Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.
Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.
复制标题
早产儿：导致哈钦森-吉尔福德早衰症和沃纳综合征的分子改变。
DOI：
10.2174/1874609810801030202
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发表时间：
2008
影响因子：
--
通讯作者：
D. Araújo
中科院分区：
文献类型：
--
作者：
L. Domínguez‐Gerpe;D. Araújo
衰老被认为是一个多基因和随机的过程，其中多种机制同时起作用。在个体有机体水平上，衰老与健康和生活质量的逐渐恶化有关，具有共同的特征，例如：脱发和白发、听力丧失、黄斑变性、神经变性、心血管疾病、骨质疏松症、白内障形成、2型糖尿病、脂肪营养不良；对感染、自身免疫性疾病和癌症等疾病的易感性普遍增加；以及应对压力的能力受损。最近对衰老过程机制的研究有助于识别与长寿相关的基因。导致过早衰老的单基因遗传性疾病和动物模型有助于理解与人类衰老相关的一些有机体水平特征。维尔纳综合征和哈钦森-吉尔福德早衰综合征是最具特征的人类疾病。沃纳综合征患者的中位预期寿命为 47 岁，临床症状从二十多岁开始出现。 Hutchinson-Gilford 早衰综合症患者的平均死亡年龄为 11-13 岁，出生后不久就会出现临床症状。在这两种综合征中，已经确定了特定基因的改变，其中 WRN 和 LMNA 基因的突变分别与每种综合征最密切相关。分子研究结果强烈表明，DNA 损伤和细胞衰老的增加是这两种人类综合征病理性过早衰老的根本机制。在经历正常衰老过程的人体细胞中也观察到了相同的一般机制。在本文中，回顾了目前提出的用于解释这两种综合征的分子机制，这也可能部分解释正常的衰老过程。
Ageing is thought to be a polygenic and stochastic process in which multiple mechanisms operate at the same time. At the level of the individual organism ageing is associated with a progressive deterioration of health and quality of life, sharing common features such as: alopecia and grey hair, loss of audition, macular degeneration, neurodegeneration, cardiovascular diseases, osteoporosis, cataract formation, type-2 diabetes, lipodystrophies; a generally increased susceptibility to infection, autoimmune disorders and diseases such as cancer; and an impaired ability to cope with stress. Recent studies of mechanisms involved in the ageing process are contributing to the identification of genes involved in longevity. Monogenic heritable disorders causing premature ageing, and animal models have contributed to the understanding of some of the characteristic organism-level features associated with human ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are the best characterized human disorders. Werner syndrome patients have a median life expectancy of 47 years with clinical conditions from the second decade of life. Hutchinson-Gilford progeria syndrome patients die at a median age of 11-13 years with clinical conditions appearing soon after birth. In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome. Results from molecular studies strongly suggest an increase in DNA damage and cell senescence as the underlying mechanism of pathological premature ageing in these two human syndromes. The same general mechanism has also been observed in human cells undergoing the normal ageing process. In the present article the molecular mechanisms currently proposed for explaining these two syndromes, which may also partly explain the normal ageing process, are reviewed.