Retroelement-Based Epigenetic Clock as a Biomarker of Biological Aging

Background & Unmet Need

• A person's biological age differs from their chronological age as it considers not just the passage of time but also factors such as genetics, lifestyle, nutrition, and comorbidities
• Assessing biological age can serve as a more effective diagnostic tool for age-related diseases and as a prognostic tool for health screening
• Epigenetic clocks are a way to determine biological age based on patterns of DNA methylation at specific regions of the human genome
• However, existing epigenetic clocks face challenges related to accuracy, tissue specificity, biological relevance, and capturing diverse aspects of aging
• Retroelements like HERVs and LINE-1 elements are kept silent by DNA methylation, but have been known to influence gene regulation, genomic stability, and disease upon reactivation with age
• Unmet Need: Improved biomarkers of biological aging for assessing age-related risk and disease

Technology Overview

• The Technology:Biomarker of biological aging based on the DNA methylation states of HERVs and LINE-1 retroelements
• HERV-Age, LINE-1-Age, and a composite Retroelement-Age clocks were developed using data from >12 K individuals based on the DNA methylation states of HERV and/or LINE-1 elements
• 100% of HERV-Age and 99.9% of LINE-1-Age methylation sites were unique and not part of existing epigenetic clocks*
• PoC Data: All three epigenetic clocks were subsequently validated in >2 K samples, with high fidelity to chronological age
• Retroelement-Age was able to measured the impact of therapeutic intervention, demonstrated by (i) a reduction in the biological age of samples from HIV patients undergoing retroviral treatment and (ii) human cortical organoids epigenetically rejuvenated through transient reprogramming

Technology Applications

• Predicting the chronological age of humans and pan-mammalian species
• Measure an individual's biological age more accurately to help predict risk of developing age-related diseases
• Tool for monitoring the effectiveness of therapeutic interventions, such as antiretroviral and anti-aging treatments

Technology Advantages

• Predicts chronological age with higher accuracy than existing models
• Elucidates the association between DNA methylation of retroelements and human aging
• Identifies potential biomarkers for anti-aging strategies

Figure 1. A) Diagram of workflow utilized to construct RetroelementAge and Retroelement-Age V2. B-E) The age estimates generated by the Retroelement-Age and Retroelement-Age V2 clocks, validated through 10-fold cross-validation on training and test datasets, exhibited strong correlations with chronological age. Panels report the sample size (n), the median absolute error (MAE), and Pearson correlation coefficient (r).