Does Regular Exercise Increase Brain NAD+ Levels and Affect Cognitive Function in Aging Mice?

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme in all living cells and is involved in neurogenesis, inflammation, the immune system, and DNA repair. The level of intracellular NAD+ reportedly decreases with age in tissues and organs, including the brain. This systemic decrease in NAD+ levels during aging is partly due to decreased nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the major NAD+ biosynthetic pathway in mammals. Furthermore, brain-specific NAMPT knockdown in young and aged mice reportedly reduces hippocampal NAD+ levels and contributes to the development of cognitive impairment. Additionally, the preventive effect of regular exercise against age-related cognitive decline is widely known. However, no research on the relationship between hippocampal NAD+, especially NAMPT levels, and improved cognitive function due to exercise has been published. Here, we aimed to determine whether regular exercise increases NAD+ levels in the hippocampus and prevents cognitive decline. Twenty-month-old female C57BL/6J mice were divided into four groups: (1) the SAL group (saline [SAL] only), (2) FK group (FK866 [FK; a NAMPT inhibitor] only), (3) SAL + Ex group (SAL + regular voluntary exercise [Ex]), and (4) FK + Ex group. All mice were intraperitoneally injected three times a week for four weeks, specifically before exercise in the SAL + Ex and FK + Ex groups. We revealed that regular exercise improved working and long-term memory in aged mice. In addition, regular exercise increased NAMPT, BDNF mRNA expression, and NAD+ levels in the hippocampus in an age-related manner. Our results suggest that the prevention of cognitive decline and improvement of cognitive function in aged mice via regular exercise are associated with increased NAD+ levels via increased NAMPT levels in the hippocampus.