Clinical Study Suggests When to Start Taking NAD⁺ Boosters to Improve Exercise

Key Points: 

• 500 mg of NR supplementation for ten days reduces oxidative stress and increases exercise performance in old but not young men.  
• Reduced oxidative stress and enhanced physical performance in older men may be due to increased NADH and NADPH. 

NAD+ is an important molecule that keeps our cells, organs, and bodies alive. Because the decline in NAD+ that occurs with age is associated with age-related disease and decreased lifespan, boosting NAD+ has become of great interest. Boosting NAD+ could mitigate age-related disease and increase lifespan. However, whether boosting NAD+ is beneficial for young people is not clear. It could be that young people already have enough NAD+ to support their cells, organs, and body. 

As reported in the European Journal of Nutrition, Dolopikou and colleagues from Aristotle University of Thessaloniki in Greece show that boosting NAD+ with NR improves exercise performance and oxidative stress levels in older men, but not younger men. These findings suggest that NR supplementation may benefit the elderly but not young and healthy individuals. 

Study Design 

NR (nicotinamide riboside) is a precursor to NAD+, taken in pill form, our cells metabolize NR to produce NAD+. To determine the effect of boosting NAD+ with NR in young versus old individuals, Dolopikou and colleagues recruited 12 young and 12 old men. As part of the study, the men took a placebo or 500 mg of NR for ten days. Before and after taking the NR or placebo, the participants performed several exercises to test their physical performance. Blood and urine samples were also taken to measure various metabolites associated with oxidative stress. 

Oxidative Stress Reduced in Older Men 

Oxidative stress increases with age due to the accumulation of reactive oxygen species (ROS) and the decline of antioxidant defenses. This was verified by Dolopikou and colleagues, as they found that old men had higher oxidative stress levels and tended to have lower antioxidant levels compared to young men. 

NAD+ may reduce oxidative stress by increasing antioxidant defenses and preventing ROS buildup. Indeed, the Greek researchers found that boosting NAD+ with NR decreased oxidative stress levels and tended to increase antioxidant levels in old men. However, NR’s effects on antioxidants were not uniform across the board in young men. For example, in some instances, antioxidants were increased (superoxide dismutase) and in others decreased (GPx).

Overall, these findings suggest that boosting NAD+ with NR decreases oxidative stress in older men, but the effect is not as strong in younger men. This could be due to the elevated oxidative stress levels that occur with aging, making oxidative stress higher in older men. Thus, there could be less room for improvement in the young men, who have not lived long enough to have high levels of oxidative stress. 

NADH and NADPH Increased in Older Men

Dolopikou and colleagues point out that many studies neglect one of the primary functions of NAD+, its role as an electron carrier. Nearly all cellular processes involve the movement of electrons from molecule to molecule. NAD+ and NADP (the phosphorylated form of NAD+) carry and transfer electrons and are involved in many of these processes. In their electron carrying form, NAD and NADP are denoted as NADH and NADPH, respectively (“H” is for hydrogen). 

Increasing the levels of NADH and NADPH could potentially enhance many of the reactions that require electron transfer. The Aristotle University scientists tested the effect of boosting NAD+ with NR on the status of NADH and NADPH in old and young men to find that NR increases both NADPH and NADH levels in both groups, suggesting increased potential for many cellular processes. 

Lactate Metabolism Increased in Older Men

When we exercise, one of the metabolites that builds up is lactate. Lactate is generated by an enzyme called lactate dehydrogenase (LDH), one of the many enzymes that uses NADH to function. Every time LDH generates a lactate molecule, it converts an NADH to an NAD+ by receiving an electron. 

To determine the effect of NR on exercise metabolism, Dolopikou and colleagues measured LDH and lactate levels in old and young men. They found that NR increased LDH levels in old but not young men. NR also induced a larger increase in lactate at the end of a fatigue test in old but not young men, suggesting that NR increased LDH activity.  

Physical Performance Increased in Older Men

To determine the effect of boosting NAD+ with NR on physical performance, Dolopikou and colleagues measured the strength and endurance of the old and young men. They found that NR increased the strength (isometric knee extensor peak torque) of old but not young men. NR also improved the resistance to fatigue (30 reps of maximal voluntary contractions) in old but not young men. Concentric strength and oxygen consumption were unchanged by NR supplementation in both groups. 

Is Boosting NAD+ in Younger Individuals Beneficial?

Dolopikou and colleagues hypothesized that since older adults have lower levels of NADPH, boosting NAD+ with NR would help improve their physical capacity. This is because NADH and NADPH are involved in regulating ROS, which during exercise contribute to fatigue. Overall, their hypothesis was correct, given that oxidative stress was reduced and exercise performance enhanced by NR in older men. 

The findings suggest that boosting NAD+ is only beneficial for older individuals. However, the young men had an average age of about 23, whereas the old men had an average age of about 77, which excludes a large range of ages. It could make sense that taking NR is not beneficial to people in their early twenties when they are still in their prime, but not the ages in between. 

Perhaps the more pertinent question is, what age does it become beneficial to start boosting NAD+? In the case of preventing the decline of physical performance, maybe this age would be around 40 since this is when age-related muscle decline (sarcopenia) can begin. Or, maybe it would be better to start boosting NAD+ before manifestations of physical decline are detectable? Maybe, in the future, it will be easier to have our NAD+ levels measured routinely to pinpoint the age at which we should start boosting NAD+.