Exercise Promotes Cell-to-Cell Communication to Boost NAD+ Levels

As we age, we move less, and our muscles weaken. We digest food and excrete waste less efficiently, and our ability to burn calories becomes sluggish. These characteristics are part of the downward spiral in the speed of our metabolism. And at the core of metabolic processes is NAD+ (nicotinamide adenine dinucleotide), a cofactor to myriad enzymatic reactions critical for cell health, which also declines with aging.  

Research from the Swinburne University of Technology in Australia shows that exercise triggers the release of tiny sacs—extracellular vesicles (EVs)—into the bloodstream containing an enzyme critical to synthesizing NAD+. These extracellular vesicles then deploy to other tissues and release an enzyme called eNAMPT that promotes NAD+ levels. This mechanism of extracellular vesicle signaling appears to have some link to both age and the physical activity level of an individual. In this way, exercise increases the release of extracellular vesicles and the release of the enzyme critical for NAD+ synthesis, predominantly in young individuals with higher aerobic fitness. In comparison, mature individuals with lower aerobic fitness showed no increased release of extracellular vesicles and the enzyme in response to exercise.

These findings suggest that starting and continuing to exercise through adulthood may support healthy aging by boosting extracellular vesicle release for NAD+ production in specific tissues throughout the body. “Our results suggest a mechanism to limit age-related NAD+ decline through the systemic delivery of eNAMPT via EVs released during exercise,” wrote senior author and neurobiologist Jason Howitt, Ph.D.

EV Phone Home

The decrease in NAD+ production has been linked to the age-related loss of circulating eNAMPT (extracellular nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in the NAD+ biosynthetic pathway. This enzyme produces NMN, the direct precursor to NAD+, and is found almost exclusively in little sacs called extracellular vesicles, which shuttle the enzyme between cells in the same or different tissues. But, it is unclear what regulates the release of eNAMPT and whether this process may be affected by age and physical exercise.

Exercise Enhances NAD+ through Extracellular Vesicles

Exercise remains a promising intervention to improve health and physical function in older adults. However, at a cellular level, our understanding of the multisystem effects of exercise is not well understood. This open question led the Australian research group to investigate the release of eNAMPT in extracellular vesicles after moderate-intensity exercise in both young and mature individuals to determine the influence aging and exercise have on extracellular signaling pathways involved in NAD+ biosynthesis.

Howitt and colleagues show that the release of small extracellular vesicles into the bloodstream is stimulated following moderate-intensity exercise in humans. Exercise also increased the eNAMPT content in extracellular vesicles, particularly in young individuals with higher aerobic fitness. Both mature-fit and young-unfit individuals exhibited a limited increase in eNAMPT-filled extracellular vesicles release following exercise, indicating that this mechanism is related to a person's age and physical fitness. Notably, unfit mature individuals could not increase the release of eNAMPT in extracellular vesicles after exercise, suggesting that lower fitness levels and aging attenuate this crucial signaling mechanism in the body.

While the number of released eNAMPT-filled extracellular vesicles and the amount of eNAMPT in the vesicles increased as a result of exercise, Howitt and colleagues still needed to show whether this had any effect on NAD+ levels and related signaling. The Australian researchers went on to show that the extracellular vesicles isolated from exercising humans containing eNAMPT were able to alter the abundance of NAD+ in recipient cells compared to pre-exercise extracellular vesicles, indicating a pathway for inter-tissue signaling promoted through exercise. Additionally, the activity levels in SIRT1, an enzyme linked to lifespan and healthy aging that depends on NAD+ to function, increased in correlation to the changes in eNAMPT signaling.

These results suggest a mechanism to limit age-related NAD+ decline through the systemic delivery of eNAMPT via extracellular vesicles released during exercise. “Our findings illustrate the important role that exercise has in promoting cellular crosstalk via extracellular vesicles to improve health during aging,” wrote Howitt and colleagues. It will be interesting to compare the effects of exercise-induced increases in NAD+ with supplementation of NAD+ precursors, such as NMN and NR. This understanding could have significant implications for older and less mobile individuals where exercise is not ideal or even in the cards.

References:

Chong MC, Silva A, James PF, Wu SSX, Howitt J. Exercise increases the release of NAMPT in extracellular vesicles and alters NAD+ activity in recipient cells. Aging Cell. 2022;e13647. doi:10.1111/acel.13647