McKiernan Susan H, Tuen Victoria C, Baldwin Katherine, Wanagat Jonathan, Djamali Arjang, Aiken Judd M
Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison, WI 53706, USA.
Am J Physiol Renal Physiol. 2007 Jun;292(6):F1751-60. doi: 10.1152/ajprenal.00307.2006. Epub 2007 Mar 6.
Adult-onset calorie restriction (A-CR) is an experimental model of life extension and healthy aging less explored, compared with calorie restriction begun at early ages, but one more realistic for human application. We examined the effect of A-CR on the aging rat kidney with respect to common structural age-dependent changes and the accumulation of mitochondrial enzyme abnormalities in tubular epithelial cells. A 40% calorie restriction was initiated in middle-aged rats, before the onset of significant age-related changes in the Fischer x Brown Norway rat kidney. This dietary intervention effectively reduced glomerulosclerosis and tubular atrophy within 6 mo and changed the rate of interstitial fibrosis formation within 1 yr and vascular wall thickening and the expression cytochrome c oxidase (COX)-deficient tubular epithelial cells in 18 mo compared with age-matched ad libitum-fed rats. Our histological approach (histochemical staining for mitochondrial enzyme activity and laser capture microdissection) coupled with mitochondrial DNA (mtDNA) PCR analyses demonstrated that COX-deficient renal tubular epithelial cells accumulated mtDNA deletion mutations and that these cells contained unique, clonally expanded mtDNA deletion mutations. Renal tubular epithelial cells with mitochondrial abnormalities presented cellular characteristics indicative of physiological dysfunction.
与幼年开始的热量限制相比，成年期开始的热量限制（A-CR）是一种较少被探索的寿命延长和健康衰老的实验模型，但对人类应用而言更具现实意义。我们研究了A-CR对衰老大鼠肾脏的影响，涉及常见的与年龄相关的结构变化以及肾小管上皮细胞中线粒体酶异常的积累。在中年大鼠中开始40%的热量限制，此时Fischer×Brown Norway大鼠肾脏尚未出现明显的与年龄相关的变化。与年龄匹配的自由进食大鼠相比，这种饮食干预在6个月内有效减轻了肾小球硬化和肾小管萎缩，并在1年内改变了间质纤维化形成的速率，在18个月时改变了血管壁增厚以及细胞色素c氧化酶（COX）缺陷的肾小管上皮细胞的表达。我们的组织学方法（线粒体酶活性的组织化学染色和激光捕获显微切割）结合线粒体DNA（mtDNA）PCR分析表明，COX缺陷的肾小管上皮细胞积累了mtDNA缺失突变，并且这些细胞含有独特的、克隆性扩增的mtDNA缺失突变。具有线粒体异常的肾小管上皮细胞呈现出指示生理功能障碍的细胞特征。
