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Peer-reviewedCC BY 4.0Biology of Sex Differences

Hormone replacement therapy through the lens of epigenetic clock: estrogen signals, glycemic status, and lifespan

  • Hong Wei1
  • Chenghua Kong2
  • Boya Gao2
  • Hanyu Chen2
  • Xiaoman Dai3,4
  • Yu Zhou2
4 affiliations
  1. 1Cadres’s Healthcare Office, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian China
  2. 2Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian China
  3. 3Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian China
  4. 4Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian China
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Abstract

Background: Epigenetic age acceleration (EAA) is a critical biomarker of aging. Hormone replacement therapy (HRT) is commonly used to alleviate age-related diseases, while glycemic status also influences the aging process. We aimed to investigate the association between estrogen and EAA, and the effects of HRT, EAA, and glycemic status on mortality.

Methods: Mendelian randomization (MR) established causal relationships between genetically predicted estrogen receptor expression and EAA markers (HorvathAA, HannumAA, PhenoAA, and GrimAA). Using data from the National Health and Nutrition Examination Survey, we employed Cox proportional hazards models to analyze the association between HRT and mortality, exploring whether it was modified by EAA and glycemic status.

Results: Elevated estrogen receptor α (ESR1) expression significantly decelerated PhenoAA (β -1.26; 95% CI: -2.16, -0.37; P = 0.005). HRT significantly correlated with a reduced risk of all-cause (HR: 0.65, 95% CI: 0.47–0.88; P = 0.006) and cardiovascular (HR: 0.52, 95% CI: 0.28–0.95; P = 0.033) mortality. Additionally, there was a significant three-way interaction among HRT, two types of EAA (HorvathAA and PhenoAA), and abnormal glucose status. Stratified analyses showed no significant interaction in the normal glucose subgroup; however, a significant antagonistic interaction emerged between HRT and both HorvathAA and PhenoAA in the abnormal glucose subgroup. Consequently, although HRT exhibited a protective main effect in patients with abnormal glucose, its survival benefits were significantly attenuated as their epigenetic aging accelerated.

Conclusions: Estrogen may decelerate PhenoAA via the ESR1 pathway. In postmenopausal women, HRT is significantly associated with a reduced risk of mortality; however, this survival benefit is substantially modified by glycemic status. Future studies should evaluate whether incorporating EAA and glycemic status into HRT decision-making could optimize clinical outcomes.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13293-026-00959-w.

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Cite

BibTeXRIS
BibTeX
@article{wei2026hormone,
  title = {{Hormone replacement therapy through the lens of epigenetic clock: estrogen signals, glycemic status, and lifespan}},
  author = {Hong Wei and Chenghua Kong and Boya Gao and Hanyu Chen and Xiaoman Dai and Yu Zhou},
  journal = {Biology of Sex Differences},
  year = {2026},
  month = jul,
  doi = {10.1186/s13293-026-00959-w},
  url = {https://doi.org/10.1186/s13293-026-00959-w},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Hormone replacement therapy through the lens of epigenetic clock: estrogen signals, glycemic status, and lifespan
AU  - Hong Wei
AU  - Chenghua Kong
AU  - Boya Gao
AU  - Hanyu Chen
AU  - Xiaoman Dai
AU  - Yu Zhou
PY  - 2026
DA  - 2026/07/31
JO  - Biology of Sex Differences
DO  - 10.1186/s13293-026-00959-w
UR  - https://doi.org/10.1186/s13293-026-00959-w
AB  - Background: Epigenetic age acceleration (EAA) is a critical biomarker of aging. Hormone replacement therapy (HRT) is commonly used to alleviate age-related diseases, while glycemic status also influences the aging process. We aimed to investigate the association between estrogen and EAA, and the effects of HRT, EAA, and glycemic status on mortality.  Methods: Mendelian randomization (MR) established causal relationships between genetically predicted estrogen receptor expression and EAA markers (HorvathAA, HannumAA, PhenoAA, and GrimAA). Using data from the National Health and Nutrition Examination Survey, we employed Cox proportional hazards models to analyze the association between HRT and mortality, exploring whether it was modified by EAA and glycemic status.  Results: Elevated estrogen receptor α (ESR1) expression significantly decelerated PhenoAA (β -1.26; 95% CI: -2.16, -0.37; P = 0.005). HRT significantly correlated with a reduced risk of all-cause (HR: 0.65, 95% CI: 0.47–0.88; P = 0.006) and cardiovascular (HR: 0.52, 95% CI: 0.28–0.95; P = 0.033) mortality. Additionally, there was a significant three-way interaction among HRT, two types of EAA (HorvathAA and PhenoAA), and abnormal glucose status. Stratified analyses showed no significant interaction in the normal glucose subgroup; however, a significant antagonistic interaction emerged between HRT and both HorvathAA and PhenoAA in the abnormal glucose subgroup. Consequently, although HRT exhibited a protective main effect in patients with abnormal glucose, its survival benefits were significantly attenuated as their epigenetic aging accelerated.  Conclusions: Estrogen may decelerate PhenoAA via the ESR1 pathway. In postmenopausal women, HRT is significantly associated with a reduced risk of mortality; however, this survival benefit is substantially modified by glycemic status. Future studies should evaluate whether incorporating EAA and glycemic status into HRT decision-making could optimize clinical outcomes.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13293-026-00959-w.
SN  - 2042-6410
ER  -