Longevity & AgingNew Feedback Loop Between Lactate and RNA Methylation Drives Macular Degeneration
Researchers identified a self-amplifying molecular loop driving age-related macular degeneration (AMD). In diseased retinal pigment epithelium (RPE), the RNA demethylase ALKBH3 is overexpressed, stripping m1A methyl marks from HK2 and VEGFA mRNAs, boosting their stability and ramping up glycolysis and angiogenesis. Excess lactate from accelerated glycolysis lactylates histone H3K18, which then transcriptionally amplifies ALKBH3 expression—completing a vicious positive feedback cycle. Breaking this loop with the ALKBH3 inhibitor HUHS015 reduced RPE degeneration and, combined with anti-VEGF drug Aflibercept, synergistically suppressed choroidal neovascularization (CNV) in mouse models. The findings reframe AMD as a metabolic-epigenetic disease and open new therapeutic avenues.
