Revealing the genetic architectures underlying organ-specific aging based on proteomic data

Area of Science:

• Genetics
• Gerontology
• Proteomics

Background:

• Organ-specific plasma protein signatures can track organ aging.
• Genetic determinants and molecular mechanisms of organ-specific aging are poorly understood.

Purpose of the Study:

• To investigate the genetic architectures underlying aging across 13 organs.
• To identify genetic loci and genes associated with organ aging.
• To explore the causal relationships between organ aging and age-related diseases.

Main Methods:

• Integrated large-scale plasma proteomic and genomic data from 51,936 UK Biobank participants.
• Performed genome-wide association studies (GWAS) to identify genetic loci associated with organ aging.
• Utilized causal inference analyses to determine the impact of organ aging on disease risk.

Main Results:

• Identified 119 genetic loci associated with organ aging, with 27 shared across multiple organs.
• Prioritized 554 risk genes involved in organ-relevant biological pathways, including T cell-mediated immunity.
• Found that accelerated heart and muscle aging increase heart failure risk; kidney aging contributes to hypertension.
• Linked smoking initiation to accelerated aging in the lung, intestine, kidney, and stomach.

Conclusions:

• Established a genetic foundation for understanding organ-specific aging.
• Provided insights into molecular mechanisms driving organ aging and its link to diseases.
• Highlighted potential targets for interventions promoting healthy longevity.