Structural decomposition enables multi-omics dissection of common and organ-specific aging

Area of Science:

• Gerontology
• Genetics
• Systems Biology

Background:

• Aging has both systemic and organ-specific aspects, but current models struggle to differentiate their contributions at a population level.
• Existing biological age gap (BAG) models do not effectively separate shared versus distinct aging determinants.

Purpose of the Study:

• To develop and validate a structural decomposition framework to partition biological age gaps into common and organ-specific components.
• To assess the predictive power of this dual-axis aging model for lifespan, healthspan, and organ-specific disease risk compared to traditional models.

Main Methods:

• Utilized a dataset of 501,388 UK Biobank participants.
• Developed a framework to decompose seven organ-based BAGs into a Common BAG (CBAG) and seven Organ-Specific BAGs (OSBAGs).
• Integrated genome-wide association studies (GWAS), proteomic, metabolomic, and drug-aging profiling data.

Main Results:

• The dual-axis model significantly outperformed undecomposed BAG approaches in predicting lifespan, healthspan, and organ-specific disease risk.
• Identified 747 novel aging loci through GWAS and revealed druggable targets like CST1 via multi-omics analysis.
• Demonstrated that CBAG reflects cross-tissue regulators (e.g., FOXO3), while OSBAGs capture organ-restricted effectors (e.g., UMOD), revealing a modular aging architecture.
• Uncovered sex-specific molecular aging trajectories and organ-specific drug-aging effects missed by simpler models.

Conclusions:

• The structural decomposition framework provides a more accurate and nuanced understanding of aging biology.
• This approach enhances prediction of health outcomes and identifies novel therapeutic targets and potential toxicities.
• The findings are integrated into HONOR, an open-access atlas for structural aging and multi-omics translation.