Pumping Up with NMN: How NMN Helps Optimize Physical Performance

Although we’d like to say that many of our characteristics may age like a fine wine, those related to physical performance pretty much don’t. The issue here is that maintaining physical mobility is essential to a happy and long life. Endurance and resistance training prevent mobility loss in aging, but exercise alone does not consistently achieve the expected improvements in our body’s function, including our muscles, lungs, and heart. Many of us look for ways to improve athletic performance and reach peak physical performance, especially those strategies that require the least amount of work. 

Levels of nicotinamide adenine dinucleotide (NAD+) — a vital molecule that plays a role in countless cell functions that include maintaining the health and functionality of muscle — decrease during aging. Exercise requires a higher energy expenditure than a resting state, so a state of NAD+ insufficiency with reduced energy metabolism could result in an inadequate exercise response. But studies in animals indicate that replenishment of cellular NAD+ can have beneficial effects on aging.  

That’s where NMN supplements come in. A growing pool of research shows that this NAD+ precursor supports physical performance in rodents by maintaining metabolic integrity and cell function in various organs. Now, we even have some data showing that NMN benefits our peak physical performance.

Exercise and muscle health

Regular exercise training has been recognized as a key component in successful aging promoting independence in older people. The benefits of exercise training in elders can affect the health of key organs, such as the brain, heart, pancreas, bones, and muscles.

The main goal of exercise interventions is preserving skeletal muscle and cardiovascular health — the heart and blood vessels, which comprise the circulatory system that holds the blood. Well-functioning skeletal muscle and cardiovascular systems are essential components for an effective response to acute exercise and adaptation to chronic exercise training.

Despite the largely recognized benefits of exercise training in preserving healthy aging of skeletal muscle and the cardiovascular system (Howden et al., 2018), it is becoming clear that the human responsiveness to exercise training varies (Redfield et al., 2005). Research has shown that poor fitness in middle age is associated with increased skeletal and cardiac muscle stiffness, a strong predictor of future risk of muscle loss and heart failure.

What’s more, exercise alone may not always induce the expected improvements in physical function among older adults. In particular, even when participants engage in carefully controlled exercise training regimens, the nature of the training response is mixed. Lifestyle modification with an optimized exercise program including high-intensity and moderate-intensity exercise training is an effective strategy to reverse the effects of sedentary aging on the heart.

Muscle and aging

Skeletal muscle enables us to do some of the most basic, essential functions, such as maintaining posture, breathing, and locomotion. Without our skeletal muscles, we are no longer mobile or able to lift objects. In other words, skeletal muscle is not only critical for exercise; it is central to human life.

Age-related loss of skeletal muscle mass and function, medically termed sarcopenia, is linked to physical frailty, morbidity, and mortality. The loss of muscle mass occurs incipiently from middle-age (roughly 1% per year), and in severe instances, can lead to a loss of about 50% by 70 years of age (Wilkinson et al., 2018).

Also, as we get older, an accumulation of several factors can contribute to heart aging. For example, researchers have found that cells in the heart become susceptible to dysfunction of mitochondria — the cell’s power-generating structures — and other cellular physiological changes that contribute to cardiac aging. These cause heart thickening (hypertrophy), scarring (fibrosis), and poorer pumping abilities (systolic and diastolic function).

The link between NAD+ and muscle health

Skeletal muscle is energetically expensive and is a significant consumer of sugars (glucose) and fats (fatty acids). NAD+ plays a vital role in energy production as it is required to metabolize sugar and fat. Also, NAD+ is a significant player in skeletal muscle development, regeneration, and aging. Many studies indicate that lower NAD+ levels are harmful to muscle health and higher NAD+ levels augment muscle health.

Recent evidence in animals suggests that one reason for the variability in the responsiveness to exercise training may be the age-related unbalancing of NAD+ metabolism. The poor-exercise-response phenomenon could be related to the observed NAD+ decline that occurs during aging. There is also evidence of a strong inverse correlation between NAD+ levels and age in human tissues; as NAD+ goes down, cell and tissue age increases. Restoring NAD+ balance has been proposed as one of the most promising strategies to counteract this functional decline.

What are the benefits of NMN?

