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Deep learning aging marker from retinal images unveils sex-specific clinical and genetic signatures

Trofimova, O.; Böttger, L.; Bors, S.; Pan, Y.; Liefers, B.; Beyeler, M. J.; Presby, D. M.; Bontempi, D.; Hastings, J.; Klaver, C. C. W.; Bergmann, S.

2025-07-29 radiology and imaging
10.1101/2025.07.29.25332359 medRxiv
Show abstract

Retinal fundus images offer a non-invasive window into systemic aging. Here, we fine-tuned a foundation model (RETFound) to predict chronological age from color fundus images in 71,343 participants from the UK Biobank, achieving a mean absolute error of 2.85 years. The resulting retinal age gap, i.e. the difference between predicted and chronological age, was associated with cardiometabolic traits, inflammation, cognitive performance, all-cause mortality, dementia, cancer, and incident cardiovascular disease. Genome-wide analyses identified genes related to longevity, metabolism, neurodegeneration, and age-related eye diseases. Sex-stratified models revealed consistent performance but divergent biological signatures: males had younger - appearing retinas and stronger links to metabolic syndrome, while in females, both model attention and genetic associations pointed to a greater involvement of retinal vasculature. Our study positions retinal aging as a biologically meaningful and sex-sensitive biomarker that can support more personalized approaches to risk assessment and aging-related healthcare.

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