ODC1 delays neurodegenerative processes in aging by promoting ammonia detoxification via neuronal urea cycle activation

Aging represents a natural and inevitable physiological process characterized by the gradual deterioration in the functions of various organ systems. One of the central hallmarks of aging is the dysregulation of both substance and energy metabolism. Previous research has associated the urea cycle (UC) with the development of neurodegenerative diseases. In this study, we observed elevated levels of urea, the end-product of the UC, upregulation of urea cycle enzymes, and an increase of the side-product putrescine in the elderly serum and aging models, while the initial substrate ammonia remained unchanged. Notably, region-specific accumulation of neuronal urea and activation of the UC were associated with age-related deficits in cognitive and motor functions. Mechanistically, urea accumulation in the brain appears to stem from dysregulated UC activity coupled with compensatory clearance mediated by the urea transporter UT-B. Exposing neurons to high urea levels accelerated UC flux and induced cellular senescence. Importantly, pharmacological inhibition or knockdown of ornithine decarboxylase 1 (ODC1) ameliorated urea metabolic dysregulation and reduced neuronal damage. Together, these findings reveal a novel connection between dysregulated neuronal urea cycle activity and age-related neural impairment, linking metabolic reprogramming to neurodegenerative pathology. Our results not only uncover a key metabolic mechanism underlying brain aging but also provide a promising dual-target therapeutic strategy, highlighting the urea cycle as a potential intervention point for delaying neurodegenerative processes associated with aging.