Tracing the Metabolic Flux of Orally Administered NAD+ Precursors in Healthy Young and Older Adults

Background and Significance

1.1 Role of NAD+ in Physiology Nicotinamide adenine dinucleotide (NAD+) is a key coenzyme in all living organisms, existing in oxidized (NAD+) and reduced (NADH) forms. Beyond its vital role in redox reactions and ATP generation, NAD+ also serves as a co-substrate for several signaling enzymes such as sirtuins, PARPs, and CD38. Systemic NAD+ insufficiency can cause diseases like pellagra; reduced NAD+ availability has been implicated in aging and age-related disorders.

1.2 Oral NAD+ Precursors Administration of NAD+ precursors (e.g., NMN, NR, NAM) can boost NAD+ levels. Although human research has shown that oral NMN raises blood NAD+ concentrations, many aspects of its absorption, metabolism, and overall bioavailability are still poorly understood. Rodent studies suggest oral NMN undergoes extensive first-pass metabolism in the gut, with partial conversion to NAM prior to entering systemic circulation.

1.3 Aging and NAD+ In rodent models, NAD+ levels frequently decline as the animals get older. Some evidence indicates that NAD+ turnover may be elevated in aging rodents, suggesting a higher rate of NAD+ consumption. However, equivalent tracer studies have not yet been conducted in humans.

1.4 Need for Human Tracer Studies These compounds are being investigated for the prevention and treatment of age-related diseases. There is a need to clarify how they are absorbed and how exactly they elevate NAD+ in different tissues. Using stable isotope-labeled NMN and NAM will help map the flux from oral precursors into blood, muscle, urine, and stool, and will also reveal how aging influences NAD+ turnover.