Boosting intracellular NAD levels: An interview with Dr. Jin-Xiong She

Dr. Jin-Xiong She

Dr. Jin-Xiong She completed his undergraduate education in China and his PhD degree in Molecular and Population Genetics in France. After a short postdoctoral training at the University of Florida (UF), he was promoted to Assistant Professor, Associate Professor, Full and Endowed Professor. He served as Division Chief of Experimental Pathology and Director of Research of the UF’s world-class Diabetes Center. In 2002, Dr. She was recruited to be the Georgia Research Alliance Eminent Scholar in Genomic Medicine at the Medical College of Georgia. He was the founding Director of the Center for Biotechnology and Genomic Medicine, Professor of the Departments of Obstetrics and Gynecology and Department of Health Technologies as well as the director of two core research facilities for Augusta University (Genomics, Proteomics & Mass Spectrometry). In his long academic career, he has authored over 400-peer reviewed papers with an H-Index of 74 and over 17,000 citations, secured over $100 million in research grants, and has been invited to speak all over the world. He also has mentored 15 doctoral students, over 50 post-docs, and 12 faculty members. Named one of the 20 “Georgia Top Medical Researchers” in 2014 by the Atlanta Business Chronicle, he served as President of the Chinese Geneticists in America and President of the American Diabetes Association’s council on Immunology, transplantation and Immunogenetics, among other honors. Currently he is the founder, CEO, and Chief Scientific Officer of Jinfiniti Precision Medicine.

NAD Research: Please tell us about your work to establish optimal intracellular NAD levels. Has it been explained in previously publicized research? Can you summarize it for us?

Dr. She: Our test is not published yet. We developed it because there was a tremendous need for a test that can be used by patients and consumers. As you know, developing a test for NAD was very difficult because of at least two primary reasons. The first one is the instability of the NAD molecule. It degrades very rapidly. So how you preserve the sample becomes a very critical issue.

The second problem was the analytical methodologies. There are several different ways you can measure the NAD molecule. Most people use mass spectrometry, which is a very good method, but it is expensive and requires skilled technicians to run the machines. It’s also difficult to obtain reproducible results. We were looking for an affordable, easy to learn, and scalable method. That meant automating the process as much as possible.

We also wanted to make the assay easy to reproduce, not only within the assay, but over time, which is extremely important. What you measure today has to be comparable to what you are going to measure in a year, 10 years, or even decades from now. If there’s variation over time, it’s not an acceptable clinical tool.

Fortunately, we do have an assay that meets all our criteria. It’s very easy to use and consumer-friendly. We mail the test kit to the patient, who pricks a finger and puts a few drops of blood on the filter paper—which is a blood collection card similar to the cards used for newborn screenings.

We actually only need one spot of blood to run the assay, but we ask for more as a backup. The patient lets the blood spots dry and then applies a stabilizing buffer. The patient mails the card back to us and we run the assay in our CLIA lab. Although it is recommended that the samples are returned to our lab as soon as possible, we can still get very accurate data from samples that are as old as 3-4 weeks. This allows us to can conduct tests from blood samples collected in different countries. The tests are being done by consumers in over 50 different countries now.

The assay is very stable over time, highly reproducible. The variation on average is 3.1% for duplicate tests on the same sample. That’s highly reproducible. A single technician can run 100 samples a day, which is a very high throughput operation. We’re now trying to make the test available to as many people as possible.

NAD Research: Are these results going to be published anytime soon? Do you have a publication pending?

Dr. She: We have done several clinical trials funded by us or for our partners.  Some of these studies are being written up for publications.

NAD Research: As you noted, NAD is a highly unstable molecule. Without revealing proprietary information, can you tell us how you’ve been able to stabilize the NAD before measuring it, and what you use to determine NAD levels?

Dr. She: I can’t share the exact formula in our proprietary NAD stabilization buffer, but I can tell you that it is a critical step for our NAD assay.  We use an enzyme-based activity assay that is automated to minimize assay variation.

NAD Research: Are you able to get an accurate measure of both oxidized (NAD+) and reduced (NADH) forms of NAD?

Dr. She: Theoretically, we can, but we don’t do it at the moment because it increases the cost. For most purposes, we don’t need to distinguish NAD+ versus NADH because our primary goal is to see whether our treatment is actually providing efficacy. I know that the NAD+/NADH ratio can be very important, but I don’t think we understand the issue well enough to use the information in a clinically meaningful manner for the moment. So, in research, we can separate the two forms; but for the moment, we don’t offer it for consumer testing.

NAD Research: So your primary purpose is to measure NAD treatment efficacy?

