Beyond age prediction: a task-oriented framework for evaluating molecular aging clocks

Biological age estimation is increasingly used in aging research, but evaluation often relies too heavily on mean absolute error (MAE) against chronological age. We conducted a narrative review of major molecular aging clocks and propose an operational framework that links clock selection to the intended task. Applications are organized into four tasks: chronological-age estimation, age-independent deviation, future disease or mortality risk, and longitudinal monitoring of aging pace or intervention response. For each task, the framework specifies the target construct, output, preprocessing and confounding checks, validation metrics, and interpretation limits. A complementary four-layer model distinguishes relatively stable molecular measures, pace-of-aging measures, dynamic functional markers, and organ-specific vulnerability. Published examples illustrate why no single metric is sufficient: low age-prediction error does not establish clinical relevance, and strong risk association does not establish responsiveness to intervention. Aging clocks should therefore be evaluated as task-bound measurement tools, with explicit attention to calibration, discrimination, reliability, transportability, uncertainty, and incremental value. This framework is intended to support transparent model selection, reporting, and interpretation rather than designate a universally superior clock.