Progresses in both basic research and clinical trials of NAD+ in Parkinson's disease

The decline of nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of aging in multiple organisms and tissues, including the human brain. Hence, agents that increase intracellular NAD+ could have beneficial effects in aging and age-related neurodegenerative diseases. Disturbances in NAD+ metabolism have also been observed in Parkinson's disease (PD), supporting a link between neuronal bioenergetics failure and disease pathogenesis. Here, we review emerging findings revealing key roles for NAD+ and related metabolites in experimental models of dopaminergic neurodegeneration and in PD patients. We discuss how increased NAD+ levels might ameliorate disease phenotypes by restoring neuronal mitochondrial energy metabolism, promoting cellular proteostasis, and modulating the immune system. Finally, we describe ongoing clinical trials targeting NAD+ in PD and highlight the need for further investigations to better delineate the association between NAD+, brain aging and disease, and optimal strategies for efficiently and safely raising NAD+ levels. A more comprehensive understanding of the basic mechanisms linking NAD+, energy metabolism, and PD, and of the impact of life-long NAD+ targeting strategies, are critical to inform future clinical applications.