Long-term impact of paediatric critical illness on the difference between epigenetic and chronological age in relation to physical growth

Ines Verlinden, Grégoire Coppens, Ilse Vanhorebeek, Fabian Güiza, Inge Derese, Pieter J. Wouters, Koen F. Joosten, Sascha C. Verbruggen, Greet Van den Berghe*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: Altered DNA-methylation affects biological ageing in adults and developmental processes in children. DNA-methylation is altered by environmental factors, trauma and illnesses. We hypothesised that paediatric critical illness, and the nutritional management in the paediatric intensive care unit (PICU), affects DNA-methylation changes that underly the developmental processes of childhood ageing. Results: We studied the impact of critical illness, and of the early use of parenteral nutrition (early-PN) versus late-PN, on “epigenetic age-deviation” in buccal mucosa of 818 former PICU-patients (406 early-PN, 412 late-PN) who participated in the 2-year follow-up of the multicentre PEPaNIC-RCT (ClinicalTrials.gov-NCT01536275), as compared with 392 matched healthy children, and assessed whether this relates to their impaired growth. The epigenetic age-deviation (difference between PedBE clock-estimated epigenetic age and chronological age) was calculated. Using bootstrapped multivariable linear regression models, we assessed the impact hereon of critical illness, and of early-PN versus late-PN. As compared with healthy children, epigenetic age of patients assessed 2 years after PICU-admission deviated negatively from chronological age (p < 0.05 in 51% of bootstrapped replicates), similarly in early-PN and late-PN groups. Next, we identified vulnerable subgroups for epigenetic age-deviation using interaction analysis. We revealed that DNA-methylation age-deceleration in former PICU-patients was dependent on age at time of illness (p < 0.05 for 83% of bootstrapped replicates), with vulnerability starting from 6 years onwards. Finally, we assessed whether vulnerability to epigenetic age-deviation could be related to impaired growth from PICU-admission to follow-up at 2 and 4 years. Multivariable repeated measures ANOVA showed that former PICU-patients, as compared with healthy children, grew less in height (p = 0.0002) and transiently gained weight (p = 0.0003) over the 4-year time course. Growth in height was more stunted in former PICU-patients aged ≥ 6-years at time of critical illness (p = 0.002) than in the younger patients. Conclusions: As compared with healthy children, former PICU-patients, in particular those aged ≥ 6-years at time of illness, revealed epigenetic age-deceleration, with a physical correlate revealing stunted growth in height. Whether this vulnerability around the age of 6 years for epigenetic age-deceleration and stunted growth years later relates to altered endocrine pathways activated at the time of adrenarche requires further investigation.

Original languageEnglish
Article number8
JournalClinical Epigenetics
Issue number1
Publication statusPublished - 14 Jan 2023

Bibliographical note

Funding Information:
This work was supported by European Research Council Advanced Grants (AdvG-2012–321670 and AdvG-2017–785809) to Greet Van den Berghe; by the Methusalem program of the Flemish government (through the University of Leuven to Greet Van den Berghe and Ilse Vanhorebeek, METH14/06); and by the Institute for Science and Technology, Flanders, Belgium (through the University of Leuven to Greet Van den Berghe, IWT/110685/TBM and IWT/150181/TBM); by the Sophia Research Foundation (SSWO) to Sascha Verbruggen; by the “Stichting Agis Zorginnovatie” to Sascha Verbruggen; and by a European Society for Clinical Nutrition and Metabolism (ESPEN) research grant to Sascha Verbruggen.

Publisher Copyright:
© 2023, The Author(s).


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