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Int J Epidemiol. 2013 Aug;42(4):1111-9. doi: 10.1093/ije/dyt094. Epub 2013 Jul 8.

Metabolomic markers reveal novel pathways of ageing and early development in human populations.

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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.



Human ageing is a complex, multifactorial process and early developmental factors affect health outcomes in old age.


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.


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.


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.


Ageing; birthweight; developmental origins of health and disease; epigenetics; metabolomics; twin studies

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