Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects.

Area of Science:

• Epigenetics
• Cellular Biology
• Aging Research

Background:

• Epigenetic aging clocks are commonly used to assess cellular reprogramming and rejuvenation.
• The accuracy of these clocks is limited by the unknown true biological age of reprogrammed cells.

Purpose of the Study:

• To develop an analytical framework for evaluating rejuvenation predictions from epigenetic clocks.
• To assess the reliability of current aging clock models in the context of cellular reprogramming.

Main Methods:

• Analysis of DNA methylation profiles during cellular reprogramming.
• Evaluation of epistemic uncertainty in age estimations from clock models.
• Comparison of predictions from different published aging clocks.

Main Results:

• DNA methylation data in reprogramming is poorly represented in training datasets, leading to high uncertainty.
• Aging clock predictions are inconsistent, with some indicating no or negative rejuvenation.
• In vitro reprogramming results are challenged by clock uncertainty, while in vivo reprogramming shows a significant age increase.

Conclusions:

• The reliability of epigenetic clocks for validating rejuvenation requires careful consideration of uncertainty.
• Future aging clock models should incorporate uncertainty estimation to prevent misinterpretation of biological age.
• Current methods may overestimate rejuvenation effects in vitro and underestimate age progression in vivo.