Australian Scientists Find Exercise Boosts NAD⁺ in Young but not Older Adults

Researchers in Australia find that exercise triggers the release of vesicles (membrane-bound sacs) containing the NAD+ synthesizing enzyme NAMPT and significantly boosts NAD+ in young but not older males.

Key Points:

Twenty minutes of cycling exercise triggers the release of tiny membrane-bound sacs called extracellular vesicles (EVs) containing NAMPT.
Post-exercise EVs from fit young males but not young unfit or older males raise NAD+ levels in mouse muscle cells.
An enzyme associated with longevity and prolonged lifespan called sirtuin 1 (SIRT1) is increased by post-exercise EVs derived from young but not older participants.

Nicotinamide adenine dinucleotide (NAD+) is essential for energy production and involved in key cellular processes associated with prolonging lifespan like DNA repair. The drop in NAD+ associated with aging has been reported to underlie nearly all age-related diseases, including neurodegeneration, diabetes, and cancer. Raising NAD+ levels has therefore become of great interest to aging individuals who wish to slow down the aging process. However, a new study shows that, for older adults, exercise isn’t enough to raise NAD+ levels.

As reported in Aging Cell, Chong and colleagues from Swinburne University of Technology in Australia show that exercise boosts NAD+ levels in young but not older adults. It was shown that 20 minutes of cycling triggered the release EVs containing the enzyme NAMPT, which synthesizes NAD+. Post-exercise EVs isolated from fit young but not unfit young or mature participants raised NAD+ levels in mouse muscle cells. Additionally, post-exercise EVs from all young males but not mature males increased SIRT1 levels.

Cycling Raises NAD+ and Sirtuin Levels in Young Men

Forty healthy males were separated into groups based on their age and fitness level. Chong and colleagues isolated EVs (containing NAMPT) from the blood of the participants before and after they performed 20 minutes of cycling exercise. The EVs were then placed into a dish containing mouse muscle cells to measure NAD+ and SIRT1 levels inside of the cells. It was found that NAD+ levels were elevated in response to exercise in fit young males. Fitness levels were measured by the maximum level of oxygen consumed during exercise (VO₂max).

(Chong et al., 2022 | *Aging Cell*) **NAD+ Abundance Increases After Exercise in Young Fit Males. (c)** Mouse muscle cells (C2C12 cells) were treated with EVs pre-and post-exercise. Young (18-35 years) participants were placed into either an unfit (YX) or fit (YF) group. Mature (50-70 years) participants were also placed into either an unfit (MX) or fit (MF) group. (d) While NAD+ levels increased in response to exercise in the YX group, this was not different from controls. However, in the YF group, NAD+ increased in response to exercise relative to controls.

Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme that synthesizes NAD+ and is reduced in older adults. NAMPT enzymes are localized in EVs, which deliver NAMPT to cells throughout the body to increase NAD+ levels. While NAD+ itself is required for cellular energy production, it also activates SIRT1. SIRT1 plays a role in prolonging lifespan through several processes, including DNA repair. Chong and colleagues found that SIRT1 activity was increased in response to exercise in both fit and unfit young males.

(Chong et al., 2022 | *Aging Cell*) **SIRT1 Activity Increases After Exercise in Young Males.** Young (18-35 years) participants were placed into either an unfit (YX) or fit (YF) group. Mature (50-70 years) participants were also placed into either an unfit (MX) or fit (MF) group. SIRT1 activity increased in response to post-exercise EVs in both YX and YF males relative to controls.

How Else Can NAD+ be Boosted in Older Adults?

While Chong and colleagues showed that post-exercise EVs from mature males did not significantly boost NAD+ or SIRT1 levels, there is evidence showing that NAMPT vesicles increase within muscle cells in response to exercise and one study showed that NAD+ levels are higher in older adults who exercise routinely. This means that exercise may still be beneficial for older adults who wish to raise their NAD+ levels, not to mention the myriad of other benefits exercise has for all individuals.

While exercise may raise NAD+ levels in older adults, whether it is enough to reap the longevity and anti-aging benefits of NAD+ reported in animal studies is largely unknown. To help assure an increase in blood NAD+, NAD+ precursor supplements like nicotinamide adenine dinucleotide (NMN) and nicotinamide riboside (NR) may be utilized. NMN has been shown to raise blood NAD+ levels in middle-aged and older adults and improve muscle function in older adults. NR has been shown to increase exercise performance in older but not younger adults.

In the future, EVs containing NAMPT may be utilized to boost NAD+ levels. The Food and Drug Administration has approved clinical trials using EVs to treat conditions like ulcers (NCT02565264), sepsis (NCT02957279), and type 1 diabetes (NCT02138331), so it’s possible that EVs could be used to treat age-related conditions. Several authors of this study are either employees or shareholders of Exopharm Limited, a company that uses EVs as therapeutics, so NAD+ boosting EV therapies are in the works.