Randerath K, Hart R W, Zhou G D, Reddy R, Danna T F, Randerath E
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Mutat Res. 1993 Jan;295(1):31-46. doi: 10.1016/0921-8734(93)90009-r.
Caloric restriction (CR), known to extend median and maximum life spans, improve resistance to carcinogenesis, and significantly retard age-associated degenerative diseases in rodents, was previously reported to modulate levels of indigenous, age-dependent DNA modifications, called I-compounds, in male Brown-Norway (B-N) rats. Since profiles of these adduct-like derivatives are species-, strain-, sex-, and tissue-specific, we explored this apparent CR/I-compound relationship in a comparative study between male B-N and male Fischer 344 (F-344) rats, the latter having a shorter life expectancy and high incidence of renal disease. Control animals were fed NIH-31 diet ad libitum (AL), while the caloric intake of CR animals was limited to 60% of AL, starting at 3.5 months. Liver and kidney DNA from 1, 8, 12, 16, 24 (AL, CR), and 30 (CR only) month old rats was analyzed by 32P-postlabeling. Corresponding tissues from the two strains yielded similar DNA profiles. Total liver I-compound levels displayed 2.3-4.6-fold age-dependent increases from 1 to 24 months, and kidney values at 24 months were 5.2-8 times higher than those at 1 month. In both strains, I-compound levels of CR animals were higher, up to 2-fold, than in age-matched AL rats. Regression analyses indicated linear relationships between most CR relative adduct labeling values (both total and individual fractions) and age, whereas many AL values exhibited this type of link with log age. These findings confirm that a correlation exists between CR and I-compound levels, and, given the above physiological benefits of CR, indicate that I-compounds represent biomarkers of aging with potential utility in intervention studies.
热量限制（CR）已知可延长平均寿命和最大寿命，提高对致癌作用的抵抗力，并显著延缓啮齿动物与年龄相关的退行性疾病，此前有报道称其可调节雄性棕色挪威（B-N）大鼠体内称为I-化合物的内源性、年龄依赖性DNA修饰水平。由于这些加合物样衍生物的谱型具有物种、品系、性别和组织特异性，我们在雄性B-N大鼠和雄性费希尔344（F-344）大鼠的比较研究中探讨了这种明显的CR/I-化合物关系，后者预期寿命较短且肾病发病率较高。对照动物自由采食NIH-31饮食（AL），而CR动物的热量摄入从3.5个月开始限制在AL的60%。对1、8、12、16、24（AL、CR）和30（仅CR）月龄大鼠的肝脏和肾脏DNA进行32P后标记分析。两个品系相应组织的DNA谱相似。从1个月到24个月，肝脏I-化合物总水平显示出2.3至4.6倍的年龄依赖性增加，24个月时肾脏的值比1个月时高5.2至8倍。在两个品系中，CR动物的I-化合物水平均高于年龄匹配的AL大鼠，最高可达2倍。回归分析表明，大多数CR相对加合物标记值（总和各部分）与年龄之间存在线性关系，而许多AL值与对数年龄呈现这种类型的关联。这些发现证实了CR与I-化合物水平之间存在相关性，并且鉴于CR的上述生理益处，表明I-化合物代表衰老的生物标志物，在干预研究中具有潜在用途。