NMN has been shown to improve peak physical performance in rodents. In mice, there have been several studies that are a springboard for studying the effect of NMN on physical performance:

NMN increases skeletal muscle mitochondrial function

NMN has also been reported to improve mitochondrial function in various metabolic organs, including skeletal muscle. In a study out of a Harvard lab focused on the anti-aging effects of NMN, raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse (Gomes et al., 2013). In skeletal muscle, NMN-treated mice have increased mitochondrial oxidative phosphorylation — the cell’s process for efficiently generating ATP (energy).

NMN supports healthy heart aging

In addition to skeletal muscle, it appears that NMN may also support healthy heart aging by improving cardiac NAD+ balance. In old mice, oral administration of NMN had an immediate effect and a short duration on improving higher workload systolic function in the heart of aging mice (Whitson et al., 2020).

NMN increases endurance in aged mice

A 2018 study on rodents demonstrated that exercise combined with NMN led to a further increase in blood flow and running endurance in healthy aged mice (Das et al., 2018). These findings suggest that NMN can improve physical performance in the elderly.

NMN supports vascular health in aged mice

In a 2016 study, eight weeks of receiving NMN supplements supported vascular health in the face of aging and improved arterial stiffening, which is critical for vascular function (de Picciotto et al., 2016). What’s more, these changes were accompanied by improvements in managing oxidative stress — an imbalance between the production of harmful compounds called reactive oxygen species and a biological system's ability to detoxify them or repair the resulting damage readily. 

NMN supports healthy physiological aging

Another study looked at the long-term effects of NMN on physical performance (Mills et al., 2016). To do so, they supplemented aging mice with NMN for a year. They found that NMN suppresses age-associated body weight gain, enhances energy metabolism, and promotes physical activity. NMN prevented age-associated gene activity changes in critical metabolic organs and enhanced metabolism in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

NMN improves peak physical performance in humans

We’re at the very beginning of testing the effects of NMN on human physical performance, but we do have some tips from some research:

NMN benefits aerobic capacity in amateur runners

To see if promising results from rodent studies translate to humans, earlier this year, a clinical study (ChiCTR2000035138) hailing from China looked at the effects of NMN on exercise (Liao et al., 2021). The six-week study included 48 young and middle-aged recreationally trained runners of the Guangzhou Pearl River running team. The researchers split the participants into four groups, each with ten male and two female participants: 300 mg/day NMN, 600 mg/day NMN, 1200 mg/day NMN, and the control group (placebo). Before and after training five or six times each week for 40-60 minutes, the researchers examined the runners’ aerobic capacity — the maximal amount of oxygen your body can consume during maximal intensity exercise.

The Chinese researchers found improvements in aerobic capacity, even among healthy young and middle-aged people — how well the body uses oxygen during exercise. In addition, the combination of taking NMN supplements and exercise further improved the ventilatory threshold. As exercise intensity progressively increases in intensity, the air into and out of your respiratory tract (called ventilation) increases. As the intensity of exercise increases, there becomes a point when ventilation starts to rise faster and faster. This point is called the ventilatory threshold. Increases in the ventilatory threshold, therefore, indicate improvements in endurance or physical abilities. These improvements are dosage-dependent — meaning a larger dosage of NMN with exercise has better effects — and were only limited to skeletal muscle; there were no improvements in the aerobic capacity of the heart.

These findings suggest that:

• NMN as an adjunct treatment may help to improve performance during exercise training.
• Exercise training combined with consuming NMN supplements may be a novel and practical strategy to increase endurance performance of athletes.

Does NMN help with weight loss?

Not only does it become harder to maintain physical strength, but keeping our weight at a healthy level can become more challenging with age. From research in rodents, we know that NMN supplements improve physical performance and help support healthy weight gain. A study in mice suggested that NMN can support characteristics of healthy weight to levels similarly induced by exercise (Uddin et al., 2016). However, there has not been data showing that NMN can support weight loss in rodents or humans.

Does NMN increase NAD+ in humans?

One of the most exciting human clinical studies on NMN came out earlier this year in the top scientific journal Science (Yoshino et al., 2021). Yoshino and colleagues report the effects of NMN supplementation in overweight or obese postmenopausal women with prediabetes. In this clinical study (NCT03151239), one of the key findings was increases in NAD+ levels or enzymes related to the synthesis and metabolism of NAD+ in specific cells and tissues after NMN treatment. The treatment supported healthy metabolism and glucose processing.

