How can NAD+ and Exercise support Healthy Aging?

Increasing healthspan, not just lifespan

Could a combination of NAD+ and exercise be the key to staying healthy well into later life?

In modern societies, thanks to advances in healthcare and nutrition, we live a lot longer than we used to. But as well as increasing our lifespan, we need to understand how to prolong our healthspan — our capacity to maintain good health throughout our lifetime.

As we age, we are more likely to develop certain diseases, such as diabetes or Alzheimer’s, and experience physical limitations, such as impaired mobility and frailty. At the cellular level, many of these difficulties are related to the breakdown of healthy energy production (metabolism) in our body, including in our muscles (Uchitomi et al., 2019; Janssens et al., 2022)

This breakdown puts our cells in our muscles under greater oxidative stress, makes them less effective, and decreases their sensitivity to insulin, which leads to aging-related physical and metabolic decline.

One of the key molecules in our cells responsible for healthy metabolism is a “helper molecule” (coenzyme) called nicotinamide adenine dinucleotide (NAD+). As we age, our NAD+ levels naturally drop (Massudi et al., 2012), and our body begins to function less well — unless we (literally!) take steps to counteract this trend.

How much exercise do I need to do in old age?

Healthcare professionals have long emphasized how crucial regular exercise is to our health, especially as we age.

The 2018 Physical Activity Guidelines from the U.S. Department of Health & Human Services (Piercy et al., 2018) recommend the following amounts of exercise for older adults (65 years of age and older):

● At least 150–300 minutes per week of moderate-intensity exercise, such as yoga or recreational swimming;

● Or at least 75–150 minutes of high-intensity exercise, such as running or playing tennis;

● Or an equivalent mixture of moderate- and high-intensity exercise.

Regularly exercising in this way benefits our health in many ways, including reducing the risk of heart disease and stroke, improving sleep and brain function, and strengthening bones and muscles.

How are NAD and exercise connected?

In an important study published in February 2022, scientists investigated the effect of exercise on NAD+ levels in the muscles of younger and older adults (Janssens et al., 2022).

As well as a group of young adults (20–30 years old) with typical levels of physical activity (10,000 steps per day), they looked at the connection between NAD and exercise in three groups of older adults:

1. Exercise-trained older adults — who took 13,000 steps per day on average;

2. Normal older adults — who took approximately 10,000 steps each day;

3. Impaired older adults — who moved less, with only 6,000 steps a day on average.

Their findings were remarkable. Not only did exercise increase levels of NAD+ in older adults, but levels in exercise-trained older adults were raised to the same as those in the young adults!

The study also confirmed that NAD+ is especially important in aging well — out of the 137 metabolism-related molecules measured, NAD+ was the most strongly associated with healthy aging.

How can I boost levels of NAD in my body?

In addition to natural ways of boosting NAD+ such as exercise, NAD+ supplements and intravenous NAD+ injections are proven ways of increasing NAD+ levels in the body (Yoshino et al., 2021; Grant et al., 2019).

The two most popular and effective NAD+ supplements available today are:

1. Nicotinamide riboside (NR);

2. Nicotinamide mononucleotide (NMN).

You can take these NAD+ precursors orally or via a transdermal patch. Once absorbed into the body, NR and NMN are converted into NAD+. Intravenous injections, on the other hand, raise NAD+ levels by delivering it directly into the bloodstream.

Is combining NAD and exercise the key to optimal health?

So what is the most effective approach to raising NAD+ levels, especially for physical health? Clinical trials investigating NAD+ supplements suggest that taking NAD boosters alone might not be enough to improve muscle and cardiovascular function (Custodero et al., 2020).

Given that NAD+ boosters and exercise both increase NAD+ levels in our body, might combining NAD and exercise provide the best route to healthy aging?

Although the scientific evidence for this is mixed at the moment (Kourtzidis et al., 2018; Custodero et al., 2020), some animal studies point in a positive direction — in one study (Crisol et al., 2019), combining NR and exercise increased the distance mice were able to run by a third, compared with exercise alone; in another study (Das et al., 2018), NMN improved physical endurance and blood flow to muscles in old mice.

These studies provide tantalizing hints that NAD and exercise could work synergistically to improve physical health in older adults. Together, they might just hold the secret to living a life that’s not only longer, but healthier too.

References

Crisol, B. M., Veiga, C. B., Braga, R. R., Lenhare, L., Baptista, I. L., Gaspar, R. C., ... & Ropelle, E. R. (2020). NAD+ precursor increases aerobic performance in mice. European Journal of Nutrition, 59(6), 2427-2437. https://doi.org/10.1007/s00394-019-02089-z

Custodero, C., Saini, S. K., Shin, M. J., Jeon, Y. K., Christou, D. D., McDermott, M. M., ... & Mankowski, R. T. (2020). Nicotinamide riboside—A missing piece in the puzzle of exercise therapy for older adults?. Experimental Gerontology, 137, 110972. https://doi.org/10.1016/j.exger.2020.110972

Das, A., Huang, G. X., Bonkowski, M. S., Longchamp, A., Li, C., Schultz, M. B., ... & Sinclair, D. A. (2018). Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell, 173(1), 74-89. https://doi.org/10.1016/j.cell.2018.02.008

Grant, R., Berg, J., Mestayer, R., Braidy, N., Bennett, J., Broom, S., & Watson, J. (2019). A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD. Frontiers in Aging Neuroscience, 11, 257. https://doi.org/10.3389/fnagi.2019.00257

Janssens, G. E., Grevendonk, L., Perez, R. Z., Schomakers, B. V., de Vogel-van den Bosch, J., Geurts, J. M., ... & Hoeks, J. (2022). Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nature Aging, 2(3), 254-263. https://doi.org/10.1038/s43587-022-00174-3

Kourtzidis, I. A., Dolopikou, C. F., Tsiftsis, A. N., Margaritelis, N. V., Theodorou, A. A., Zervos, I. A., ... & Nikolaidis, M. G. (2018). Nicotinamide riboside supplementation dysregulates redox and energy metabolism in rats: Implications for exercise performance. Experimental Physiology, 103(10), 1357-1366. https://doi.org/10.1113/EP086964

Massudi, H., Grant, R., Braidy, N., Guest, J., Farnsworth, B., & Guillemin, G. J. (2012). Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue. PLOS ONE, 7(7), e42357. https://doi.org/10.1371/journal.pone.0042357

Piercy, K. L., Troiano, R. P., Ballard, R. M., Carlson, S. A., Fulton, J. E., Galuska, D. A., George, S. M., & Olson, R. D. (2018). The Physical Activity Guidelines for Americans. JAMA, 320(19), 2020–2028. https://doi.org/10.1001/jama.2018.14854

Uchitomi, R., Hatazawa, Y., Senoo, N., Yoshioka, K., Fujita, M., Shimizu, T., ... & Kamei, Y. (2019). Metabolomic analysis of skeletal muscle in aged mice. Scientific Reports, 9(1), 1-11. https://doi.org/10.1038/s41598-019-46929-8

Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., ... & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229. https://doi.org/10.1126/science.abe9985