A team at Wuhan Asia Heart Hospital applies bi-directional two-sample Mendelian randomization on GWAS data from FinnGen to uncover causal links between epigenetic clocks (IEAA, GrimAge, PhenoAge) and thromboembolism, highlighting key factors like PAI-1 and FGF23 in clot formation.
Key points
Intrinsic epigenetic age acceleration (IEAA) inversely associates with deep venous thrombosis of lower extremities (OR 0.963).
Genetically predicted PAI-1 levels show a modest causal link to other arterial embolism and thrombosis (OR 1.0005).
FGF23 elevation causally increases risk of lower extremity arterial thrombosis (OR 1.68) and other arterial embolism (OR 1.66).
Reverse MR reveals portal vein thrombosis decelerates PhenoAge and venous thromboembolism accelerates GrimAge metrics.
Analyses employ IVW, weighted median/mode, MR-Egger and sensitivity tests (Cochran’s Q, MR-PRESSO, leave-one-out) to rule out pleiotropy.
Why it matters:
This study leverages Mendelian randomization to move beyond correlations and establish genetic causality between epigenetic aging biomarkers and thromboembolic disease. Identifying molecules like PAI-1 and FGF23 as drivers of clot formation opens avenues for targeted prevention and personalized risk prediction in cardiovascular aging.
Q&A
What is an epigenetic clock?
How does Mendelian randomization work?
Why are PAI-1 and FGF23 important?
What is inverse variance-weighted analysis?
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Academy
Epigenetic Aging and Epigenetic Clocks
Epigenetics refers to chemical modifications to DNA and histones that regulate gene activity without altering the underlying genetic code. These modifications respond to environmental factors like diet, stress, or toxins. An epigenetic clock is a statistical model that uses DNA methylation patterns—chemical tags added to DNA—to estimate an individual’s biological age. Biological age can differ from chronological age, providing insights into health, disease risk, and the pace of aging.
DNA Methylation and Biological Age
DNA methylation involves attaching a methyl group (–CH3) to cytosine bases in DNA, often influencing gene expression. Over time, certain CpG sites gain or lose methyl groups in predictable patterns. Epigenetic clocks analyze methylation levels at hundreds of these sites to calculate a DNA methylation age. When this age exceeds chronological age, it indicates epigenetic age acceleration, a marker of faster aging linked to higher disease risk and mortality.
Types of Epigenetic Clocks
- Horvath Clock (IEAA): Uses 353 CpG sites to measure intrinsic aging across tissues; resistant to blood cell–type changes.
- Hannum Clock: Based on 71 CpGs, predicts age in blood samples, sensitive to immune cell shifts.
- PhenoAge: Integrates clinical biomarkers (e.g., CRP, albumin) with 513 CpGs to assess morbidity and mortality risk.
- GrimAge: Combines methylation surrogates for smoking and seven plasma proteins across 1,030 CpGs; strongest mortality predictor.
Applications in Longevity Research
Epigenetic clocks help scientists:
- Identify individuals with accelerated aging and elevated disease risk.
- Monitor the impact of lifestyle interventions (diet, exercise) on biological age.
- Evaluate anti-aging drugs and therapies by tracking changes in methylation age over time.
- Understand mechanisms linking aging to cardiovascular, metabolic, and neurodegenerative diseases.
Limitations and Future Directions
While epigenetic clocks are powerful, they have limitations: variability across populations, sensitivity to blood cell composition, and incomplete coverage of all aging pathways. Future work aims to develop more accurate, tissue-specific clocks, integrate multi-omic data (transcriptomics, proteomics), and refine causal links between epigenetic aging markers and disease, paving the way for personalized longevity interventions.