Dr. She: Actually, there are two purposes. One is, we want to know what intracellular NAD baseline, optimal, deficient, and very deficient levels are. We put everyone in one of the categories and we defined the optimum range by testing large number of individuals both before and after supplementation.

The first question is to know where people are in terms of NAD levels. The second question is whether the supplementation actually elevates intracellular NAD, or I would prefer to say “optimizes NAD levels” because some people actually can get their level too high. You probably don’t want NAD levels to be too high and you definitely don’t want them to be too low. You want them to be somewhere right in the middle.

NAD Research: Have you been able to observe, or have patients been able to report, improved clinical outcomes corresponding to their increased intracellular NAD levels?

Dr. She: Yes, we have unbelievable and very positive patient response. Most people report improved energy, which is understandable, since NAD is involved in ATP (adenosine triphosphate) production. Another common benefit is improved sleep, because NAD regulates the circadian genes. Mental clarity is another common one. Others are particular to individual health conditions.

For example, one woman had leg cramps at night, which disappeared the second day after supplementation. Reduced joint or muscle pain, or arthritis, is another common benefit. I’m a tennis player and had problems with joint pain, back pain, and sciatica. I would often not be able to stand up after a day of work, and I often had difficulty getting up off the couch after sitting for too long. But after three months of NAD supplementation, my intracellular NAD reached optimal levels, and these problems have gone away. Other people have reported improvement in heart conditions, and I even have one woman who reported improved vision. That result surprised me; however, she no longer has to wear eyeglasses when working at her computer. Another woman had a thyroid nodule that disappeared after a month on the supplement.

NAD Research: And this is with oral supplementation? Not sublingual, but ingested NAD supplement?

Dr. She: It’s with oral Accuri™ Vitality Boost, which contains the NAD precursor NMN (nicotinamide mononucleotide) and three additional ingredients for elevating NAD and optimizing cellular function. We are submitting a patent and will disclose the content in a few weeks.

NAD Research: And the supplement isn’t affected by digestion?

Dr. She: It may be affected, but enough is getting into the cells to raise the NAD levels. That’s all I really care about. I’m not trying to optimize absorption. I’m trying to optimize NAD levels.

NAD Research: Interesting. So, your tests measure both intracellular NAD and extracellular, or circulating, NAD. What’s the difference?

Dr. She: Right. So intracellular NAD is inside the cells, which we can measure from blood or other tissues, but blood is the easiest way to do it. Extracellular, or circulating, NAD is outside of the cells, in bodily fluids such as saliva and plasma. We don’t know what NAD is doing in saliva; but NAD in plasma is circulating through the body, so that’s where it gets its name.

NAD Research: Since most of NAD’s known functions take place within the cell, what do you suspect is the role of extracellular NAD?

Dr. She: Very good question. Most of the known functions of NAD are attributable to intracellular NAD. Nevertheless, extracellular NAD or circulating NAD may also be playing critical roles that are less well understood because we know that certain cell types—neuronal cells and immune cells—contain NAD receptors. We also know that NAD is a neurotransmitter and that it regulates immune cells and controls immune response.

In fact, I think the clinical benefits that we see from intravenous NAD infusions are due to circulating NAD—which explains why the clinical benefits are primarily addressing neurological problems, such as dementia and addiction, as well as certain infectious diseases like Lyme’s disease and more recently, COVID, or long COVID. The clinical benefits for these conditions are undeniable, although there are no published studies of large-scale clinical trials yet, as far as I know.

We just finished a clinical trial a week ago that demonstrated conclusively that intravenous NAD infusions do not increase intracellular NAD. Prior to that, we collected data a number of patients who have had intravenous NAD infusions with no increase in intracellular NAD levels.

The evidence is very clear. There’s no gray zone. It’s black and white. So now we have to reconcile why intravenous NAD delivers the clinical outcomes in neurological function, but we don’t see an increase in intracellular NAD. The answer is that the results are being delivered by circulating NAD.

