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Clouds in the Sky
Ananya Khan

Ananya Khan

Post Graduate

Assessing the utility of epigenetic clocks for health prediction in South Korean

Published on: January 23, 2025

Original author: Dong Jun Kim, et al. 2024 (doi: 10.3389/fragi.2024.1493406)

The development and recent increase in the application of epigenetic clocks in healthcare research has primarily been focused among the European, African, or Hispanic individuals. The use of epigenetic clocks is limited among the east Asian population despite having notable differences in epigenetic clocks among various ethnic groups. If the biological age is higher than chronological age, it is called Epigenetic Age Acceleration (EAA). It is typically derived by regressing the epigenetic age of clocks on chronological age, assesses whether individuals are aging faster or slower than their chronological age. EAA indicates higher risk of chronic diseases, mortality, and adverse health outcomes and thereby indicates faster aging. First-generation epigenetic clocks, such as Horvath’s and Hannum’s clocks, estimate chronological age based on DNA methylation patterns, while second-generation clocks, like PhenoAge, GrimAge, and DunedinPACE, focus on biological age by incorporating clinical biomarkers, aging pace, and mortality risk. Second-generation clocks outperform first-generation clocks in predicting lifespan and health outcomes. The study assessed the performance of epigenetic clocks in the East Asian population and explored the association of EAAs from each clock with health outcomes, health behaviors, and the time to onset of chronic diseases, and confirmed these findings in an independent South Korean cohort. Methods The present study classified participants into case and control groups for type 2 diabetes (T2D) and hypertension using diagnostic history, fasting glucose levels, and blood pressure measurements. DNA methylation data were analyzed from 1,925 KARE participants and 822 HEXA participants, combining data from Illumina 450K and EPIC BeadChips with batch effects corrected using the ComBat function. Epigenetic age was estimated using eight clocks (four first-generation and four second-generation) and evaluated for epigenetic age acceleration (EAA) by regressing epigenetic age on chronological age. Statistical analyses, including t-tests, Pearson correlations, regression, and survival analyses, were performed using R, with visualizations created via ggplot2. The study prioritized principal component-based clocks to minimize noise and improve accuracy. Results The findings show no significant association of first-generation epigenetic clocks with chronic diseases or health markers. On the contrary, second-generation clocks demonstrated strong correlations with adverse health outcomes, such as increased risk of type 2 diabetes, hypertension, and elevated levels of ALT, AST, TG, and hs-CRP, while showing decreased levels of HDL, FEV1% PRED, and FVC% PRED. Males exhibited faster epigenetic aging across most clocks. Environmental factors like smoking and high BMI accelerated aging, while regular exercise and higher socioeconomic status slowed it. Findings were validated in an independent cohort, reinforcing the utility of second-generation clocks in health prediction for East Asians​. Discussion The findings of the study depict higher accuracy of second-generation epigenetic clocks in predicting health outcomes compared to first-generation clocks. Second-generation clocks, such as PCGrimAge and DunedinPACE, were strongly associated with chronic diseases, mortality risk, and environmental factors, highlighting their relevance for healthspan and lifespan predictions. While first-generation clocks primarily estimate chronological age, second-generation clocks incorporate health biomarkers and lifestyle data, making them more robust in assessing biological aging. Lifestyle factors, like smoking and high BMI, accelerated epigenetic aging, while exercise and higher socioeconomic status slowed it. Despite the study's focus on East Asians, the findings highlighted the general utility of second-generation clocks across populations. Conclusion Overall, this study underscores the utility of epigenetic clocks in the East Asian population. The study evaluated different epigenetic clocks and confirmed that the epigenetic age from second-generation clocks provide valuable health predictions, while also suggesting potential for slowing aging through healthier lifestyles. The findings demonstrate the potential of second-generation clocks as tools for early detection of health risks and guiding interventions, particularly in East Asian populations. It suggests that epigenetic clocks developed for different ancestries can be valuable for individuals of East Asian populations. The study underscores the need for population-specific clocks, given that most existing clocks were developed in non-Asian populations. Future Implications Although the study validated results using an independent cohort, certain limitations remain, including the inability to analyze lung function and smoking pack-years, the lack of statistical significance for psychosocial stress on epigenetic age acceleration (EAA), and insufficient follow-up cases for type 2 diabetes and hypertension to confirm their impact on disease onset. The findings emphasize the need for larger sample sizes and a comprehensive interpretation of aging indicators using multiple epigenetic clocks for a deeper understanding of their associations with health outcomes.

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