A combined artificial intelligence–wet lab approach identifies a pivotal role of the NAD + –mitophagy axis on aging and neurodegeneration

Abstract INTRODUCTION Emerging evidence points to a role of nicotinamide mononucleotide (NAD + ) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age‐dependent impairment of the NAD + –mitophagy axis contributes to brain aging and neurodegeneration. METHODS We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD + –mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans , a human Tau cell model, and induced pluripotent stem cell (iPSC)‐derived cortical neurons. RESULTS The NAD + –mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD‐protective genes ( ULK1 , OPA1 , LAMP2 , MFN1 , and ATP6V0E1 ) linked to synaptic resilience and/or reduced Tau pathology. DISCUSSION Our study combines artificial intelligence‐driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD + –mitophagy axis as a central player in brain aging and AD.