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

Cristina Menni, Gabriella Kastenmüller, Ann Kristin Petersen, Jordana T. Bell, Maria Psatha, Pei Chien Tsai, Christian Gieger, Holger Schulz, Idil Erte, Sally John, M. Julia Brosnan, Scott G. Wilson, Loukia Tsaprouni, Ee Mun Lim, Bronwyn Stuckey, Panos Deloukas, Robert Mohney, Karsten Suhre, Tim D. Spector, Ana M. Valdes

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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 (R2=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.

Original languageEnglish
Article numberdyt094
Pages (from-to)1111-1119
Number of pages9
JournalInternational journal of epidemiology
Volume42
Issue number4
DOIs
Publication statusPublished - 1 Aug 2013

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Keywords

  • Ageing
  • Birthweight
  • Developmental origins of health and disease
  • Epigenetics
  • Metabolomics
  • Twin studies

ASJC Scopus subject areas

  • Epidemiology

Cite this

Menni, C., Kastenmüller, G., Petersen, A. K., Bell, J. T., Psatha, M., Tsai, P. C., Gieger, C., Schulz, H., Erte, I., John, S., Brosnan, M. J., Wilson, S. G., Tsaprouni, L., Lim, E. M., Stuckey, B., Deloukas, P., Mohney, R., Suhre, K., Spector, T. D., & Valdes, A. M. (2013). Metabolomic markers reveal novel pathways of ageing and early development in human populations. International journal of epidemiology, 42(4), 1111-1119. [dyt094]. https://doi.org/10.1093/ije/dyt094