Multi-omics liquid biopsy identifies mitochondrial dysfunction in geographic atrophy and supports the longevity-associated metabolite α-ketoglutarate as a therapeutic strategy

<b>Questions:</b> What specific mitochondrial and TCA-cycle dysfunctions occur in the aqueous humor (AH) of patients with geographic atrophy (GA), and can oral α-ketoglutarate (α-KG) supplementation measurably remodel these metabolic pathways in the living human eye?<b>Findings:</b> AH proteomics in GA patients revealed significant mitochondrial disruption and a coordinated depletion of TCA-cycle enzymes. In a paired-eye interventional metabolomics study, oral α-KG significantly increased intraocular α-KG levels and the α-KG-to-succinate ratio, proving that systemic therapy can drive measurable metabolic modulation within the human eye.<b>Meaning:</b> Multi-omics liquid biopsy provides a direct, eye-specific readout of mitochondrial metabolism in GA and offers early human proof-of-concept that a systemic metabolic therapy can successfully reach and modify intraocular pathways, paving the way for biomarker-guided clinical trials in AMD.