Epigenetic Age Acceleration in Adolescents Associates with Inflammation, BMI, and Increased Cardiovascular Disease Risk in Middle Age

The concept of "accelerated aging," where biological age surpasses chronological age, is a powerful predictor of chronic diseases like cardiovascular disease (CVD) in adults. This is often assessed using DNA methylation patterns, which create an "epigenetic clock." However, it's less clear if this phenomenon in adolescence can predict long-term health risks. Current CVD risk prediction models, like the Framingham algorithms, rely on factors measured in adulthood. Investigating epigenetic age acceleration in younger populations could identify at-risk individuals decades earlier, potentially allowing for preventative interventions. This study explores whether epigenetic age in teenagers is linked to concurrent and future markers of adiposity and cardiovascular health, bridging a critical gap in early-life disease prediction.

This observational study analyzed data from 995 adolescents (49.6% female, mean age 17.3 years). DNA was extracted from peripheral blood to measure DNA methylation and calculate two estimates of epigenetic age acceleration: intrinsic (IEAA) and extrinsic (EEAA). The study assessed adiposity through anthropometry, ultrasound, and DXA scans at ages 17, 20, and 22. At age 17, researchers measured key CVD risk factors, including lipids, insulin resistance (HOMA-IR), blood pressure, and inflammatory markers. Finally, they used Framingham algorithms to project the risk of developing CVD by age 47. The analysis used regression models to associate each 5-year increment in epigenetic age acceleration with these outcomes.

Extrinsic epigenetic age acceleration (EEAA) was significantly associated with several adverse health markers. Each 5-year increase in EEAA at age 17 was linked to a 2.4% (95% CI, 1.2% to 3.6%) higher BMI at age 17 and a 2.4% (95% CI, 0.8% to 3.9%) higher BMI five years later at age 22. This epigenetic aging was also strongly tied to inflammation, even after adjusting for BMI and insulin resistance. A 5-year acceleration in EEAA corresponded to a 23% (95% CI, 3% to 33%) increase in high-sensitivity C-reactive protein (hs-CRP), a 10% (95% CI, 4% to 17%) increase in interferon-γ-inducible protein of 10 kDa (IP-10), and a 4% (95% CI, 2% to 6%) increase in soluble TNF receptor 2.

Critically, this adolescent metric projected long-term risk: each 5-year EEAA acceleration was associated with a 4% increased risk for hard CVD endpoints by age 47, an association that remained significant (a 3% increase) even after adjusting for conventional risk factors.