title: Metabolomic markers reveal novel pathways of ageing and early development in human populations.
abstract: BACKGROUND
  Human ageing is a complex, multifactorial process and early developmental factors affect health outcomes in old age.
  
  
  METHODS
  Metabolomic profiling on fasting blood was carried out in 6055 individuals from the UK. Stepwise regression was performed to identify a panel of independent metabolites which could be used as a surrogate for age. We also investigated the association with birthweight overall and within identical discordant twins and with genome-wide methylation levels.
  
  
  RESULTS
  We identified a panel of 22 metabolites which combined are strongly correlated with age (R(2) = 59%) and with age-related clinical traits independently of age. One particular metabolite, C-glycosyl tryptophan (C-glyTrp), correlated strongly with age (beta = 0.03, SE = 0.001, P = 7.0 × 10(-157)) and lung function (FEV1 beta = -0.04, SE = 0.008, P = 1.8 × 10(-8) adjusted for age and confounders) and was replicated in an independent population (n = 887). C-glyTrp was also associated with bone mineral density (beta = -0.01, SE = 0.002, P = 1.9 × 10(-6)) and birthweight (beta = -0.06, SE = 0.01, P = 2.5 × 10(-9)). The difference in C-glyTrp levels explained 9.4% of the variance in the difference in birthweight between monozygotic twins. An epigenome-wide association study in 172 individuals identified three CpG-sites, associated with levels of C-glyTrp (P < 2 × 10(-6)). We replicated one CpG site in the promoter of the WDR85 gene in an independent sample of 350 individuals (beta = -0.20, SE = 0.04, P = 2.9 × 10(-8)). WDR85 is a regulator of translation elongation factor 2, essential for protein synthesis in eukaryotes.
  
  
  CONCLUSIONS
  Our data illustrate how metabolomic profiling linked with epigenetic studies can identify some key molecular mechanisms potentially determined in early development that produce long-term physiological changes influencing human health and ageing.
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK, Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany, Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany, Institute of Epidemiology I, Helmholtz Zentrum München, Neuherberg, Germany, Pfizer Research Laboratories, Groton, CT, USA, Worldwide R&D, Pfizer Inc., Cambridge, MA, USA, School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK, Metabolon Inc., 617 Davis Drive, Durham, NC 27713, USA; Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, State of Qatar and Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.forename: Gabriella
authors.initials: G
authors.lastname: Kastenmüller
authors.forename: Ann Kristin
authors.initials: AK
authors.lastname: Petersen
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.forename: Maria
authors.initials: M
authors.lastname: Psatha
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.forename: Idil
authors.initials: I
authors.lastname: Erte
authors.forename: Sally
authors.initials: S
authors.lastname: John
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Loukia
authors.initials: L
authors.lastname: Tsaprouni
authors.forename: Ee Mun
authors.initials: EM
authors.lastname: Lim
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Stuckey
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Robert
authors.initials: R
authors.lastname: Mohney
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism*; D001724:Birth Weight / Q000502:physiology; D015519:Bone Density / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology; D005541:Forced Expiratory Volume / Q000502:physiology; D006801:Humans; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D010641:Phenotype; D014364:Tryptophan / Q000378:metabolism; D014430:Twins, Monozygotic; D014797:Vital Capacity / Q000502:physiology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D014364:Tryptophan
keywords: Ageing; birthweight; developmental origins of health and disease; epigenetics; metabolomics; twin studies