Researchers here show that present epigenetic clocks perform poorly in the context of retinal aging and the dysfunction of age-related macular degeneration. Epigenetic age acceleration is the difference between epigenetic age as assessed by the clock algorithm and chronological age. In the more established clocks, a higher epigenetic age correlates with risk of mortality and many age-related conditions. It remains largely unknown as to how specific forms of age-related damage and dysfunction lead to specific epigenetic changes, however, and therefore poor performance in any given use case can only be discovered, not predicted in advance. This makes it a challenge to use epigenetic clocks in their most desired capacity, as a low-cost, fast alternative to life span studies in the assessment of potential rejuvenation therapies.
This is the first study to our knowledge formally evaluating whether epigenetic age acceleration (EAA) in Horvath-multi tissue, Hannum, and Skin and Blood epigenetic clocks is associated with age-related macular degeneration (AMD) and important risk factor covariates including smoking status. We sought to address whether EAA is observed in the retinal pigment epithelium (RPE), as it is a primary site of AMD pathogenesis, and in whole blood, as the epigenetic clocks have been widely applied and validated in blood-derived genomic DNA.
EAA was not observed in AMD. However, we observe positive EAA in blood of smokers, and in smokers with AMD. In the RPE, we observed a marked negative EAA across all groups with no significant differences in EAA between AMD and normal samples using all three clocks. This result cannot be characterised as true negative age acceleration because of poor performance of the epigenetic clocks in RPE. The consistent poor correlation of predicted DNAm age with chronological age observed in the RPE markedly improved when analysing whole blood-derived genomic DNA data, explained by the datasets used to train each respective epigenetic clock.
Reasonable performance of each respective epigenetic clock in whole blood strengthens the observation of no association of EAA with AMD in blood, though this remains open to further investigation in the RPE, which can be addressed using a bespoke RPE epigenetic clock with greater predictive accuracy. Construction of a tissue-specific RPE clock is necessary for future studies to capture the specific epigenetic ageing processes in the RPE.