周期停滞，统称为 作为衰老相关分泌表型(SASP)。事实上，细胞衰老有助于 血管老化，因此代表了一个新的治疗目标，以降低心血管疾病的风险与老龄化。 我们已经证明，在老年动物中，基于遗传和药物的衰老细胞清除(衰老分解) 改善动脉功能；然而，研究的感觉神经溶解疗法对数据的翻译潜力受到阻碍 通过它们对非衰老细胞的毒性和/或不利的安全性特征。因此，它是生物医学上的 与开发新型和安全的感光剂有关。天然的食源性化合物代表着非常有前途的 实现这一目标的方法。鱼腥草素是一种黄酮类化合物，具有促衰老作用，在多种植物中均有发现。 黄瓜和草莓等常用食物。由于食物中的含量不同， 富含鱼腥草素的饮食是不可行的；然而，鱼腥草素可以作为一种安全的饮食补充剂。 人类的个人资料。此外，短期(1-2个月)、大剂量间歇给药 这种方式正在成为一种很有前途的、非药物的、老年治疗的策略。因此，Fisetin是一种 优秀的临床翻译候选人。 通过NIH膳食补充剂办公室，这一行政补充的目的是 食源性降钙素治疗老年性动脉功能不全的疗效观察 并将感觉化作用确立为其有益效果的主要机制。本研究 代表着这种膳食补充剂最终临床翻译到人类身上的关键一步。 假设1：口服非瑟丁可以改善老龄小鼠的动脉功能。改进之处 将类似于在体内观察到的衰老细胞的遗传清除。 假设2：非瑟素对动脉功能的改善将由细胞衰老的减少推动。 假设3：循环环境中与非瑟素相关的改变/SASP将改善内皮细胞 功能，这些作用将通过减少细胞衰老来调节。

PROJECT SUMMARY/ABSTRACT Aging is the primary risk factor for cardiovascular diseases (CVD). Increased CVD risk with aging is mediated primarily by arterial dysfunction, including impaired vascular endothelial and increased large elastic artery (e.g., aorta) stiffening. These changes in vascular function are largely due to excess reactive oxygen species (ROS), which reduces the bioavailability of the vasodilatory molecule nitric oxide (NO) and induces structural changes in arteries. However, the upstream events regulating these processes are incompletely understood. A mechanism thought to underly age-related arterial dysfunction is cellular senescence, a largely permanent cell cycle arrest which leads to the secretion of pro-inflammatory molecules, collectively referred to as the senescence-associated secretory phenotype (SASP). Indeed, cellular senescence contributes to vascular aging and therefore represents a novel therapeutic target for reducing the risk of CVD with aging. We have shown that genetic- and pharmacological-based senescent cell clearance (senolysis) in aged animals improves arterial function; however, the translational potential of senolytic therapies studied to data is hindered by their toxicity to non-senescent cells and/or unfavorable safety profiles. Therefore, it is biomedically relevant to develop novel and safe senolytics. Natural, food-derived compounds represent highly promising approaches to accomplish this goal. Fisetin is a flavonoid with proposed senolytic properties found in a variety of commonly consumed foods such as cucumbers and strawberries. Due to the content variations in food, fisetin-rich diets are not feasible; however, fisetin is available as a dietary supplement with a favorable safety profile in humans. Moreover, short-term (1-2 months), high dose fisetin administration in an intermittent manner is emerging as a promising, non-pharmacological, senotherapeutic strategy. As such, fisetin is an excellent candidate for clinical translation. The purpose of this administrative supplement, through the NIH Office of Dietary Supplements, is to determine the efficacy of the food-derived senolytic fisetin for treating age-related arterial dysfunction in old mice and to establish senolysis as the primary mechanism underlying the beneficial effects. This study represents a critical step for the eventual clinical translation of this dietary supplement to humans. Hypothesis 1: Oral supplementation with fisetin will improve arterial function in old mice. The improvements will be similar to those observed with in vivo genetic clearance of senescent cells. Hypothesis 2: Improvements in arterial function with fisetin will be driven by reductions in cellular senescence. Hypothesis 3: Fisetin-associated alterations in the circulating milieu/the SASP will improve endothelial cell function and these effects will be mediated via reductions in cellular senescence.