Dr. Nandana Bhardwaj

As we age, we lose skeletal and muscle mass. The good news is, skeletal muscle can be maintained with aerobic and resistance exercise training1. Over the last three decades, there has been a global increase (around 37%), in the number of adults with a body mass index (BMI) over 252,3. Muscle loss and weight gain are associated with aging, mainly due to mitochondrial dysfunction and low energy (low ATP) production.

The link between NAD+ and NMN

Obesity and aging decrease (~50% decline) the levels of an essential metabolic cofactor nicotinamide adenine dinucleotide (NAD+), which is vital for keeping us healthy. It is widely accepted that physical activity and exercise increase NAD+ levels in the body, and improve mitochondrial function4. NAD+ is a coenzyme, also known as the “Fountain of Youth'', as it provides 80% improvement in cellular energy production when levels decline due to aging, and plays a vital role in maintaining various metabolic and biological processes within our body5.

Exercise increases NAD+ levels, leading to stimulation of mitochondrial function, and facilitates burning of fat and carbohydrate stores6,7. Muscle aging generally occurs from exercise-induced muscle fatigue or damage, leading to a slower rate of muscle recovery. Various animal studies suggest that increasing NAD+ levels may be effective in improving physical training and muscle recovery in humans8. NAD+ is available in our body mainly through precursors in the form of NMN (nicotinamide mononucleotide), and NR (nicotinamide riboside). NMN, naturally found in our body and certain foods, is a key component for the production of NAD+. Declining levels, as found in aging, drastically affect the production of NAD+9.

Sources and dosage of NMN

NMN is naturally abundant in various vegetables and fruits such as broccoli, cabbage, avocado, tomato, and others in the range of 0.25 to 1.12 mg NMN/100 gm10. Broccoli and cabbage are the richest sources of NMN (between 0.25 mg and 1.12 mg per 100 gram). According to the FDA, at least 500 mg of NMN per day is required for a person to boost metabolism12.. Studies show that oral NMN is safe and free from side effects in healthy men11. In order to achieve the FDA’s recommendation of 500mg/day, one would need to consume ~1,500 pounds of broccoli per day! As such, supplementing with NMN is much more feasible.

The Science behind NMN to improve muscle fatigue

Regular exercise slows down muscle fatigue and builds muscle. Age-related muscle loss, namely sarcopenia, is a condition where muscles begin to shrivel, and become weaker with age. Harvard University professor David Sinclair, who has extensively researched NMN, notes that NMN supplementation aids muscle growth and recovery by improving blood and nutrient supply to the muscles13,14.

Dr. David Sinclair, who extensively studies NMN and aging, consumes 1 gram of NMN daily. In a series of experiments, Dr. Sinclair reported decline of SIRT1 protein in blood vessels, generally decline with aging, and results in slowing down of blood flow. NMN is a key regulator of SIRT1 and therefore its supplementation activates Sirtuin1 signaling pathways and helps in generating new blood capillaries. NMN supplementation boosts levels of NAD+, which lead to restoration of endothelial cells growth and facilitates supply of oxygen and nutrients to muscle for its recovery through stimulation of SIRT1 protein14.

In another study conducted by researchers from Washington University School of Medicine, there was significant reduction in aging associated with weight gain with long term administration of NMN (12 months) in dose dependent manner in mice. The results indicated oral administration of NMN showed reduction in mice’s weight by 4 and 9 % with dose of 100 and 300-mg/kg, respectively10. These remarkable benefits of NMN treatment in rodents led to development of several companies across Japan, USA and China using NMN as a dietary supplement or a nutraceutical.

When combined with training, supplementing with NMN may improve performance and muscle recovery through stimulation of signaling pathways and maintenance of blood flow.

Dr. Bhardwaj is currently working as Senior Research Scientist with STANVAC group. She has received her Ph. D and Post-doctoral research in Biomedical Engineering from Indian Institute of Technology (IIT) Kharagpur, India and School of Materials Science and Engineering, Nanyang Technological University (NTU), Singapore. Her research interests stretching from Biomaterials, Tissue Engineering, Stem cells, drug delivery, wound healing, 3D bioprinting, disease tissue/organ models to regenerative medicine. She has published 35+ articles in top tier journals of biomedical engineering and multiple awards in her name with ~6000 citations and H-index of 19. She has also been featured in “Top 2% Scientist” globally and in biomedical engineering research in a list prepared by Stanford University (published in PLoS Biology, October16, 2020).

References:

1. de Guia RM, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, Larsen S, Brandauer J, Houmard JA, Treebak JT. Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiological Reports 2019;7: e14139. doi: 10.14814/phy2.14139.
2. Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study. The Lancet 2014; 384: 766–781.
3. Mitchell, S. & Shaw, D. The worldwide epidemic of female obesity. Best Practice & Research Clinical Obstetrics & Gynaecology 2015; 29: 289–299.
4. Canto, C. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell metabolism 2010; 11: 213–219.
5. https://eternumlabs.com.au/anti-ageing-unlocking-more-energy-with-nmn/.
6. Gomes, A. P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 2013; 155: 1624–1638.
7. Price, N. L. et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell metabolism 2012; 15: 675–690.
8. Poddar SK, Sifat AE, Haque S, Nahid NA, Chowdhury S, Mehedi I. Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules. 2019; 9 :34. doi: 10.3390/biom9010034.
9. https://www.genengnews.com/news/anti-aging-nutraceutical-improves-muscle-remodeling-and glucose-metabolism-in-older-women/.
10. Mills, K.F.; Yoshida, S.; Stein, L.R.; Grozio, A.; Kubota, S.; Sasaki, Y.; Redpath, P.; Migaud, M.E.; Apte, R.S.; Uchida, K.; et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metabolism 2016; 24: 795–806.
11. https://www.nmn.com/news/results-of-first-human-study-of-nmn-administration-reveal-no-safety concerns
12. https://www.wisepowder.com/nicotinamide-mononucleotide-nmn-benefits/.
13. Uddin GM, Youngson NA, Doyle BM, Sinclair DA, Morris MJ. Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Scientific Reports 2017; 8; 7:15063. doi: 10.1038/s41598-017-14866-z.
14. Rajman L, Chwalek K, Sinclair DA. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 2018; 27:529-547. doi:10.1016/j.cmet.2018.02.011.