NAD+ supplementation with NMN and NR

NAD+ is a bulky molecule that is not absorbed orally and needs to be given intravenously.  Intravenous administration can be inconvenient and costly.  On the other hand, two key NAD+ precursors (see Figure 7), NMN (Nicotinamide Mononucleotide) and NR (Nicotinmaide Riboside), are smaller and cheaper than NAD+, and can be taken orally.  Unlike NAD+ whose scientific data in the context of longevity is lacking, NMN and NR have been extensively investigated in various settings including in animals and sometimes in humans.  Two important questions come up:
1) Will taking NMN or NR boost NAD+ levels in our body

and

2) provide the benefits of NAD+?     

Question 1: The first question is whether taking NMN and NR increases NAD+ levels?  It appears so as evidence listed below shows. 

NMN

NMN administration effectively enhances NAD+ levels in various peripheral tissues:

• Pancreas (Yoshino et al., 2011)
• Liver (Peet et al., 2013, Yoshino et al., 2011)
• Adipose tissue (Stormsdorfer et al., 2016, Yoshino et al., 2011)
• Heart ( Karamanlidis et al., 2013, Martin et al., 2017, North et al., 2014, Yamanmoto et al., 2014)
• Skeletal muscle ( Gomes et al., 2013)
• Kidney (Guan et al., 2017)
  Testis (North et al., 2014)
• Eyes (Lin et al., 2016)
• Blood vessel  (de Picciotto et al., 2016). 
  
  

NR

NR has shown to increase NAD+ levels in multiple tissues and in blood in both mice and humans.  In a study conducted in 2017, a dose of 250mg NR plus polyphenol 50mg increased blood NAD+ levels by 40% (see Figure 8 below).  A dose of 500mg NR plus polyphenol 100mg increased blood NAD+ levels by 90%. 

Figure 8: NAD+ level as a result of NR intake. 

Figure borrowed from Dellinger, R.W., Santos, S.R., Morris, M. et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. npj Aging Mech Dis 3, 17 (2017).

Question 2: The second question is whether taking NMN and NR show benefits associated with elevated NAD+ levels.  

Therapeutic benefits of NMN shown in mice, consistent with elevated NAD+ levels, can be summarized as follows:

• Improvement in insulin secretion and insulin sensitivity- Revolio et al., 2007 and  Ramsey et al., 2008, Yoshino et al., 2011, Caton et al., 2011, Stromsdorfer et al., 2016, Mills et al., 2016
• Improved skeletal muscle function – Gomes et al., 2013
• Improved neural function – Stein and Imai, 2014, Park et al., 2016
• Improved mitochondrial function – Long et al., 2015 , Mills et al., 2016
• Improved cardiac function – de Picciotto et al., 2016, Lee et al., 2016
• Protected from retina injury – Lin et al., 2016, Stromsdorfer et al., 2016
• Improved cognitive function – Wang et al., 2016, Yao et al., 2017
• Protected kidneys from chemotherapy – Guan et al., 2017

Therapeutic benefits of NR shown in mice, consistent with elevated NAD+ levels, are as follows:

• Improved insulin sensitivity – Canto et al., 2012
• Improved cognitive function – Gong et al., 2013
• Improved muscle endurance and function – Cerutti et al., 2014, Frederick et al., 2016, Ryu et al., 2016, Elhassan et al., 2019
• Protection against tumor growth in livers – Tummala et al., 2014
• Lowered cholesterol –  Lee et al., 2015
• Protected against neural pain – Trammell et al., 2016
• Increased lifespan – Zhang et al., 2016, Fang et al., 2016
• Improved motor coordination – Fang et al., 2016