Epigenetic Insights into Adolescent Sleep and Cardiometabolic Health

Adolescence is a critical developmental stage increasingly characterized by inadequate sleep. In the United States, approximately 58% of middle school students and nearly 73% of high school students report obtaining less sleep than recommended on school nights.¹ Insufficient, disturbed and misaligned sleep contribute to heightened cardiometabolic risk, including increased adiposity, elevated blood pressure, insulin resistance, and altered cardiac autonomic modulation.^2–5 However, the underlying pathophysiological mechanisms linking inadequate sleep with adverse health outcomes remain relatively underexplored in adolescents. Epigenetic factors bridge environmental exposures and gene expression⁶ and may provide insight into the mechanisms by which inadequate sleep elevates cardiometabolic risk. For example, DNA methylation, the addition of methyl groups to cytosine residues at CpG sites, is a prominent regulator of gene expression.⁶ Emerging evidence indicates that insufficient sleep can lead to detectable changes in DNA methylation,^7,8 including during adolescence.^9,10

In the current issue of SLEEP, Jansen and colleagues¹¹ conducted an epigenome-wide analysis of blood leukocyte DNA methylation in approximately 500 adolescents (mean age ~14), using 7-day actigraphy to measure sleep. They found that even typical variations in sleep duration and timing were associated with subtle, yet widespread, methylation differences, identifying 1,875 differentially methylated regions (DMRs) distinctly linked to sleep duration versus sleep timing. Notably, males exhibited a stronger epigenetic response, with over 3,200 DMRs compared to ~1,300 in females, suggesting a sex-specific sensitivity. While the effects at individual CpG sites were modest, evidenced by very few single-site associations reaching stringent statistical significance, the regional clustering of these subtle methylation changes into biologically relevant pathways suggests true functional importance. In males, sleep duration was associated with metabolic and DNA maintenance pathways, while sleep timing was linked to developmental and neurological pathways. In the full sample, insulin secretion emerged as one of the most significant pathways associated with weekend sleep midpoint. These findings imply that inadequate adolescent sleep, including both sleep duration and timing, leave coordinated imprints on the blood methylome, potentially influencing metabolic and developmental health through separate epigenetic pathways, particularly in males.

Complementary findings have been identified in prior studies across different age groups. Huang and colleagues (2017) compared college-aged short and long sleepers and identified 87 differentially methylated CpG sites across 52 genes, some of which appear to influence sleep homeostasis and overall sleep architecture, as demonstrated by altered sleep duration and bout patterns in a C. elegans model.¹² Misaligned sleep timing has also been shown to influence methylation, particularly within circadian genes. Jansen and colleagues (2021) conducted a pilot study in Mexican adolescents (mean age ~14), finding that a later sleep midpoint was associated with increased methylation in clock genes such as RORB, PER1, CRY2, and NR1D1.¹³ These methylation changes suggest that a circadian sleep phase delay, common with the onset of puberty but that can worsen quickly over time, may epigenetically reprogram the molecular clock. In addition, Larsen and colleagues (2023) further linked delayed sleep initiation in adolescents (mean age ~16) to methylation changes in genes involved in cardiometabolic and other biological pathways.¹⁰ At odds with these studies, a meta-analysis of ~3,500 young children (mean age ~8) found minimal sleep-methylation associations, suggesting that epigenetic signals may intensify with or after pubertal development.¹⁴ Collectively, these findings suggest that sleep duration (insufficient sleep) and sleep timing (circadian misalignment) are associated with differential methylation during the critical period of adolescence.

Accumulating evidence, together with that presented by Jansen and colleagues, indicates that sleep timing and duration are associated with distinct DNA methylation patterns in neurological and metabolic pathways, such as those regulating insulin sensitivity, suggesting molecular mechanisms linking poor sleep to metabolic dysfunction and diabetes risk.¹¹ Validation of these methylation patterns could yield diagnostic or therapeutic biomarkers, enabling early identification of at-risk adolescents and guiding targeted interventions. The reversibility of DNA methylation also suggests potential use in tracking treatment effectiveness, providing clinicians with practical tools. The non-overlapping methylation regions linked to sleep timing and duration further suggest that DNA methylation could identify the impact of specific sleep disruptions, paving the way for personalized interventions based on individual methylome profiles.

The findings by Jansen and colleagues,¹¹ similarly to prior DNA methylation studies, need to be interpreted in light of some limitations. Most current studies measure methylation in leukocytes, which may not fully reflect methylation changes in metabolic- or circadian-relevant tissues such as hepatic, pancreatic or hypothalamic tissues. Additionally, cross-sectional designs prevent determination of causality or distinguishing between causal and non-causal associations. Moreover, as these studies involved relatively healthy adolescents, direct links between observed methylation changes and clinical cardiovascular outcomes remain unestablished. Despite these limitations, the study has notable strengths, including a robust epigenome-wide analysis and clear insights into distinct biological pathways associated separately with sleep duration and sleep timing. These findings provide valuable clues about mechanisms potentially linking inadequate sleep and adverse health outcomes. Future studies should prioritize longitudinal designs to establish causality and track epigenetic changes over time. These studies should also aim to link sleep-related DNA methylation patterns to specific cardiometabolic outcomes, such as insulin resistance, diabetes, inflammation, endothelial function or hypertension among many others, to assess whether these epigenetic markers are merely associations or hold predictive value for clinically relevant health conditions. Furthermore, longitudinal research will offer the opportunity to explore the reversibility of adverse methylation changes through sleep interventions or treatments, which could serve as a valuable marker for treatment response and efficacy. By integrating these elements with direct clinical assessments, future research can enhance the validation of these epigenetic associations and establish their potential clinical utility as diagnostic tools, therapeutic targets, or indicators of treatment success.

In summary, DNA methylation represents a promising approach for elucidating molecular connections between adolescent sleep and related adverse health outcomes. Integrating epigenetic findings with clinical and lifestyle data could significantly enhance the precision and effectiveness of interventions tailored to individual needs.