Hi Leonid @ygordinaol-com
I reespect Dr She but I do not believe anybody should be using NMN, NR or NAD on a consistent basis.
There is little argument that NAD levels decline with age and that higher NAD levels seem to be associated with better health. Indeed, supplementation with NAD+ and its precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), is thought to represent a preventive approach for aging and its associated disorders.
However, NAD+ and some of its regulatory enzymes also play a crucial role in cancers and NAD biosynthesis is often upregulated in tumor cells. In fact, several recent studies showed that NAD may actually be driving our damaged senescent cells. Increased NAD+ can drive cells that have become senescent into secreting more SASPs (Senescent associated secretory phenotype) and promoting a more tumor-friendly environment. (1,2) Stimulation of these SASPs is potentially more serious with increasing age, as older people are more likely to have mutated incipient precancerous cells.
So are we actually doing more harm than good by upregulating NAD levels with oral NAD, NAD infusions and supplements like Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR)? The answer is, “We really have no idea !”
Our bodies need energy called ATP to run. Energy production within a cell involves a series of intricately coordinated pathways. Most of these pathways are combinations of oxidation and reduction reactions. Oxidation and reduction occur in balance. An oxidation reaction takes an electron from a compound, and the electron is donated to another compound in a reduction reaction. Because oxidation and reduction usually occur together, these are known as redox reactions. The balance between oxidation and reduction in this process is critical and when that balance is disrupted there are many downstream effects! Altered redox balance is associated with many diseases and neurodegenerative disorders and has been implicated as an important factor in regulating cell growth, senescence, and aging. So people try to put back compounds like NAD to restore this energy metabolism or take antioxidants to restore balance. Simplistically, this seems to make sense. But, picture this whole process like trying to fill a bucket that you know needs water, but you have no idea how much water it needs to be full. If you keep filling it or if the bucket has a hole in it then the water runs all over your floor ruining your house! Cellular metabolism is a very delicate and precise process and you cannot just keep dumping in compounds that alter that process with no idea as to how much you need! So our goal in restoring cellular health needs to focus on not just filling the bucket but patching the holes and regulating the tap!
Focusing on the processes that go awry with aging and disease instead of the result is the key to safely improving cell energy! So instead of simply throwing more water in the bucket with NAD and its precursors, we need to fix the bucket.
Enter 1-Methylnicotinamide or 1-MNA. 1-MNA is an endogenous substance that is produced in the liver when nicotinic acid is metabolized. It is also a myokine, produced by muscles in response to exercise. It has significant anti-inflammatory and anti-thrombotic properties and it has a positive effect on vascular endothelium and improves skeletal muscle energy metabolism.
1-MNA also plays a key role in NAD metabolism. It blocks an enzyme called Nicotinamide N-methyltransferase (NNMT) which is a key regulator of the delicate redox balance. NNMT levels are significantly elevated in all age related diseases and, in fact, high levels are associated with many types of cancers, neurodegenerative diseases like Parkinson’s and Alzheimer’s, and muscle loss. In fact, there is active research ongoing to discover inhibitors of NNMT enzyme activity to treat cancers, metabolic syndrome, sarcopenia (muscle loss), and neurodegeneration. NNMT upregulation is also one of the causes of the decline in NAD with age and disease. Unfortunately, both NR and NMN can increase nicotinamide levels, which increases NNMT activity thus increasing the risk of diseases like cancers. (7) 1-MNA, on the other hand, reduces NNMT activity to restore the delicate Redox balance!
In a recent study post-COVID, 1‐MNA supplementation significantly improved physical performance in a 6‐minute walk test and reduced the percentage of patients with severe fatigue. (4)
1‐MNA has also been demonstrated to improve oxidative stress and regulate cell death, reduce the expression of inflammatory cytokines such as TNF‐α, IL‐6, and IL‐1 in vitro and in vivo, prevent cardiac and pulmonary scarring, and activate SIRT1 (a longevity gene). (5)
1-MNA also may promote fat loss and muscle growth. In mice, 1-MNA was secreted by muscles and stimulated fat loss directly, with no effect on glucagon or insulin secretion, identifying it as a novel myokine that enhances the utilization of energy stores in response to low muscle energy availability. (6)
This supplement is finally available to the US market and may be a critical player in our goal to not only more safely and effectively restore NAD levels and optimize cellular redox pathways, but also to improve all aspects of age-related disease.
This product can safely be used continuously since it does not disturb redox nor feed senescent, cancer, or fat cells like NAD and its precursors do by upregulating NNMT. I use 2-3 in my long coviders , cancer pts, metabolically unstable and 1 daily for maintenance.
Dr Yurth
1)Mendelsohn, A. R., & Larrick, J. (2019). Interacting NAD+ and Cell Senescence
pathways complicate anti‐aging therapies. Rejuvenation
Research. doi:10.1089/rej.2019.2218
2)Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, Aird KM, Iwasaki O, Kossenkov AV, Schultz D, et
- NAD(+) metabolism governs the proinflammatory senescence‐associated secretome. Nat Cell Biol.2019;21:397–407.
3)Yahyah Aman, Yumin Qiu, Jun Tao, Evandro F. Fang,
Therapeutic potential of boosting NAD+ in aging and age-related diseases,
Translational Medicine of Aging, Volume 2,2018,
4)Chudzik, Michał, Joanna Kapusta, and Monika Burzyńska. “Use of 1‐MNA to Improve Exercise Tolerance and Fatigue in Patients After COVID‐19,” July 14, 2021. https://doi.org/10.1101/2021.07.14.21259081.
5)Song, Z., Zhong, X., Li, M., Gao, P., Ning, Z., Sun, Z., & Song, X. (2021). 1-MNA Ameliorates High Fat Diet-Induced Heart Injury by Upregulating Nrf2 Expression and Inhibiting NF-κB in vivo and in vitro. Frontiers in Cardiovascular Medicine, 8. https://doi.org/10.3389/fcvm.2021.721814
6) Ström, K., Morales-Alamo, D., Ottosson, F. et al. N1-methylnicotinamide is a signaling molecule produced in skeletal muscle coordinating energy metabolism. Sci Rep 8, 3016 (2018). https://doi.org/10.1038/s41598-018-21099-1
7) Poljšak, B.; Kovač, V.; Milisav, I. Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies. Antioxidants 2022, 11, 1637. https://doi.org/10.3390/antiox11091637
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