From oxidative damage to actionable lesion: Telomeric 8-oxoGuanine and OGG1 modulation in aging and disease.

Oxidative stress is widely implicated in aging and chronic disease, but current insights have not led to the definition of a lesion state in the progression of disease or to broad guidance of therapy. So far, reactive oxygen species describe a chemical environment rather than a specific molecular entity. In contrast, 8-oxoG represents a defined oxidative DNA lesion with a defined genomic context impacting biological processes. Here, we propose that 8-oxoG and its downstream repair intermediates define a functionally relevant lesion state at telomeres. At chromosome ends, oxidized guanine can impair replication, activate DNA damage signalling, contribute to telomere attrition and drive senescence. Still, persistent lesions and the toxicity of downstream base excision repair intermediates contribute to this process. This distinction has direct therapeutic consequences: OGG1 inhibitors suppress inflammatory and transcriptional responses, whereas activators and organocatalytic switches promote lesion clearance. We propose that going forward, the choice between these strategies should depend on the dominant lesion state rather than global measures of oxidative stress.