Associations of four biological age markers with child development: a multi-omic analysis in the European HELIX cohort
- Imperial College London, United Kingdom
- Vytautas Magnus University, Lithuania
- Barcelona Institute of Science and Technology, Spain
- Barcelona Institute for Global Health, Spain
- University of Southern California, United States
- Norwegian Institute of Public Health, Norway
- Hasselt University, Belgium
- Université Grenoble Alpes, Inserm U1209, CNRS UMR 5309, France
- University of Crete, Greece
- Bradford Royal Infirmary, United Kingdom
Abstract
Background: While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators , to child developmental outcomes, including growth and adiposity, cognition, behaviour, lung function and onset of puberty, among European school-age children participating in the HELIX exposome cohort.
Methods: The study population included up to 1,173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma protein and urinary and serum metabolite data) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity and study centre. The clock derived markers were expressed as Δ age (i.e., predicted minus chronological age).
Results: Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r= 0.93 and r= 0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators. Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age and high family affluence with longer telomere length. Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p = 4e -3) and reduced inattentiveness (p= 4e -4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviours (p= 0.01). Shorter telomere length was also associated with poorer externalizing behaviours (p=0.03).
Conclusions: In children, as in adults, biological ageing appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological ageing. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological ageing, apparent even in children.
Funding: UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583).
Data availability
Due to data protection regulations in each participating country and participant data use agreements, human subject data used in this project cannot be freely shared. The raw data supporting the current study are available on request subject to ethical and legislative review. The "HELIX Data External Data Request Procedures" are available with the data inventory in this website: http://www.projecthelix.eu/data-inventory. The document describes who can apply to the data and how, the timings for approval and the conditions to data access and publication. Researchers who have an interest in using data from this project for reproducibility or in using data held in general in the HELIX data warehouse for research purposes can apply for access to data. Interested researchers should fill in the application protocol found in ANNEX I at https://www.projecthelix.eu/files/helix_external_data_request_procedures_final.pdf and send this protocol to helixdata@isglobal.org. The applications are received by the HELIX Coordinator, and are processed and approved by the HELIX Project Executive Committee. All code used for data analysis has been provided as supplementary material. Deidentified dataset for generation of figures 1 and 2 has been provided as a supplementary dataset.
Article and author information
Author details
Kristine Bjerve Gutzkow
Funding
UK Research and Innovation (MR/S03532X/1)
- Oliver Robinson
- Chung-Ho E Lau
European Commission (308333; 874583)
- Oliver Robinson
- Chung-Ho E Lau
- Sandra Andrusaityte
- Eva Borras
- Paula de Prado-Bert
- Lida Chatzi
- Hector C Keun
- Regina Grazuleviciene
- Kristine Bjerve Gutzkow
- Lea Maitre
- Dries S Martens
- Eduard Sabido
- Valérie Siroux
- Jose Urquiza
- Marina Vafeiadi
- John Wright
- Tim S Nawrot
- Mariona Bustamante
- Martine Vrijheid
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Prior to the start of HELIX, all six cohorts had undergone the required evaluation by national ethics committees and obtained all the required permissions for their cohort recruitment and follow-up visits. Each cohort also confirmed that relevant informed consent and approval were in place for secondary use of data from pre-existing data. The work in HELIX was covered by new ethical approvals in each country and at enrolment in the new follow-up, participants were asked to sign a new informed consent form. Additionally, the current study was approved by the Imperial College Research Ethics Committee (Reference: 19IC5567).
Reviewing Editor
- Sara Hägg, Karolinska Institutet, Sweden
Version history
- Received: November 22, 2022
- Preprint posted: January 23, 2023 (view preprint)
- Accepted: June 6, 2023
- Accepted Manuscript published: June 6, 2023 (version 1)
- Version of Record published: July 12, 2023 (version 2)
Copyright
© 2023, Robinson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Associations of four biological age markers with child development: a multi-omic analysis in the European HELIX cohort
eLife 12:e85104.
https://doi.org/10.7554/eLife.85104
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