Lifestyle weight-loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial

Background: DNA methylation age (mAge), a methylation biomarker for the aging process, might serve as a more accurate predictor of morbidity and aging status than chronological age. We evaluated the role of multiple factors, including fat deposition, cardiometabolic risk factors and lifestyle weight-loss intervention, on the deviation of mAge from chronological age (mAge deviation) or 18-month change in mAge (Delta mAge). In this sub-study of the CENTRAL magnetic resonance imaging weight-loss trial, we evaluated mAge by a validated 240-CpG-based prediction formula at baseline and after 18-month intervention of either low fat (LF) or mediterranean/low carbohydrate (MED/LC) diets. Results: Among 120 CENTRAL participants with abdominal obesity or dyslipidemia, mAge (mean +/- SD: 60.3 +/- 7.5 years) was higher than the chronological age (48.6 +/- 9.3 years) but strongly correlated (r = 0.93; p = 3.1 x 10(-53)). Participants in the lowest tertile of mAge deviation from their chronological age had significantly lower waist-circumference, visceral adipose tissue, intrahepatic fat (IHF) content, fasting-glucose and HOMA-IR, as compared with participants in the highest sex-specific residual tertile (p < 0.05 for all). IHF% remained associated with greater mAge deviation after further adjustments (beta = 0.23; p = 0.02). After 18-month weight-loss lifestyle intervention, mAge remained significantly correlated with chronological age (r = 0.94, p = 1.5 x 10(-55)). mAging occurred, with no difference between lifestyle intervention groups (Delta = 0.9 +/- 1.9 years in MED/LC vs. Delta = 1.3 +/- 1.9 years in LF; p = 0.2); however, we observed a mAging attenuation in successful weight losers (> 5% weight loss) vs. weight-loss failures (Delta = 0.6 years vs. Delta = 1.1 years; p = 0.04), and in participants who completed the trial with healthy liver fat content (< 5% IHF) vs. participants with fatty liver (Delta = 0.6 years vs. Delta = 1.8 years; p = 0.003). Overall, 18 months of weight-loss lifestyle intervention attenuated the mAging of the men, mainly the older, by 7.1 months than the expected (p < 0.05). Conclusions: Lifestyle weight-loss intervention may attenuate mAging. Deviation of mAge from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases.