Science is advancing rapidly, and the field of aging research is no exception. Our understanding of aging has grown a great deal in the last decade, and we are now reaching the point at which the first therapies that target aging are starting to arrive. Unlike the snake oil of previous years, some of these might actually work; today, we are going to have a look at NAD+ repletion, one such promising therapy.
In the near term, nicotinamide adenine dinucleotide (NAD+) is showing potential for addressing some of the aging processes. NAD+ levels decline significantly during aging in both humans and animals, and studies on old mice have shown that restoring NAD+ levels causes them to look and act like younger mice while increasing their lifespan.
What is NAD+?
NAD+ is a molecule that is present in all living cells and is essential for a myriad of cellular processes, including regulating metabolism, performing signaling, facilitating DNA repair and blood vessel growth, and regulating some aspects of aging.
In the body, NAD+ is created from simple building blocks, such as the amino acid tryptophan, and it is created in a more complex way via the intake of food containing nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and other NAD+ precursors.
These different pathways ultimately feed into a salvage pathway, which recycles them back into the active NAD+ form. This salvage pathway, shown on the bottom right of the diagram, includes NAM, NMN, NAD+, and their associated steps.
As this diagram shows, NA has many chemical steps that it must go through before it is converted into NAD+, NR is closer to the salvage pathway, and requires fewer steps to become NAD+ and NMN is within the salvage pathway. Some research suggests that NMN brought in from outside of the cell generally has to convert back into NR to pass through the plasma cell membrane of most cells, but this does not appear to be a bottleneck given how fast it increases NAD+ throughout the body in mice .
Unfortunately, it is difficult to infuse cells directly with NAD+ as the molecule is too large for most cell types to take it in through the plasma cell membrane, so adding NAD+ to the bloodstream would not enter most cells. However, there is some research that suggests that NAD+ and NMN might enter certain types of cells directly and this is something researchers are currently trying to ascertain, we will talk about that in a future article.
Making old mice younger
In March 2017, researcher David Sinclair and his team published a study in the journal Science showing that by feeding mice the NAD+ precursor, NMN, they were able to restore lost NAD+ levels within hours . In just a week, some signs of aging in muscle and other tissues had been reversed so much so that the researchers could no longer tell the difference between these 2-year-old mice and the tissues of 4-month-old mice.
This study also showed the exact mechanism by which NAD+ facilitates DNA repair via a special pocket-like structure. The study has implications for cancer survivors, aging research, and even potentially space travel, given that DNA damage is the primary reason for genomic instability and makes us prone to cancer and aging. Being able to boost our DNA repair would be very useful indeed for repairing DNA damage from aging, cancer, and environmental radiation, which is prevalent in space.
In 2018, a study by David Sinclair and his team showed that vascular aging could also be reversed using NMN . Compromised blood flow plays a key role in aging, since it starves tissues and organs, including the brain, of the essential nutrients and oxygen they need. This loss of blood supply is also implicated in sarcopenia, the age-related loss of muscle mass that leads to frailty and loss of independence in older people due to poor mobility.
In this study, Sinclair and his team found that they could restore lost blood flow in old mice using NMN to encourage blood vessel growth. The cells took up the NMN and converted it into NAD+, spurring the formation of new tiny blood vessels to improve muscle tissue; in fact, the mice treated with NMN increased the treadmill running time by an impressive 60% compared to control animals that did not receive NMN. In some cases, the old mice had endurance levels that matched and, in some cases, even exceeded those of younger mice.
In a broad sense, NMN improves blood flow in the same way that exercise does, as it interacts with a family of molecules called sirtuins. This means that if NMN works as hoped, it would be an exercise mimetic, and using it would have similar benefits to actual exercise; this could be useful for older people who are already suffering from loss of mobility and cannot exercise. It also has potential as a preventative for vascular aging in general and for improving tissue regeneration and wound healing.
This is great if you are a mouse, but what about humans?
Scientists are hoping to translate these murine findings to humans, and in 2017, a group of researchers ran a randomized control trial using NR . These researchers reported that there was a significant and sustained increase of NAD+ levels over a two-month period in people taking the supplement. We should, however, take this study with a pinch of salt, as it was partially funded by the sole producer of NR as well as public money via the NIH.
Meanwhile, David Sinclair and his team are running a small-scale human trial on NMN at the Brigham and Women’s Hospital in Boston, Massachusetts, which is adjacent to Harvard Medical School, where Sinclair has his lab. This initial study is important, as in the past, the results of various “anti-aging” compounds shown to be effective in mice have not translated to humans.
David Sinclair and his team are keen to rigorously test NMN in humans and gain clear results. He plans to test NMN in healthy elderly people to see if they receive the same improvements in blood flow that animals receive.
While you can buy NMN as a supplement, the usual concerns about purity and efficacy are there, and until there are clinical trials we advise waiting for the results from those to come in before deciding if it’s worth taking or not. However, if you must self-test, we suggest using a science-based approach.
It is also fair to say that while NMN does not address all of the aging processes, it does address altered nutrient sensing and genomic instability somewhat in mice. There is little doubt that more robust therapies will arrive in time, but NMN could be useful as a stop-gap, assuming, of course, that the results translate from mice to men. The good news is that we may not need to wait too long to find out.
And finally, the Sinclair lab also launched an NMN project with us on 18th September over at Lifespan.io which could help to speed up progress and deepen our knowledge about NAD+ biology and aging.
 Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.
 Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J., … & Aravind, L. (2017). A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science, 355(6331), 1312-1317.
 Das, A., Huang, G. X., Bonkowski, M. S., Longchamp, A., Li, C., Schultz, M. B., … & Treviño-Villarreal, J. H. (2018). Impairment of an Endothelial NAD+-H 2 S Signaling Network Is a Reversible Cause of Vascular Aging. Cell, 173(1), 74-89.
 Martens, C. R., Denman, B. A., Mazzo, M. R., Armstrong, M. L., Reisdorph, N., McQueen, M. B., … & 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.
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