Lawton Kay A, Berger Alvin, Mitchell Matthew, Milgram K Eric, Evans Anne M, Guo Lining, Hanson Richard W, Kalhan Satish C, Ryals John A, Milburn Michael V
Metabolon, Inc, 800 Capitola Dr. Suite 1, Durham, NC 27713, USA.
Pharmacogenomics. 2008 Apr;9(4):383-97. doi: 10.2217/14622416.9.4.383.
It is well established that disease states are associated with biochemical changes (e.g., diabetes/glucose, cardiovascular disease/cholesterol), as are responses to chemical agents (e.g., medications, toxins, xenobiotics). Recently, nontargeted methods have been used to identify the small molecules (metabolites) in a biological sample to uncover many of the biochemical changes associated with a disease state or chemical response. Given that these experimental results may be influenced by the composition of the cohort, in the present study we assessed the effects of age, sex and race on the relative concentrations of small molecules (metabolites) in the blood of healthy adults.
Using gas- and liquid-chromatography in combination with mass spectrometry, a nontargeted metabolomic analysis was performed on plasma collected from an age- and sex-balanced cohort of 269 individuals.
Of the more than 300 unique compounds that were detected, significant changes in the relative concentration of more than 100 metabolites were associated with age. Many fewer differences were associated with sex and fewer still with race. Changes in protein, energy and lipid metabolism, as well as oxidative stress, were observed with increasing age. Tricarboxylic acid intermediates, creatine, essential and nonessential amino acids, urea, ornithine, polyamines and oxidative stress markers (e.g., oxoproline, hippurate) increased with age. Compounds related to lipid metabolism, including fatty acids, carnitine, beta-hydroxybutyrate and cholesterol, were lower in the blood of younger individuals. By contrast, relative concentrations of dehydroepiandrosterone-sulfate (a proposed antiaging androgen) were lowest in the oldest age group. Certain xenobiotics (e.g., caffeine) were higher in older subjects, possibly reflecting decreases in hepatic cytochrome P450 activity.
Our nontargeted analytical approach detected a large number of metabolites, including those that were found to be statistically altered with age, sex or race. Age-associated changes were more pronounced than those related to differences in sex or race in the population group we studied. Age, sex and race can be confounding factors when comparing different groups in clinical studies. Future studies to determine the influence of diet, lifestyle and medication are also warranted.
众所周知，疾病状态与生化变化相关（例如，糖尿病/葡萄糖、心血管疾病/胆固醇），对化学物质（例如，药物、毒素、外源性物质）的反应也是如此。最近，非靶向方法已被用于识别生物样本中的小分子（代谢物），以揭示许多与疾病状态或化学反应相关的生化变化。鉴于这些实验结果可能受到队列组成的影响，在本研究中，我们评估了年龄、性别和种族对健康成年人血液中小分子（代谢物）相对浓度的影响。
使用气相色谱和液相色谱结合质谱法，对从269名年龄和性别均衡的队列中收集的血浆进行非靶向代谢组学分析。
在检测到的300多种独特化合物中，100多种代谢物的相对浓度随年龄有显著变化。与性别相关的差异较少，与种族相关的差异更少。随着年龄的增长，观察到蛋白质、能量和脂质代谢以及氧化应激的变化。三羧酸中间体、肌酸、必需和非必需氨基酸、尿素、鸟氨酸、多胺和氧化应激标志物（例如，氧脯氨酸、马尿酸盐）随年龄增加。与脂质代谢相关的化合物，包括脂肪酸、肉碱、β-羟基丁酸酯和胆固醇，在年轻人血液中的含量较低。相比之下，硫酸脱氢表雄酮（一种被认为具有抗衰老作用的雄激素）的相对浓度在最年长的年龄组中最低。某些外源性物质（例如，咖啡因）在老年受试者中的含量较高，这可能反映了肝细胞色素P450活性的降低。
我们的非靶向分析方法检测到大量代谢物，包括那些在统计学上随年龄、性别或种族而改变的代谢物。在我们研究的人群组中，与年龄相关的变化比与性别或种族差异相关的变化更为明显。在临床研究中比较不同组时，年龄、性别和种族可能是混杂因素。未来也有必要开展研究以确定饮食、生活方式和药物的影响。
