The Center of Human Development and Aging, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103-2714, USA.
Annu Rev Med. 2012;63:293-301. doi: 10.1146/annurev-med-050311-104846. Epub 2011 Oct 17.
The model we propose to explain the links between atherosclerosis and telomere dynamics (birth telomere length and its age-dependent shortening) in leukocytes takes cues from three facts: atherosclerosis is a disease of the vascular endothelium; the hematopoietic system and the vascular endothelium share a common embryonic origin; interindividual variation in leukocyte telomere length (LTL) in the general population has a genetic explanation. The model posits that LTL dynamics mirror telomere dynamics in hematopoietic stem cells (HSCs), where telomere length is an index of HSC reserves. Diminished HSC reserves at birth, their accelerated attrition rate afterward, or both are are reflected in shortened LTL during adulthood-a phenomenon that confers increased risk for atherosclerosis. We explain how telomere length in HSCs serves as both a biomarker of atherosclerosis and a determinant of its development. Our model comes down to this proposition: Shortened LTL predicts increased atherosclerotic risk because the injurious component of atherosclerosis exceeds the repair capacity of HSC reserves, which largely depend on HSC telomere length.
我们提出的解释动脉粥样硬化与白细胞端粒动力学（出生端粒长度及其随年龄缩短）之间联系的模型，受到三个事实的启发：动脉粥样硬化是血管内皮的一种疾病；造血系统和血管内皮具有共同的胚胎起源；白细胞端粒长度（LTL）在普通人群中的个体间差异具有遗传解释。该模型假设 LTL 动力学反映了造血干细胞（HSCs）中的端粒动力学，端粒长度是 HSC 储备的指标。出生时 HSC 储备减少，随后其损耗速度加快，或两者兼而有之，都会导致成年期 LTL 缩短——这一现象增加了动脉粥样硬化的风险。我们解释了 HSCs 中的端粒长度如何既是动脉粥样硬化的生物标志物，也是其发展的决定因素。我们的模型归结为这样一个命题：缩短的 LTL 预示着动脉粥样硬化风险增加，因为动脉粥样硬化的损伤成分超过了 HSC 储备的修复能力，而 HSC 储备在很大程度上取决于 HSC 端粒长度。
