Resilience and vulnerability in the midbrain dopamine system during aging

The midbrain dopamine system is integral to movement, reward, and motivation, and its dysfunction underlies a range of brain disorders. Age is a primary risk factor for many of these disorders, yet systematic analysis of how the dopamine system changes during healthy aging remains relatively understudied. In this review, we first examine the impact of healthy aging on the dopamine system across sexes and species, including flies, mice, rats, and humans. We next consider the neuroadaptive mechanisms that sustain dopamine neuron function with age. Finally, we contrast the molecular mechanisms of age-related neurodegenerative diseases with those of healthy aging, exploring the possibility that loss of neuroadaptive reserve drives dopamine neurodegeneration. Elucidating these neuroadaptive mechanisms could offer a path toward preserving dopamine neuron function across the lifespan and potentially preventing age-related neurodegeneration.