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

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...

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Bibliographic Details
Published in:International journal of epidemiology 2013-08, Vol.42 (4), p.1111-1119
Main Authors: MENNI, Cristina, KASTENMÜLLER, Gabriella, BROSNAN, M. Julia, WILSON, Scott G, TSAPROUNI, Loukia, EE MUN LIM, STUCKEY, Bronwyn, DELOUKAS, Panos, MOHNEY, Robert, SUHRE, Karsten, SPECTOR, Tim D, VALDES, Ana M, PETERSEN, Ann Kristin, BELL, Jordana T, PSATHA, Maria, TSAI, Pei-Chien, GIEGER, Christian, SCHULZ, Holger, ERTE, Idil, JOHN, Sally
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Aging - physiology
Biological and medical sciences
Biomarkers - metabolism
Birth Weight - physiology
Bone Density - physiology
DNA Methylation - physiology
Forced Expiratory Volume - physiology
General aspects
Humans
Medical sciences
Metabolomics
Metabolomics - methods
Middle Aged
Miscellaneous
Phenotype
Public health. Hygiene
Public health. Hygiene-occupational medicine
Tryptophan - metabolism
Twins, Monozygotic
Vital Capacity - physiology
Young Adult
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Summary: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.
ISSN:0300-5771
1464-3685
DOI:10.1093/ije/dyt094