ProtPhenoAge: Integrating plasma proteomics to predict Aging-Related disease Risks

Introduction Plasma proteins reflect the combined influence of both internal and external factors, making proteomics-based aging clocks a promising approach for quantifying the aging process. Objective This study aims to develop and validate a novel proteomics-based aging clock by integrating plasma proteomics with composite biomarkers. Methods We used a prospective cohort of 37,433 participants (median follow-up: 164.73 months) from the UK Biobank (UKB) with Olink Explore data. We calculated biological age (PhenoAge) and used the Boruta-SHAP (SHapley Additive exPlanations) algorithm to select PhenoAge-related proteins. Based on these proteins, six machine learning models were trained to develop a proteomics-based PhenoAge (ProtPhenoAge). We selected the best model as ProtPhenoAge based on the predictive capabilities of each model for PhenoAge and all-cause mortality. Phenome-wide association study (PheWAS) and Mendelian randomization (MR) explored associations between ProtPhenoAge Acceleration (ProtPhenoAgeAccel) and phenotypes. Genome-wide association study (GWAS) and colocalization analysis identified aging-associated loci. Results A total of 185 PhenoAge-related plasma proteins were used to develop ProtPhenoAge. The ProtPhenoAge model, using extreme gradient boosting (XGBoost), showed strong correlation with PhenoAge ( r = 0.96, R 2 = 0.92) and performed well in predicting all-cause mortality [area under the curve (AUC) = 0.76], outperforming previous aging clocks: chronological age (CA), PhenoAge and ProtAge. ProtPhenoAgeAccel was significantly associated with 313 disease phenotypes, covering a broad range of aging-related phenotypes. Compared with previous clocks, it identified more age-independent but aging-related phenotypes. In the GWAS, we identified 10 aging-associated loci. Among them, rs1045929 ( P = 2.61 × 10 -9 ) and rs429358 ( P = 7.96 × 10 -12 ) are respectively related to epigenetic aging and the well-recognized aging gene APOE . Conclusion Based on genomic and phenomic evidences, ProtPhenoAge was regarded to better quantifies the aging process by overcoming the limitations of previous clocks, which failed to detect time-independent aging features. These findings suggested that ProtPhenoAge is a reliable tool to assess aging and supporting aging research.