Should You Supplement NAD+?

Some people have called NAD+ an  anti-aging miracle drug. In the last post I briefly mentioned that NAD+ is considered a longevity compound. NAD+ and its precursors are key compounds that Dr. David Sinclair focuses on in his lab at Harvard and that he personally takes daily.[1] In this post, I hope to share what NAD+ is, and why you may want to consider boosting your levels.

NAD+ is a vitamin B3 derivative. It is critical to every cell and is required for energy production and cellular repair. Think high-school biology, Krebs cycle and the Electron Transport Chain. NAD+ is necessary for moving electrons around, which allows us to generate the cellular energy of ATP. It allows us to extract cellular energy from carbohydrates, proteins, and fats.

In addition to energy production, NAD+ also turns on multiple longevity genes, especially the sirtuins.  The sirtuin family of genes are regulators of epigenetics. The sirtuins create enzymes that help keep DNA organized so the DNA can function properly. Sirtuins also help in the repair of damaged DNA, reduce inflammation, and help with stress resistance. As we age, our levels of NAD+ decline, and we have a corresponding decrease in sirtuin activity.  Some researchers suspect that replacing and replenishing NAD+ levels may help stem the aging process.

Some of the studied benefits of increasing NAD+ include:

1.  Improved heart health by decreased arterial stiffness and lower blood pressure. [3,4]
2. Improvement of mitochondrial and neuronal health. In an Alzheimers mouse model, NAD supplementation through precursors slowed cognitive decline. [5,6,7]
3. Life span extension in yeast, worms and rodents. [8,9]

You may wonder why many of the longevity studies on NAD+ are in animal models.  Animals have similar genetic and molecular pathways as humans and unlike humans they do not live as long.  A study in humans on longevity could take a century, whereas in animals the study could be done in 3-5 years. 

Most of the studied benefits with NAD+ have been demonstrated using oral precursors since oral NAD+ is not easily absorbed. An alternative delivery system, IV NAD+, has not been studied as thoroughly, though there are many reported benefits, which include improvements in: 

ADHD, 
executive function, 
addiction,
anxiety, 
depression, 
chronic fatigue and 
cognitive decline.

Given the studied and reported benefits, you may wonder how to increase your NAD+.
​We can maintain youthful levels of NAD+ by either:
1. Decreasing use/destruction of NAD+
2. Increasing production or levels of NAD+

NAD+ is consumed primarily by 1. PARPs (in DNA repair) 2. Sirtuins (as discussed above) and 3. CD-38 (to be discussed below). The largest consumer of NAD as we age appears to be CD-38.  CD-38 is a signaling molecule induced by zombie cells or senescent cells from molecules they secrete. If we want to increase our pool of NAD+ by decreasing usage, the primary target should be cd-38 and zombie cells. [10]

To decrease use of NAD+:
1. Minimize cellular stressors. This includes the boring truisms of reducing or eliminating smoking, eating real foods rather than processed, lowering your intake of sugar, getting enough sleep, and stress management.
2. Lower cd-38 levels. This can be accomplished by lowering the number of zombie cells.  The best way to lower the load is through the use of senolytics. Examples of senolytics include supplements like quercetin, fiscetin and curcumin. A promising animal trial at Mayo Clinic showed a significant reduction in zombie cells using a medication called Desatinib  and quercetin. [11]

NAD+ levels can be increased by: 
1. Fasting
2. Exercise
3. IV NAD+ and oral NAD+ precursors: Animal studies have shown that taking precursors can raise blood levels of NAD by 2.7X, [12] and human studies of IV NAD+ show that NAD+ is both safe and readily taken up by tissues. [13]

To bring it all together, NAD+ is important in energy metabolism and DNA repair. With age, our NAD+ levels fall, and we are more prone to age-related diseases.  NAD+ has been shown in humans to reduce the risk of some age-related diseases and in animals to extend their lifespan.  Though I am hoping to see more research in this area, given the low risk, good safety profile, and potential upside, I personally take oral NAD+ precursors and IV NAD.  As always, talk to your doctor before starting any supplements.

Hope you have enjoyed this,

Amy

References:
1.  Sinclair, David A and LaPlante, Matthew D.  2019 Lifespan: Why We Age and Why We Don’t Have To. NY, NY. Simon and Schuster.

​2. It takes two to tango: NAD+ and sirtuins in aging/longevity control, Shin-ichiro Imai,* and Leonard Guarente. NPJ Aging Mech Dis. 2016; 2: 16017). 

3. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. de Picciotto NE et al. Aging Cell. 2016 Jun;15(3):522-30. doi: 10.1111/acel.12461. Epub 2016 Mar 11 +

4. Nicotinamide riboside supplementation reduces aortic stiffness and blood pressure in middle-aged and older adults. MArtens, C et al. Artery Research Dec 2017 Vol 20:49.)  

5  Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model Long, A et al. BMC Neurology 15, no. 1 (March 2015).

6  The association between PGC-1α and Alzheimer's disease. Sweeney, G et al. Anat Cell Biol. 2016 Mar;49(1):1-6.

7. 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. Gong B et al. Neurobiol Aging. 2013 Jun;34(6):1581-8.)

8. The NADthplus/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling Mouchiroud, L. et al. Cell 154, no. 2 (July 2013): 430–41.

9. NAD+  repletion improves mitochondrial and stem cell function and enhances life span in mice Zhang, H. et al. Science 352, no. 6292 (April 2016): 1436–43. 

10. [CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism.  Camacho-Pereira, M.G. Tarragó, C.C.S. Chini, V. Nin, C. Escande, G.M. Warner, A.S. Puranik, R.A. Schoon, J.M. Reid, A. Galina, E.N. Chini, Cell Metabolism 23 (2016) 1127–1139]

11. The Multi-faceted Ecto-enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases. Hogan, K et al. Front Immunol. 2019; 10: 1187.

12. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.Trammell et al.  Nat Commun. 2016 Oct 10;7:12948.

13.(A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+. Grant, R et al. Front Aging Neurosci. 2019; 11: 257.