[Editor’s Note: Based on our intravenous NAD pharmacokinetic study with Ross Grant’s group at the University of New South Wales, we think all, or most, of the intravenous NAD is broken down in the first two hours, or at least very quickly, to adenosine, AMP, and nicotinamide. In addition, we see a rise in nitric oxide that remains throughout the infusion period. We see a rise in plasma NAD reaching a peak in 4-6 hours and sustained for 2 hours after the infusion. Thus, IV NAD infusions are exerting a metabolic influence at multiple levels, which can be studied further. We know that central and peripheral levels of NAD are linked, so it is reasonable to surmise that some of the infused NAD will make it across the blood-brain barrier, where it has some direct neurotransmitter action. In addition, the rapid metabolism to (and therefore rise in) the metabolites adenosine and AMP also have beneficial effects, including cardiovascular effects and effects on the central nervous system. In the brain, adenosine acts as an inhibitory neurotransmitter (i.e., a nervous system depressant), promoting sleep and suppressing arousal and excessive neuronal excitation; effects that appear particularly beneficial when managing alcohol withdrawal. So, in short, while NAD precursor supplements can increase intracellular NAD, we believe they are unlikely to initiate the wide range of cellular and neurobiological effects associated with IV NAD infusions.]

NAD Research: However, you are increasing intracellular NAD and are also seeing dramatic clinical outcomes.

Dr. She: That’s because we are increasing intracellular NAD by supplementation with NAD precursors; that is the distinction. The NAD molecule is probably too big to get inside of the cells. One theory proposes that NAD is broken down into smaller molecules that can enter the cells and, once inside, can be used to make NAD. But we don’t see that happening. The smaller components may get inside the cells but it’s not enough to boost intracellular NAD levels. As you have shown in your paper on the pharmacokinetic study of NAD, the infused NAD gets broken down very quickly. Jinfiniti doesn’t have patient data on that, but we do know that if you spike the NAD molecule in blood in your test tube, the NAD is gone within minutes. It is broken down very, very quickly. And then in the body, it would be excreted into the urine. So not enough NAD gets into the tissue to provide a clinical benefit.

NAD Research: Very, very interesting. Have you been able to standardize the test values for variations in age, gender, race, and or various health conditions?

Dr. She: Yes and no. We have data on thousands of people and we noticed the decline in NAD levels by age 50. So yes, there’s a tremendous variation by age. For example, 75% of teenagers have intracellular NAD levels above 40 micromoles and 25% have less than that. But you do see a small proportion of teenagers who have very low levels of NAD. However, young individuals who have very low levels of NAD usually have major health problems.

We were surprised to discover how quickly NAD levels declined — as early as the late 20s and early 30s, increasing percentages of individuals have suboptimal levels of NAD as we age. And by our 50s, the levels have already reached almost the bottom. There is not much further decline after the 50s. In other words, the levels we see in 80-year-olds, or even 90-year-olds, are not necessarily that much lower than what we see in those in their 50s and 60s. So the decline happens earlier than most people believed.

NAD Research: I’m sorry to hear that.

Dr. She: I know [laughs]. I’m sorry too, but the good news is that once you’ve tested and found out that your NAD levels are low, you can raise your levels very easily. However, testing and supplementation really need to occur much earlier than most of us realize. As more people seek to supplement their NAD levels, we should be able to get the price down so everyone can benefit from the optimal energy levels that NAD provides. I believe there’s a lot that we public health and medical professionals can do to educate the population about the importance of cellular energy production. Policymakers, too, need to understand that why this is an important public health issue. I’m devoting myself to educating the population and the policymakers to make this happen—hopefully in my lifetime.

NAD Research: Well, if you’re taking NAD, you’ll have a long life. Just don’t get hit by a train.

Dr. She: That’s right.

NAD Research: Have you been able to distinguish any differences in NAD levels by gender or race?

Dr. She: We have not really analyzed the data yet regarding gender. I’ll start taking a closer look now. We have, however, seen a pretty clear trend that Asians—Chinese, Japanese, Indian—have lower NAD levels than Caucasians. I don’t have enough data yet on Africans to say.

NAD Research: When you say that Asians tend to have lower NAD levels, do you mean their optimal range is lower, or that they tend to have levels at the lower end of the range?

Dr. She: I think they are at the lower end of the range. I don’t believe there should be race- or gender-specific range for optimal levels, because I think everyone needs to get intracellular NAD levels above 40 micromole, and ideally, above 50 micromole. That’s not only the levels we see in most healthy teenagers, but also is the level when we see clinical improvement in physiology or physical and mental abilities.

NAD Research: Have you seen any biomarker changes that you relate to NAD levels?

Dr. She: Yes, two big ones that are very clear. One is reduction in ALT (alanine aminotransferase), a liver enzyme. We see NAD supplementation reduce ALT in 50 to 70 percent of people with elevated ALT levels, which is good. We’ve also seen some reductions in triglyceride levels, and I think there’s a pretty clear reduction in CRP (C-reactive protein) levels. There may be other biomarkers, but we only test about 17 different biomarkers. There could also be a relationship with telomeres and biological age, but we don’t have enough data to make a definitive conclusion.

