A clinically practical aging clock (physical clock) for healthy aging: development, validation, and application for...

Area of Science:

• Gerontology and Geriatric Medicine
• Biomarker Discovery
• Clinical Epidemiology

Background:

• Aging is a primary risk factor for chronic diseases, with significant variation between chronological and biological age.
• Current multi-omics aging clocks are accurate but limited by cost and complexity for clinical use.
• There is a need for scalable, clinically actionable alternatives to assess biological aging.

Purpose of the Study:

• To develop and validate a novel physical aging clock using routine clinical biomarkers and physical performance measures.
• To assess the association of the physical clock-derived accelerated aging with health outcomes, including chronic disease, functional decline, and mortality.
• To establish healthy reference intervals and explore modifiable factors influencing physical aging.

Main Methods:

• Developed an ElasticNet regression model integrating clinical biomarkers and physical performance in the PENG ZU cohort.
• Reduced the model to an 11-marker simplified version focusing on kidney function, glucose metabolism, and physical performance.
• Validated the physical clock (ΔPhysicalAge) in independent UKB Biobank and NHANES cohorts, comparing its predictive performance against ΔPhenoAge.

Main Results:

• Accelerated aging (ΔPhysicalAge) strongly correlated with increased chronic disease incidence, functional decline, reduced intrinsic capacity, and mortality.
• The physical clock robustly predicted disease onset and mortality across validation cohorts and outperformed ΔPhenoAge in predicting major age-related diseases.
• Preliminary evidence suggests postmenopausal hormone replacement therapy (HRT) is associated with lower ΔPhysicalAge; healthy lifestyle factors correlate with slower aging.

Conclusions:

• The developed physical clock offers a clinically accessible tool for assessing biological aging and stratifying health risks.
• The physical clock demonstrates validity and responsiveness, identifying individuals at risk even within conventionally low-risk groups.
• Establishing healthy reference intervals and identifying modifiable lifestyle factors provides pathways for personalized interventions to promote healthy aging.