Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK.
J Proteome Res. 2013 Jul 5;12(7):3117-27. doi: 10.1021/pr301097k. Epub 2013 Jun 25.
Modeling aging and age-related pathologies presents a substantial analytical challenge given the complexity of gene-environment influences and interactions operating on an individual. A top-down systems approach is used to model the effects of lifelong caloric restriction, which is known to extend life span in several animal models. The metabolic phenotypes of caloric-restricted (CR; n = 24) and pair-housed control-fed (CF; n = 24) Labrador Retriever dogs were investigated by use of orthogonal projection to latent structures discriminant analysis (OPLS-DA) to model both generic and age-specific responses to caloric restriction from the ¹H NMR blood serum profiles of young and older dogs. Three aging metabolic phenotypes were resolved: (i) an aging metabolic phenotype independent of diet, characterized by high levels of glutamine, creatinine, methylamine, dimethylamine, trimethylamine N-oxide, and glycerophosphocholine and decreasing levels of glycine, aspartate, creatine and citrate indicative of metabolic changes associated largely with muscle mass; (ii) an aging metabolic phenotype specific to CR dogs that consisted of relatively lower levels of glucose, acetate, choline, and tyrosine and relatively higher serum levels of phosphocholine with increased age in the CR population; (iii) an aging metabolic phenotype specific to CF dogs including lower levels of liproprotein fatty acyl groups and allantoin and relatively higher levels of formate with increased age in the CF population. There was no diet metabotype that consistently differentiated the CF and CR dogs irrespective of age. Glucose consistently discriminated between feeding regimes in dogs (≥312 weeks), being relatively lower in the CR group. However, it was observed that creatine and amino acids (valine, leucine, isoleucine, lysine, and phenylalanine) were lower in the CR dogs (<312 weeks), suggestive of differences in energy source utilization. ¹H NMR spectroscopic analysis of longitudinal serum profiles enabled an unbiased evaluation of the metabolic markers modulated by a lifetime of caloric restriction and showed differences in the metabolic phenotype of aging due to caloric restriction, which contributes to longevity studies in caloric-restricted animals. Furthermore, OPLS-DA provided a framework such that significant metabolites relating to life extension could be differentiated and integrated with aging processes.
鉴于基因-环境影响和相互作用在个体上的复杂性，对衰老和与年龄相关的病变进行建模是一项重大的分析挑战。采用自上而下的系统方法来模拟终生热量限制的影响，已知这种方法可以延长几种动物模型的寿命。通过正交投影到潜在结构判别分析（OPLS-DA）对热量限制的通用和年龄特异性反应进行建模，研究了热量限制（CR；n=24）和配对饲养对照喂养（CF；n=24）拉布拉多猎犬的代谢表型，以研究年轻和老年犬的 ¹H NMR 血清谱。确定了三种衰老代谢表型：（i）与饮食无关的衰老代谢表型，其特征是高水平的谷氨酰胺、肌酸、甲胺、二甲胺、三甲胺 N-氧化物和甘油磷酸胆碱，以及甘氨酸、天冬氨酸、肌酸和柠檬酸水平降低，表明与肌肉质量相关的代谢变化；（ii）CR 犬特有的衰老代谢表型，包括 CR 人群中随年龄增长葡萄糖、乙酸盐、胆碱和酪氨酸相对较低，而磷酸胆碱血清水平相对较高；（iii）CF 犬特有的衰老代谢表型，包括 CF 人群中随年龄增长脂蛋白脂肪酸基团和尿囊素水平降低，而甲酸盐水平相对较高。无论年龄大小，没有一种饮食代谢类型能始终区分 CF 和 CR 犬。葡萄糖在狗（≥312 周）的喂养方式中始终具有区分能力，在 CR 组中相对较低。然而，观察到 CR 犬的肌酸和氨基酸（缬氨酸、亮氨酸、异亮氨酸、赖氨酸和苯丙氨酸）水平较低，提示能量来源利用的差异。对纵向血清谱的 ¹H NMR 光谱分析能够对终生热量限制调节的代谢标志物进行无偏评估，并显示由于热量限制导致衰老代谢表型的差异，这有助于热量限制动物的长寿研究。此外，OPLS-DA 提供了一个框架，可以区分与寿命延长相关的重要代谢物，并将其与衰老过程相结合。
