A mouse model of accelerated liver aging caused by a defect in DNA repair.
A mouse model of accelerated liver aging caused by a defect in DNA repair.
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DOI：
10.1002/hep.24713
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Niedernhofer LJ
中科院分区：
文献类型：
--
作者：
Gregg SQ;Gutiérrez V;Robinson AR;Woodell T;Nakao A;Ross MA;Michalopoulos GK;Rigatti L;Rothermel CE;Kamileri I;Garinis GA;Stolz DB;Niedernhofer LJ
肝脏随着年龄的增长而变化，导致老年人对肝脏损伤的反应能力受损，并增加肝脏疾病的发病率。因此，迫切需要快速模型系统来研究与衰老相关的肝脏变化。一个潜在的机会是人类早衰症或加速衰老疾病的小鼠模型。Ercc 1 −/Δ小鼠模型是一种罕见的人类早衰综合征，由DNA修复的遗传缺陷引起。为了确定Ercc 1 −/Δ小鼠是否过早发生正常衰老时发生的肝脏变化，我们系统地比较了5个月大的早衰Ercc 1 −/Δ小鼠与老年（24-36个月）野生型（WT）小鼠的肝脏。两者均显示坏死区域、肝细胞变性灶和急性炎症。Ercc 1 −/Δ小鼠的肝结构丧失、纤维化、脂肪变性、假毛细血管化和异核现象比老年WT小鼠更为显著。Ercc 1 −/Δ小鼠和老年WT小鼠血清中的肝酶显著升高，而白蛋白降低，表明肝损伤和功能障碍。部分肝切除术后Ercc 1 −/Δ肝脏的再生能力显著降低。有证据表明Ercc 1 −/Δ和老年WT肝脏中的氧化损伤增加，包括脂褐质、脂质氢过氧化物和丙烯醛以及肝细胞衰老增加。老年WT和16周龄但不是5周龄Ercc 1 −/Δ小鼠之间的全基因组转录变化具有高度显著的相关性，强调Ercc 1 −/Δ小鼠在成年早期获得衰老特征。在DNA修复缺陷驱动的加速衰老和正常衰老之间存在很强的功能、调节和组织病理学相似性。这支持了DNA损伤在驱动衰老中的作用，并验证了用于快速测试关于衰老相关肝脏变化的原因和治疗的假设的小鼠模型。
The liver changes with age leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging-related liver changes. One potential opportunity is murine models of human progerias, or diseases of accelerated aging. Ercc1−/Δ mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine if hepatic changes that occur with normal aging occur prematurely in Ercc1−/Δ mice, we systematically compared liver from 5 month-old, progeroid Ercc1−/Δ mice to old (24–36 month) wild-type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in Ercc1−/Δ mice than in old WT mice. Liver enzymes were significantly elevated in serum of Ercc1−/Δ mice and old WT mice, while albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of Ercc1−/Δ liver following partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in Ercc1−/Δ and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein as well as increased hepatocellular senescence. There was a highly significant correlation in genome-wide transcriptional changes between old WT and 16 but not 5 week-old Ercc1−/Δ mice emphasizing that the Ercc1−/Δ mice acquire an aging profile in early adulthood. There are strong functional, regulatory and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging-related hepatic changes.
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DOI：
10.1093/gerona/glq184
发表时间：
2011-03-01
影响因子：
5.1
作者：
Labbe, Adam;Garand, Chantal;Lebel, Michel
通讯作者：
Lebel, Michel
影响因子：
12.7
作者：
de Waard MC;van der Pluijm I;Zuiderveen Borgesius N;Comley LH;Haasdijk ED;Rijksen Y;Ridwan Y;Zondag G;Hoeijmakers JH;Elgersma Y;Gillingwater TH;Jaarsma D
通讯作者：
Jaarsma D
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
DOI：
10.3402/pba.v1i0.7219
发表时间：
2011-01-01
期刊：
PATHOBIOLOGY OF AGING AND AGE-RELATED DISEASES
影响因子：
--
作者：
Dolle, Martijn E. T.;Kuiper, Raoul V.;van Steeg, Harry
通讯作者：
van Steeg, Harry