So! What's aging? Is cardiovascular aging a disease?
So! What's aging? Is cardiovascular aging a disease?
复制标题
DOI：
10.1016/j.yjmcc.2015.04.005
复制
发表时间：
2015-06
影响因子：
5
通讯作者：
Lakatta EG
中科院分区：
文献类型：
--
作者：
Lakatta EG
“每个老人的内心都有一个年轻人，想知道发生了什么。”那么，什么是老化？衰老是分子机制的渐进性、时间依赖性失效的表现，这些分子机制在DNA及其环境（细胞核、细胞溶质、组织、器官、生物体、其他生物体、社会、陆地、大气、宇宙）的系统内产生紊乱。在这些环境中以不同的动力学传递的连续信号赋予了一种“相互奴役”，在系统内的组件之间创建有序的功能。随着时间的推移，即在衰老过程中，这种分子障碍的累积引起心脏和动脉的结构和功能的进行性变化，这在人类、非人灵长类动物、兔和大鼠中非常相似，损害心血管储备功能，并赋予突发心血管疾病的显著风险。随着年龄的增长，心脏和动脉内DNA环境系统中几乎所有方面的信号都变得紊乱：信号发生变化，信号的感知，信号的传递和对信号的反应，受损的细胞更新，由于基因组转录，mRNA翻译和蛋白质稳定的改变而引起的蛋白质组变化。一些分子的密度降低，翻译后修饰，例如氧化和硝化磷酸化，导致错误折叠改变和分子相互作用紊乱。酶的化学计量和动力学以及那些构成关键的心脏和血管细胞功能和去除受损细胞器和蛋白质的强大储备机制基础的反应恶化。CV细胞产生炎症防御，试图限制分子紊乱。然而，所产生的促炎环境不是由“专职”炎性细胞（即白色血细胞）执行的，而是通过激活导致内皮和血管平滑肌以及心脏细胞的表型转变的肾素-血管紧张素-醛固酮内皮素信号级联，从而导致炎性细胞因子的产生。随着时间的推移，心脏和动脉内的进行性分子紊乱导致CV系统上的过度非稳态负荷，这导致炎症防御信号传导的增加和“过冲”。这种与年龄相关的分子紊乱诱导的炎症在心脏和动脉中累积，本身不会引起CVD的临床体征或症状。然而，当心脏和动脉中与年龄相关的炎症超过阈值时，这些心血管疾病的临床体征和症状开始出现。因此，一种新兴的思想流派认为，心脏和动脉内与年龄相关的加速变化本身应该被认为是一种CVD，因为随着年龄的增长，心脏和动脉内产生的分子紊乱和炎症环境是大多数心血管疾病（例如动脉粥样硬化和高血压）的病理生理学根源。由于衰老对心血管系统的许多影响可以通过改变生活方式（如饮食和运动）或通过目前可用的药物（如抑制血管紧张素II信号传导的药物）来延迟或减弱，因此心血管衰老是预防心脏病学中一个有前途的前沿领域，不仅成熟，而且迫切需要关注！将心血管衰老作为一种疾病的概念纳入临床医学是一个紧迫的问题。但是，可悲的是，心脏和动脉内与年龄相关的分子紊乱的现实在很大程度上被排除在主流临床医学之外。这篇文章是题为CV老化的特刊的一部分。
“Inside every old person is a young person wondering what happened.” So, what is aging? Aging is a manifestation of progressive, time-dependent failure of molecular mechanisms that create disorder within a system of DNA and its environment (nuclear, cytosolic, tissue, organ, organism, other organisms, society, terra firma, atmosphere, universe). Continuous signaling, transmitted with different kinetics across each of these environments, confers a “mutual enslavement” that creates ordered functions among the components within the system. Accrual of this molecular disorder over time, i.e. during aging, causes progressive changes in the structure and function of the heart and arteries that are quite similar in humans, non-human primates, rabbits and rats that compromise cardiovascular reserve function, and confer a marked risk for incident cardiovascular disease. Nearly all aspects of signaling within the DNA environment system within the heart and arteries become disordered with advancing age: Signals change, as does sensing of the signals, transmission of signals and responses to signals, impaired cell renewal, changes in the proteome due to alterations in genomic transcription, mRNA translation, and proteostasis. The density of some molecules becomes reduced, and post-translational modifications, e.g. oxidation and nitration phosphorylation, lead to altered misfolding and disordered molecular interactions. The stoichiometry and kinetics of enzymatic and those reactions which underlie crucial cardiac and vascular cell functions and robust reserve mechanisms that remove damaged organelles and proteins deteriorate. The CV cells generate an inflammatory defense in an attempt to limit the molecular disorder. The resultant proinflammatory milieu is not executed by “professional” inflammatory cells (i.e. white blood cells), however, but by activation of renin–angiotensin–aldosterone endothelin signaling cascades that leads to endothelial and vascular smooth muscle and cardiac cells' phenotype shifts, resulting in production of inflammatory cytokines. Progressive molecular disorder within the heart and arteries over time leads to an excessive allostatic load on the CV system, that results in an increase and “overshoot” in the inflammatory defense signaling. This age-associated molecular disorder-induced inflammation that accrues in the heart and arteries does not, itself, cause clinical signs or symptoms of CVD. Clinical signs and symptoms of these CVDs begin to emerge, however, when the age-associated inflammation in the heart and arteries exceeds a threshold. Thus, an emerging school of thought is that accelerated age-associated alterations within the heart and arteries, per se, ought to be considered to be a type of CVD, because the molecular disorder and the inflammatory milieu it creates within the heart and arteries with advancing age are the roots of the pathophysiology of most cardiovascular diseases, e.g. athersclerosis and hypertension. Because many effects of aging on the CV system can be delayed or attenuated by changes in lifestyle, e.g. diet and exercise, or by presently available drugs, e.g. those that suppress Ang II signaling, CV aging is a promising frontier in preventive cardiology that is not only ripe for, but also in dire need of attention! There is an urgency to incorporate the concept of cardiovascular aging as a disease into clinical medicine. But, sadly, the reality of the age-associated molecular disorder within the heart and ateries has, for the most part, been kept outside of mainstream clinical medicine. This article is part of a Special Issue entitled CV Aging.