Abstract
BackgroundMany CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated.ResultsPan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used.ConclusionsVarious methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.
Highlights
Many CpGs become hyper or hypo-methylated with age
There were significant difference among them: GrimAge was higher than Pan-tissue, and both were higher than chronological age whereas Skin & Blood and PhenoAge were both lower than chronological age, and PhenoAge was lower than Skin & Blood (GrimAge > Pan-tissue > chronological age > Skin & Blood > PhenoAge) (Table 2, Fig. 1, Supplementary Figure 2)
DNA methylation (DNAm) ages were not associated with estimated glomerular filtration, both PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were positively associated with repeated measures of albumin excretion rate (AER, natural log transformed) which remained significant after adjustment of HbA1c levels
Summary
Multiple methods have been developed by Horvath et al to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. In 2013, Horvath used publicly available DNA methylation (DNAm) data to define and evaluate a DNAm age predictor, Pan-tissue, which is accurate across most tissues and cell types. Some risk factors for type 2 diabetes (T2D) including BMI, waist circumference, and fasting glucose have been associated with higher Pan-tissue epigenetic age acceleration (EAA = epigenetic age − chronological age) [5, 6]. On average liver Pan-tissue EAA increased significantly by 0.33 years per BMI unit [7]
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