Dreesen Oliver, Stewart Colin L
Institute of Medical Biology, 8A Biomedical Grove, #06-06 Immunos, 138648 Singapore.
Aging (Albany NY). 2011 Sep;3(9):889-95. doi: 10.18632/aging.100383.
Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner's develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely affected tissues. Defective Lamin processing, associated with DNA damage, is present in VSM from old individuals, indicating processing defects may be a factor in normal aging. Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.
哈钦森-吉尔福德早衰症（HGPS）和沃纳综合征是临床上类似于加速衰老某些方面的疾病。HGPS是由LMNA基因突变引起的，导致翻译后加工缺陷，从而引发儿童早衰。沃纳综合征由WRN解旋酶基因突变引起，导致年轻人早衰。这些疾病背后的分子机制是什么，以及这些疾病的哪些方面类似于人类生理衰老？我们所了解的大部分内容来自对患者来源的成纤维细胞的研究，这两种突变都会导致DNA损伤增加，主要是在端粒处。然而，在体内，沃纳综合征患者会出现动脉硬化以及其他病变。在HGPS患者中，包括来自HGPS患者的诱导多能干细胞，以及一些早衰症小鼠模型中，血管平滑肌（VSM）似乎是受影响最严重的组织之一。与DNA损伤相关的核纤层蛋白加工缺陷存在于老年人的VSM中，这表明加工缺陷可能是正常衰老的一个因素。由于并非所有早衰样Lmna突变都会导致DNA损伤和基因组不稳定，持续的DNA损伤，尤其是在端粒处，是否是这些病变的根本原因仍有待确定。
