title: Analysis of the adult human plasma metabolome.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Metabolon, Inc, 800 Capitola Dr. Suite 1, Durham, NC 27713, USA.
authors.forename: Kay A
authors.initials: KA
authors.lastname: Lawton
authors.forename: Alvin
authors.initials: A
authors.lastname: Berger
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitchell
authors.forename: K Eric
authors.initials: KE
authors.lastname: Milgram
authors.forename: Anne M
authors.initials: AM
authors.lastname: Evans
authors.forename: Lining
authors.initials: L
authors.lastname: Guo
authors.forename: Richard W
authors.initials: RW
authors.lastname: Hanson
authors.forename: Satish C
authors.initials: SC
authors.lastname: Kalhan
authors.forename: John A
authors.initials: JA
authors.lastname: Ryals
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008660:Metabolism / Q000502:physiology*; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry / Q000378:metabolism*