NAD+ for Anti-Aging

Targeting the causes of aging

We’re all familiar with the external, visible signs of aging — grey hair, wrinkles, memory problems, and many more besides. Now, cutting-edge scientific research is revealing the causes of aging at the cellular level and how they might be remedied (Lopez-Otin et al., 2013). 

This in-depth scientific understanding is beginning to call into question many long-held beliefs about the inevitability of aging. Might it be possible to slow or even reverse the effects of aging on the body?

To address this question, scientists are actively investigating the potential benefits of a number of treatments that target the underlying causes of aging at the cellular level.

NAD+ levels and aging are closely linked

One of the most promising treatments for aging is nicotinamide adenine dinucleotide (NAD+), a coenzyme (helper molecule) found naturally in the body. NAD+ contributes to healthy energy production, metabolism, and genomic and genetic stability.

Aging decreases NAD+ levels in tissues and organs throughout the body, with levels in middle and older age individuals (51 years of age and above) less than 50% of those in younger individuals (30–50 years of age) (Massudi et al., 2012). 

In addition to contributing to the harmful effects of aging, decreased levels of NAD+ are associated with a wide range of aging-related diseases, including: 

  • Metabolic disorders (e.g., diabetes);
  • Cardiovascular disorders (e.g., atherosclerosis);
  • Neurodegenerative diseases (e.g., Alzheimer’s disease).

The precise mechanisms underlying the dramatic decrease in NAD+ levels with age remain unclear. However, the evidence suggests that aging is linked to an imbalance in NAD+ production and consumption in the body with age.

Boosting NAD+ levels in the body

How can NAD+ levels be increased? Along with natural ways of boosting NAD+, such as exercise, fasting, and eating foods that promote NAD+ production, levels of NAD+ can be increased via NAD+ supplements or via intravenous NAD+ injections.

The two most widely used and studied NAD+ supplements are: 

  1. Nicotinamide riboside (NR);
  2. Nicotinamide mononucleotide (NMN). 

These are precursors of NAD+ that are taken orally, after which the body absorbs them and uses them as building blocks to produce NAD+. In contrast, injections deliver NAD+ intravenously, directly into the bloodstream.

Can increased NAD+ treat aging and aging-related diseases?

Extensive research in animals such as mice points to the benefits of NAD+ for treating aging and aging-related diseases. 

For example, in one study, mice were given NMN for a whole year (Mills et al., 2016). The results were remarkable — the treatment reversed a number of the harmful effects of aging by decreasing body weight, enhancing energy metabolism, and decreasing insulin sensitivity.

Likewise, both NR and NMN have been found to successfully treat aging-related diseases in animals, for example: 

  • Diabetes: The use of either supplement in mice reversed a number of the symptoms of diabetes by increasing glucose tolerance, preventing the build-up of fat in the liver, and reducing weight gain (Yoshino et al., 2011; Trammell et al., 2016). 
  • Alzheimer’s disease: Cognitive and behavioral improvements have been reported in mice with Alzheimer-like symptoms given NMN or NR supplements (Gong et al., 2013; Wang et al., 2016).

Remarkably, boosting NAD+ levels not only reduces some of the hallmarks of aging and aging-related diseases, but also increases lifespan in mice (Zhang et al., 2016) and a range of other organisms (Rajman et al., 2018). 

NAD+ treatments for anti-aging in humans

Over 30 clinical trials investigating the therapeutic effects of NR or NMN in humans are currently ongoing, according to the NIH Clinical Trials database (Reiten et al., 2021). A number of these trials are studying the effects of NAD+ on aging and aging-related diseases, but they are yet to publish their findings. 

However, results regarding the safety of NR and NMN in humans are available. The evidence suggests that doses of NR of up to 1,000 mg can be taken twice daily without serious adverse effects (Dollerup et al., 2018; Martens et al., 2018). For NMN, the evidence is more limited, but indicates that a dose up to 500 mg/day is safe (Irie et al., 2020; Yoshino et al., 2021).

Likewise, the safety of NAD+ injection has been little studied, but one study in eight healthy men found that intravenous injection of 750 mg NAD+ over 6 hours was safe (Grant et al., 2019). 

Crucially, these trials have confirmed that both NAD+ supplements and NAD+ injections increase levels of NAD+ or its metabolites (breakdown products of NAD+) in the body, proportional to the dose taken.

The coming months and years promise to be an exciting time as clinical trials investigating NAD+ supplementation publish their results. These will reveal whether NAD+ has the same remarkable effects on aging, aging-related diseases, and lifespan in humans as it does in animals.

References

Dollerup, O. L., Christensen, B., Svart, M., Schmidt, M. S., Sulek, K., Ringgaard, S., … & Jessen, N. (2018). A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. The American Journal of Clinical Nutrition, 108(2), 343-353. https://doi.org/10.1093/ajcn/nqy132

Gong, B., Pan, Y., Vempati, P., Zhao, W., Knable, L., Ho, L., … & Pasinetti, G. M. (2013). Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiology of Aging, 34(6), 1581-1588. https://doi.org/10.1016/j.neurobiolaging.2012.12.005

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

Irie, J., Inagaki, E., Fujita, M., Nakaya, H., Mitsuishi, M., Yamaguchi, S., … & Itoh, H. (2020). Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine Journal, 67(2), 153-160. https://doi.org/10.1507/endocrj.EJ19-0313

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039

Martens, C. R., Denman, B. A., Mazzo, M. R., Armstrong, M. L., Reisdorph, N., McQueen, M. B., Chonchol, M., & Seals, D. R. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 9(1), 1286. https://doi.org/10.1038/s41467-018-03421-7

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

Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Imai, S. I. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism, 24(6), 795-806. https://doi.org/10.1016/j.cmet.2016.09.013

Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metabolism, 27(3), 529-547. https://doi.org/10.1016/j.cmet.2018.02.011

Reiten, O. K., Wilvang, M. A., Mitchell, S. J., Hu, Z., & Fang, E. F. (2021). Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mechanisms of Ageing and Development, 111567. https://doi.org/10.1016/j.mad.2021.111567

Trammell, S. A., Weidemann, B. J., Chadda, A., Yorek, M. S., Holmes, A., Coppey, L. J., … & Brenner, C. (2016). Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Scientific Reports, 6(1), 1-7. https://doi.org/10.1038/srep26933

Wang, X., Hu, X., Yang, Y., Takata, T., & Sakurai, T. (2016). Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Research, 1643, 1-9. https://doi.org/10.1016/j.brainres.2016.04.060

Yoshino, J., Mills, K. F., Yoon, M. J., & Imai, S. I. (2011). Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet-and age-induced diabetes in mice. Cell Metabolism, 14(4), 528-536. https://doi.org/10.1016/j.cmet.2011.08.014

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

Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., … & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443. https://doi.org/10.1126/science.aaf2693

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