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Published on: July 12, 2012
Long-term impact of paediatric critical illness on the difference between epigenetic and chronological age in
Ines Verlinden1, Grégoire Coppens1, Ilse Vanhorebeek1
1Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
Insights
Paediatric critical illness can decelerate biological ageing in children, particularly those aged six and older, leading to stunted growth. Nutritional management in the paediatric intensive care unit (PICU) did not alter these DNA-methylation changes.
Area of Science:
- Epigenetics
- Developmental Biology
- Paediatric Critical Care
Background:
- Altered DNA methylation impacts biological aging and childhood development.
- Environmental factors, trauma, and illnesses can modify DNA methylation.
- Paediatric critical illness and intensive care unit (PICU) nutritional management may affect DNA methylation and childhood development.
Purpose of the Study:
- To investigate the impact of critical illness and early versus late parenteral nutrition (PN) on epigenetic age deviation in former paediatric intensive care unit (PICU) patients.
- To assess the relationship between epigenetic age deviation and impaired growth in these children.
- To identify subgroups vulnerable to epigenetic age deviation based on age at critical illness.
Main Methods:
- Epigenetic age deviation was calculated using the PedBE clock in buccal mucosa samples from 818 former PICU patients and 392 healthy children.
- Bootstrapped multivariable linear regression models assessed the impact of critical illness and early-PN versus late-PN.
- Interaction analysis identified vulnerable subgroups, and repeated measures ANOVA examined growth differences.
Main Results:
- Former PICU patients exhibited negative epigenetic age deviation compared to healthy children, irrespective of early or late PN.
- Vulnerability to epigenetic age deceleration began at age six, with significant impact on DNA methylation age.
- Former PICU patients showed reduced height growth over four years, particularly those aged six or older at critical illness.
Conclusions:
- Former PICU patients, especially those over six years old at the time of illness, experience epigenetic age deceleration and stunted height growth.
- The findings suggest a potential link between age-related vulnerability during critical illness and long-term growth impairment.
- Further research is needed to explore the role of endocrine pathways, such as those activated during adrenarche, in these developmental alterations.
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.
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