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Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and DNA-methylation based PAI1.

Authors
  • Kusters, Cynthia D J1, 2, 3
  • Paul, Kimberly C4
  • Lu, Ake T5, 6
  • Ferruci, Luigi7
  • Ritz, Beate R8, 4, 9
  • Binder, Alexandra M8, 10
  • Horvath, Steve5, 6, 11
  • 1 Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA. [email protected].
  • 2 Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA. [email protected].
  • 3 Department of Epidemiology, Fielding School of Public Health at UCLA, Box 708822, 650 Charles E. Young Drive South, CA, 90095-7088, Los Angeles, USA. [email protected].
  • 4 Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA.
  • 5 Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA.
  • 6 Altos Labs, San Diego, USA.
  • 7 Longitudinal Studies Section, Translational Gerontology Branch, National Institute On Aging, National Institutes of Health, Baltimore, USA.
  • 8 Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
  • 9 Department of Environmental Health, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
  • 10 Population Sciences in the Pacific Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • 11 Department of Biostatistics, School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
Type
Published Article
Journal
GeroScience
Publication Date
Feb 01, 2024
Volume
46
Issue
1
Pages
1053–1069
Identifiers
DOI: 10.1007/s11357-023-00832-3
PMID: 37369886
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort, the Baltimore Longitudinal Study of Aging, and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sex Hormone Binding Globulin (SHBG) was associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1. © 2023. The Author(s).

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