NAD Research: What do the tests cost and how long does it take to receive the results?

Dr. She: The test is $248. And the maximum time it takes to receive the report after we receive the samples is one week.

Dr. Richard F. Mestayer, III, on exciting developments in NAD research

Editor’s Note: With the following interview with Dr. Richard F. Mestayer, III, medical director of NAD Research and of Springfield Wellness Center, we begin a series of blog posts updating BR+ Fellows, BR+NAD Brain Restoration Summit attendees, and others on the most exciting developments we’re tracking in NAD research. If you are aware of, or conducting, research you’d like to bring to our attention, please let us know by emailing leslee@alchemyondemand.com.

Editor: The last Brain Restoration Summit was in 2020. What are the major NAD research developments since then, and which are you most excited about?

Mestayer: There are a number of different research threads being pursued—all of which are important and exciting in terms of advancing understanding of NAD’s role in the human body. Probably the project I’m most excited about is with Ross Grant’s team in Australia. His group is working to understand standard NAD levels in various populations, and we hope to begin a project with them by January.

We’re also seeking funding to study NAD’s effect on people with CTE, and a third project will quantify NAD’s ability to minimize long-term cravings after alcohol detox.

A little further back in the queue is a study of NAD’s benefits for people with PTSD. We’re also pursuing ongoing studies of NAD administration via SphenoCath, which can deliver NAD along with a little bit of Lidocaine into the sphenopalatine ganglion area to improve cognition, reduce or eliminate migraines, and improve the central nervous system effects of NAD.

Earlier this year we presented a case report of a patient receiving intranasal (IN) BR+NAD for pain associated with migraine headaches, followed by sublingual Real NAD for three months. The patient tolerated the procedure well and reported no return of migraine headaches up to a year post-treatment. She also had improved cognitive functioning.  Another case report utilizing IN NAD will be presented at the Society for Neuroscience in San Diego this November.

These are quite a few projects to be pursuing simultaneously, and each of them has its own moving parts. The underpinning for all of them is getting the funding, which is always a work in progress.

Editor: Back to the first project—nailing down NAD levels in various populations—why is that significant?

Mestayer: Because nobody really knows what a normal NAD level is, yet. We’re trying to establish that, just like we can for hemoglobin and white blood cell counts. Doing so would enable us to say to a 50-year-old, for example, your NAD level is this; here’s what it should be at 50; and here’s what it was as a healthy 30-year-old. These are the measures you can take to boost your NAD level, and we’d hope to be able to predict what the clinical response would be.

Editor: Great. Thank you. Can you tell us more about the projects regarding CTE and alcohol that you’re hoping to fund?

Mestayer: Well, the details are confidential, but basically, we want to be able to measure and compare alcohol detox via intravenous NAD versus standard-of-care detox as defined by ASAM, the American Society for Addiction Medicine.

Anecdotally we know that NAD really drives down cravings and that mental clarity returns pretty quickly. We believe that liver enzymes and oxidative stress levels also improve, but we’d like to demonstrate all of these things in a study.

We’re waiting on funding, as I said; however, while we wait other interesting parameters may come into focus. For example, we might want to see whether NAD can address DNA changes in alcohol methylation. So, the field is always changing.

Editor: And, what about the CTE study?

Mestayer: Well, as you know, CTE is a diagnosis that is definitively made only upon autopsy. Nevertheless, we’ve had patients with a history of head injuries come to us for alcohol detox and experience dramatic improvements in their CTE symptoms. So, our first step will be to try to find some solid biomarkers for CTE while our patients are living. That information would enable us to measure and quantify how NAD is able to help. We believe we have some funding tentatively lined up, and in the meantime, we are working to decide upon a protocol and to request IRB approval. I’m hopeful that in the next six months we’ll be able to get something going.

Editor: What do you know about the research progress of investigators who participated in the 2020 BR+NAD Brain Restoration Summit?

Mestayer: I understand that Tom Ubl is making progress on his study regarding KR+NAD, which is his terminology for Kidney Restoration, which could present an alternative to dialysis. He’s got a protocol in place, and I’d love to hear how his work is going.  Dave Workman, who is working with the NAD sphenopalatine ganglion stimulation strategy and is about to open up a clinic in Utah, has been combining NAD with ketamine and getting some interesting results. He’ll share more of that in a later post. Again, this is all anecdotal. We need studies to document these results.

Editor: If people are interested in funding this research, what can they do to help?

Mestayer: We have a nonprofit set up for people to contribute to and receive a charitable tax deduction. Or people can reach out to me personally at rfmestayer@yahoo.com.


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