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Heterogeneity of increased biological age in type 2 diabetes correlates with differential tissue DNA methylation, biological variables, and pharmacological treatments

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Abstract

Biological age (BA) closely depicts age-related changes at a cellular level. Type 2 diabetes mellitus (T2D) accelerates BA when calculated using clinical biomarkers, but there is a large spread in the magnitude of individuals’ age acceleration in T2D suggesting additional factors contributing to BA. Additionally, it is unknown whether BA can be changed with treatment. We hypothesized that potential determinants of the heterogeneous BA distribution in T2D could be due to differential tissue aging as reflected at the DNA methylation (DNAm) level, or biological variables and their respective therapeutic treatments. Publicly available DNAm samples were obtained to calculate BA using the DNAm phenotypic age (DNAmPhenoAge) algorithm. DNAmPhenoAge showed age acceleration in T2D samples of whole blood, pancreatic islets, and liver, but not in adipose tissue or skeletal muscle. Analysis of genes associated with differentially methylated CpG sites found a significant correlation between eight individual CpG methylation sites and gene expression. Clinical biomarkers from participants in the NHANES 2017–2018 and ACCORD cohorts were used to calculate BA using the Klemera and Doubal (KDM) method. Cardiovascular and glycemic biomarkers associated with increased BA while intensive blood pressure and glycemic management reduced BA to CA levels, demonstrating that accelerated BA can be restored in the setting of T2D.

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Funding

This study was supported by the Institutional Startup Funds to CAM. (Joslin Diabetes Center) and NIH grants P30 DK036836 Joslin Diabetes Research Center (Bioinformatic Core) and 1R01DK132535 to CAM. ALG is a Wellcome Senior Research Fellow in Basic Biomedical Science. This work was funded at Stanford by the Wellcome (095101, 200837 [ALG]). This work was partially supported by grant 1 UG3CA268202 from NIH NCI (SenNet Consortium) to NN.

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Authors and Affiliations

  1. Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Briana N. Cortez, Hui Pan & Cristina Aguayo-Mazzucato

  2. University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA

    Briana N. Cortez

  3. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02912, USA

    Samuel Hinthorn & Nicola Neretti

  4. Division of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA

    Han Sun & Anna L. Gloyn

  5. Stanford Diabetes Research Center, Stanford School of Medicine, Stanford University, Stanford, CA, USA

    Anna L. Gloyn

  6. Department of Genetics, Stanford School of Medicine, Stanford University, Stanford, CA, USA

    Anna L. Gloyn

Authors
  1. Briana N. Cortez
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  2. Hui Pan
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  3. Samuel Hinthorn
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  4. Han Sun
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  7. Cristina Aguayo-Mazzucato
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Correspondence to Cristina Aguayo-Mazzucato.

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Supplementary information

ESM 1

Supplemental Figure 1: Inclusion flowchart showing those ACCORD participants included in our analysis, given availability of biomarkers required for calculation of BA using KDM. (PNG 116 kb) (PDF 70 kb)

ESM 2

Supplemental Figure 2: In individuals with obesity, there is no difference in DNAm PhenoAge between nondiabetic and T2D in whole blood (A) and subcutaneous adipose tissue (B). Nonparametric t-test was performed. Standard error of mean (SEM) is shown. *p<0.05, **p<0.01, *** p<0.001. Relates to Fig. 1 in text. (PNG 116 kb)

High resolution image (TIFF 305 kb)

ESM 3

Supplemental Figure 3: Methylation age (mAge) was determined using publicly available DNAm from nondiabetic and T2D tissues using Horvath’s mAge clock. Increased mAge was observed in whole blood (A). No significant changes were observed in pancreatic islets (B), and liver (C), skeletal muscle (D), subcutaneous (E), or visceral (F) adipose tissue. Nonparametric t-test was performed. Standard error of mean (SEM) is shown. (PNG 354 kb)

High resolution image (TIF 454 kb)

ESM 4

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Cortez, B.N., Pan, H., Hinthorn, S. et al. Heterogeneity of increased biological age in type 2 diabetes correlates with differential tissue DNA methylation, biological variables, and pharmacological treatments. GeroScience 46, 2441–2461 (2024). https://doi.org/10.1007/s11357-023-01009-8

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  • DOI: https://doi.org/10.1007/s11357-023-01009-8

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