Region-based epigenetic clock design improves RRBS-based age prediction

Area of Science:

• Epigenetics
• Aging Research
• Genomics

Background:

• Epigenetic rejuvenation strategies, including pharmacological interventions and reprogramming, show promise for anti-aging research.
• Mouse models are crucial for in vivo testing of rejuvenation techniques.
• Existing epigenetic clocks for mouse reduced-representation bisulphite sequencing (RRBS) data exhibit poor transferability across datasets due to variable CpG site coverage.

Purpose of the Study:

• To address the limitations of current RRBS-based epigenetic clocks in mice.
• To develop novel strategies for more robust and transferable age prediction from RRBS data.
• To validate improved epigenetic clocks in mouse models, including those undergoing calorie restriction.

Main Methods:

• Developed two novel regional clock design strategies using average methylation over large regions (sliding windows or CpG clustering) instead of individual CpGs.
• Applied and validated these regional blood clocks (RegBCs) on external RRBS datasets.
• Assessed clock performance, robustness to low coverage data, and ability to detect age acceleration in calorie-restricted mice.

Main Results:

• Regional blood clocks (RegBCs) demonstrated improved correlation and reduced error compared to individual-CpG-based clocks on external datasets.
• RegBCs showed enhanced robustness with low-coverage RRBS data.
• Calorie restriction in mice was associated with negative age acceleration detected by RegBCs.

Conclusions:

• Regional averaging of methylation data significantly improves the accuracy and transferability of mouse epigenetic clocks derived from RRBS data.
• The developed RegBCs provide a more reliable method for age prediction in mouse models, overcoming limitations of individual CpG-based approaches.
• These findings support the utility of regional epigenetic clocks for advancing in vivo rejuvenation research and understanding aging processes.