Accelerated epigenetic aging in newborns with Down syndrome

Area of Science:

• Genetics and Epigenetics
• Developmental Biology
• Aging Research

Background:

• Down syndrome (DS) is characterized by accelerated aging, including early-onset Alzheimer's disease and premature aging of various systems.
• While accelerated epigenetic aging is observed in adults with DS, the onset during development remains unclear.

Purpose of the Study:

• To investigate if accelerated aging in Down syndrome is detectable in blood at birth.
• To determine if epigenetic age acceleration in DS begins prenatally.

Main Methods:

• Utilized Illumina MethylationEPIC DNA methylation array data from 346 newborns with DS and 567 controls.
• Assessed five epigenetic clocks (DNAmSkinBloodClock, pan-tissue DNAmAge, Haftorn, Knight, Bohlin) and performed targeted GATA1 sequencing.
• Employed linear regression analysis, adjusting for age, sex, batch, blood cell proportions, and genetic ancestry.

Main Results:

• Newborns with DS exhibited significant epigenetic age acceleration (244 days) in the DNAmSkinBloodClock (p < 0.0001).
• Epigenetic age acceleration was also associated with somatic GATA1 mutations in newborns with DS (p = 0.015).
• No association was found between DS and epigenetic gestational age acceleration.

Conclusions:

• Accelerated epigenetic aging in Down syndrome begins prenatally, detectable in blood at birth.
• These findings suggest early-life interventions may impact aging-related pathophysiology in DS.
• The study highlights the utility of epigenetic clocks in understanding developmental trajectories in genetic syndromes.