Skeletal muscle from individuals in the group that received NMN had increased activity for genes in the platelet-derived growth factor (PDGF) pathway and increased expression of PDGF receptor β. This receptor is found at high levels on pericytes — cells that wrap around endothelial cells that line blood vessels. Active PDGF receptor β contributes to muscle and blood vessel synthesis during muscle growth and regeneration. These results suggest a critical role for muscle pericytes in response to NMN therapy for improving metabolic health.

Looking forward

The results of all of these studies support the potential action of NMN supplementation in humans to improve physical performance. And there’s lots of ongoing research in this area. For example, there’s a clinical study (​​NCT04664361) examining the effect of NMN on muscle recovery and physical capacity in healthy volunteers with moderate physical activity.

That being said, there’s a lot of work to do to get a better handle on how much NMN you should take and how long to achieve specific results on physical performance. 

References:

Custodero C, Saini SK, Shin MJ, Jeon YK, Christou DD, McDermott MM, Leeuwenburgh C, Anton SD, Mankowski RT. Exp Gerontol. 2020 Aug;137:110972. DOI: 10.1016/j.exger.2020.110972. Epub 2020 May 22. PMID: 32450270; PMCID: PMC8204261.

​​Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, Kim LJ, Osborne B, Joshi S, Lu Y, Treviño-Villarreal JH, Kang MJ, Hung TT, Lee B, Williams EO, Igarashi M, Mitchell JR, Wu LE, Turner N, Arany Z, Guarente L. Cell. 2018 Mar 22;173(1):74-89.e20. DOI: 10.1016/j.cell.2018.02.008. Erratum in: Cell. 2019 Feb 7;176(4):944-945. PMID: 29570999; PMCID: PMC5884172.

De Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR. Aging Cell. 2016 Jun;15(3):522-30. DOI: 10.1111/acel.12461. Epub 2016 Mar 11. PMID: 26970090; PMCID: PMC4854911.

Howden EJ, Sarma S, Lawley JS, Opondo M, Cornwell W, Stoller D, Urey MA, Adams-Huet B, Levine BD. Circulation. 2018 Apr 10;137(15):1549-1560. DOI: 10.1161/CIRCULATIONAHA.117.030617. Epub 2018 Jan 8. PMID: 29311053; PMCID: PMC5893372.

Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL. Cell. 2013 Dec 19;155(7):1624-38. DOI: 10.1016/j.cell.2013.11.037. PMID: 24360282; PMCID: PMC4076149.

Goody MF, Henry CA. Skelet Muscle. 2018 Mar 7;8(1):9. DOI: 10.1186/s13395-018-0154-1. PMID: 29514713; PMCID: PMC5840929.

Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. J Int Soc Sports Nutr. 2021 Jul 8;18(1):54. DOI: 10.1186/s12970-021-00442-4. PMID: 34238308; PMCID: PMC8265078.

Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI. Cell Metab. 2016 Dec 13;24(6):795-806. DOI: 10.1016/j.cmet.2016.09.013. Epub 2016 Oct 27. PMID: 28068222; PMCID: PMC5668137.

Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Circulation. 2005 Oct 11;112(15):2254-62. DOI: 10.1161/CIRCULATIONAHA.105.541078. Epub 2005 Oct 3. PMID: 16203909.

Uddin GM, Youngson NA, et al. Front Pharmacol. 2016 Aug 19;7:258. DOI: 10.3389/fphar.2016.00258. PMID: 27594836; PMCID: PMC4990541.

Whitson JA, Bitto A, Zhang H, Sweetwyne MT, Coig R, Bhayana S, Shankland EG, Wang L, Bammler TK, Mills KF, Imai SI, Conley KE, Marcinek DJ, Rabinovitch PS. Aging Cell. 2020 Oct;19(10):e13213. DOI: 10.1111/acel.13213. Epub 2020 Aug 11. PMID: 32779818; PMCID: PMC7576234.

Wilkinson DJ, Piasecki M, Atherton PJ. Ageing Res Rev. 2018 Nov;47:123-132. DOI: 10.1016/j.arr.2018.07.005. Epub 2018 Jul 23. PMID: 30048806; PMCID: PMC6202460.

Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S. Science. 2021 Jun 11;372(6547):1224-1229. DOI: 10.1126/science.abe9985. Epub 2021 Apr 22. PMID: 33888596.