Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health.

Comprehensive narrative review

“This manuscript was carried out as a comprehensive narrative review, with the goal of synthesizing current evidence on NAD+ metabolism, NAD+ precursors derived from vitamin B3, exercise interventions, interactions involving the gut microbiota, and their possible contributions to brain aging and NDDs.”

Molecular mechanisms, preclinical models (cellular and animal), and human clinical investigations regarding NAD+ metabolism, brain aging, and neurodegenerative disorders

“Both preclinical research (cellular and animal models) and human studies were included to offer a translational perspective, with particular emphasis on studies assessing NAD+ precursors, exercise-related regulation of NAD+, and microbiota-driven metabolic pathways.”

NAD+ decline is linked to mitochondrial dysfunction, oxidative stress, and cognitive deterioration in brain aging

“A decline in NAD+ with age may trigger a cascade of linked pathological processes, such as diminished mitochondrial ATP production, greater accumulation of reactive oxygen species (ROS), decreased DNA repair capacity, and sustained inflammatory activation.”

Vitamin B3 precursors increase NAD+ levels but clinical evidence for cognitive benefits in humans remains limited

“Current clinical investigations are evaluating their safety, pharmacokinetics, effects on NAD+-related biomarkers, and potential functional outcomes, but definitive evidence for disease-modifying effects in NDDs is not yet available.”

Exercise modulates NAD+ metabolism and neurotrophic signaling, though direct translation to cognitive outcomes in humans is uncertain

“However, the extent to which exercise-induced changes in NAD+ directly contribute to cognitive or disease-related outcomes in humans remains uncertain.”

Definitive therapeutic applications require further validation, and evidence for direct causal links between microbiome changes and brain NAD+ availability is scarce

“Nonetheless, the evidence for direct causal links between changes in the microbiome and brain NAD+ availability is still scarce, underscoring a key translational gap that calls for longitudinal human studies.”