Boosting NAD metabolism to prevent pathological brain aging

In response to the urgent need for effective interventions in age-related cognitive dysfunction and dementia, our research proposal addresses the challenge of delayed treatment initiation and the potential of dietary interventions. We aim to prevent pathological brain aging and cognitive disorders by targeting brain metabolism early. Our pilot study adopts a double-blind, placebo-controlled design, focusing on older, frail individuals not yet affected by dementia. Central to our approach is nicotinamide adenine dinucleotide (NAD)-replenishment therapy using nicotinamide riboside (NR), aimed at enhancing neuronal resilience and resistance to cognitive disorder-related stresses. We will leverage our clinical and translational expertise in trials, nutrition, metabolism, the gut microbiome, and neurodegeneration. Clinical endpoints, imaging, and biological samples will be collected to investigate the interplay between nutrition, the gut microbiome, host metabolism, cognitive function, and NR treatment response. Our specific aims include assessing NR treatment’s efficacy in reducing physical and cognitive dysfunction in aging-related frailty, its potential to lower the risk of cognitive dysfunction and dementia, and analyzing individual variability in NAD bioavailability and clinical effects post-NR intake. We will also elucidate the gut microbiome’s role in NR and NAD metabolism and its impact on clinical responses, as well as NR treatment’s effects on microbiome composition and metabolism. Additionally, we will explore the relationship between dietary factors and cognitive function in large cohorts of older individuals. Ultimately, this research promises to transform our approach to dementia and cognitive disorders, offering new pathways for innovative, nutrition-based therapeutic and preventive interventions that could change the landscape of treatment and prevention strategies for these debilitating conditions.