| Title: | Integrated plasma proteomics and metabolomics reveal immunometabolic pathways and predictive signatures for age-related eye diseases |
| Journal: | Metabolism |
| Published: | 30 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42066985/ |
| DOI: | https://doi.org/10.1016/j.metabol.2026.156624 |
Publication 20244
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Abstract
BACKGROUND AND AIMS: Age-related eye diseases (AREDs) share aging as a major risk factor, but the systemic molecular changes preceding disease onset remain incompletely understood. We aimed to define the shared and disease-specific immunometabolic architecture of major AREDs and to examine how circulating molecular features relate to retinal phenotypes, pre-diagnostic patterns, and disease risk.</p>
METHODS: We performed a large-scale prospective multi-omics study in the UK Biobank integrating baseline plasma proteomics, metabolomics, retinal imaging-derived phenotypes, and longitudinal follow-up across five major AREDs: age-related macular degeneration, cataract, diabetic retinopathy, glaucoma, and retinal vascular occlusion. Cox regression, functional enrichment, protein-metabolite correlation, mediation analysis, trajectory analysis, and machine-learning models were applied.</p>
RESULTS: Proteome-wide analyses identified both shared and disease-specific circulating signatures, mainly involving immune, extracellular matrix, vascular, and stress-response pathways. Reconstructed population-level molecular patterns diverged from controls up to 15 years before diagnosis, with marked heterogeneity across diseases. Integration with retinal imaging linked immune- and matrix-related proteins to retinal neurodegenerative and microvascular phenotypes. Metabolite clustering and mediation analyses highlighted recurrent lipoprotein-related pathways, particularly HDL-related structure and composition, as cross-layer features associated with systemic protein signals, metabolic states, and disease risk. Combined proteomic-metabolomic models improved prediction of incident disease compared with protein-only models.</p>
CONCLUSIONS: Major AREDs share a systemic immunometabolic aging architecture while retaining substantial disease-specific molecular features. Circulating molecular alterations are detectable years before clinical onset and may support future biological stratification and risk prediction.</p>
11 Keywords
- Aged
- Aging
- Eye Diseases
- Female
- Humans
- Macular Degeneration
- Male
- Metabolomics
- Middle Aged
- Prospective Studies
- Proteomics
4 Authors
- Xuehao Cui
- Qiuchen Zhao
- Jiajia Yuan
- Patrick Yu-Wai-Man
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