Abstract:Background
One of the major challenges in obesity treatment is to explain the high variability in the individual’s response to specific dietary and physical activity interventions. With this study, we tested the hypothesis that specific DNA methylation changes reflect individual responsiveness to lifestyle intervention and may serve as epigenetic predictors for a successful weight-loss.
Methods
We conducted an explorative genome-wide DNA methylation analysis in blood samples from 120 subjects (90% men, mean ±… Show more
“…4 ), including 120 participants, according to the following criteria: both baseline and 18 months available blood samples and additional consent to genetic analysis. Sample selection was detailed elsewhere [ 44 ]. Fig.…”
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 (∆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 × 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 (β = 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 × 10–55). mAging occurred, with no difference between lifestyle intervention groups (∆ = 0.9 ± 1.9 years in MED/LC vs. ∆ = 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 ( ∆ = 0.6 years vs. ∆ = 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 (∆ = 0.6 years vs. ∆ = 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.
Trial registration: ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724.
“…4 ), including 120 participants, according to the following criteria: both baseline and 18 months available blood samples and additional consent to genetic analysis. Sample selection was detailed elsewhere [ 44 ]. Fig.…”
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 (∆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 × 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 (β = 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 × 10–55). mAging occurred, with no difference between lifestyle intervention groups (∆ = 0.9 ± 1.9 years in MED/LC vs. ∆ = 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 ( ∆ = 0.6 years vs. ∆ = 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 (∆ = 0.6 years vs. ∆ = 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.
Trial registration: ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724.
“…Similarly, the 18-month randomized controlled trial (CENTRAL) of the Mediterranean/low-carbohydrate or low-fat diet revealed substantial differences in DNA methylation between responders, who dropped more than 16% of their body weight, and non-responders. NUDT3 (nudix hydrolase 3), NCOR2 (nuclear receptor corepressor 2), LRRC27 (leucine-rich repeat-containing 27), CRISP2 (cysteine-rich secretory protein 2), and SLFN12 (schlafen family member 12) genes, which regulate cell adhesion, metabolism, chromatin modification, and calcium signaling, were among those with significant changes in DNA methylation [128].…”
Obesity has become a global epidemic that has a negative impact on population health and the economy of nations. Genetic predispositions have been demonstrated to have a substantial role in the unbalanced energy metabolism seen in obesity. However, these genetic variations cannot entirely explain the massive growth in obesity over the last few decades. Accumulating evidence suggests that modern lifestyle characteristics such as the intake of energy-dense foods, adopting sedentary behavior, or exposure to environmental factors such as industrial endocrine disruptors all contribute to the rising obesity epidemic. Recent advances in the study of DNA and its alterations have considerably increased our understanding of the function of epigenetics in regulating energy metabolism and expenditure in obesity and metabolic diseases. These epigenetic modifications influence how DNA is transcribed without altering its sequence. They are dynamic, reflecting the interplay between the body and its surroundings. Notably, these epigenetic changes are reversible, making them appealing targets for therapeutic and corrective interventions. In this review, I discuss how these epigenetic modifications contribute to the disordered energy metabolism in obesity and to what degree lifestyle and weight reduction strategies and pharmacological drugs can restore energy balance by restoring normal epigenetic profiles.
“…Consequently, narrowing down our list of potential lifestyle discriminating candidates regions by including an additional adjustment for smoking resulted in identification of a top DMR on chromosome 6 annotated to the Ring Finger Protein 39 ( RNF39 ). This DMR is overlapping a larger region very recently described to successfully discriminate responder from non-responder to an lifestyle intervention based on either Mediterranean/low-carbohydrate or low-fat diet with or without physical activity 7 .…”
Section: Discussionmentioning
confidence: 78%
“…Recent studies demonstrated that successful short term weight loss interventions may reduce methylation age (mAge) to the chronological age level 4 . Furthermore, DNA methylation patterns may predict the success of lifestyle-induced weight loss 5–7 .…”
Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects (diet, physical activity, smoking and alcohol) on blood DNA methylation in participants of the LIFE-Adult study, a well-characterized population-based cohort from Germany. Fifty subjects with an extremely healthy and 50 with an extremely unhealthy lifestyle were selected for genome-wide DNA methylation analysis in blood samples. Whereas obesity was only marginally related to variability in DNA methylation pattern, comparisons between lifestyle categories resulted in 145 Differentially Methylated Positions (DMPs) and 4682 Differentially Methylated Regions (DMRs) annotated to 4426 unique genes. Intersection analysis showed that diet, physical activity, smoking and alcohol intake are equally contributing to the observed differences, which particularly affects pathways related to glutamatergic synapse and axon guidance. DNA methylation patterns help discriminate individuals with a healthy vs. unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.
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