Nicotinamide adenine dinucleotide, better known as NAD, is truly the “spark of life” involved in everything from cellular energy and metabolism to DNA repair and aging. This mighty coenzyme is found in all cells and helps other enzymes catalyze over 500 different reactions, some of which literally produce power. With aging NAD plummets and replacing NAD may be one key to avoid disease and delay aging, but are we playing with fire?
NAD for cellular energy
NAD works through oxidation-reduction reactions, meaning it loses or gains electrons in the process of encouraging chemical reactions. It enables other enzymes to do their job, thus earning it’s title as a “coenzyme”. Through complex biochemical reactions in the energy producing mitochondria within our cells, NAD essentially leads to the currency of energy, called ATP (adenosine triphosphate).
NAD as a metabolic monitoring system
Other major families of enzymes consume NAD as a substrate not only affecting NAD bioavailability and biosynthesis, but also having a major impact on energy metabolism, cell survival, and aging. These other enzyme systems respond to varying levels of NAD thus serving as metabolic sensors, and signals for the body to respond and adapt to metabolic conditions.
NAD as a supplier
Sirtuins are a family of signaling proteins and are perhaps the most well known enzyme system that depends on NAD. Sirtuins play a role in activation or suppression of certain genes. In mammals there are 7 sirtuin proteins.
SIRT1 is the most understood sirtuin protein, responding to metabolic stressors such as fasting, caloric restriction or exercise. Activation of SIRT1 causes the body to better adapt to stressful nutritional and energy states by altering cellular metabolism. It is limited by the availability of NAD.
Other NAD dependent SIRT proteins play a role in tumor suppression, mitochondrial function, cellular survival, insulin secretion, detoxification, and DNA repair.
Another group of proteins that depend on NAD are known as PARPs, or poly-ADP ribose proteins. PARPs main function is to repair DNA damage. If not able to repair the damage then PARPs may initiate the death of damaged cells. It is thought that healthy PARP function contributes to longevity.
Research suggests SIRT proteins and PARPs may compete for NAD, but another enzyme called CD38 may hold the keys to NAD levels. CD38 requires massive amounts of NAD to function. When levels of CD38 go up, NAD goes down, and this may be real reason NAD declines with aging.
CD38 is found mostly in immune cells and involved with various immune functions. But CD38 also plays a role in aging. As we age, our cells also age and die, in a process called “cellular senescence”. Senescent, or aging/dying cells release inflammation causing compounds called “inflammagens” that trigger a rise in CD38, which uses up the cellular NAD. By taking away the cellular energy source the senescent cell quickly dies.
Aging leads to more senescence and more inflammation thus driving CD38 levels higher and higher, lowering NAD, and causing more cell death. As more cells die there is more inflammation and the vicious cycle continues.
Too much of a good thing
If declining NAD levels contribute to aging, then raising NAD levels should be a good thing. At least that’s the idea. But, there is some evidence that raising NAD levels too much can actually interfere with the normal process of cellular senescence. In the case of cancer this may be a bad thing. Cancer cells also release inflammagens and also die in the absence of NAD. There is some research showing excess levels of NAD promote cancer cell survival.
It appears having just the right balance of NAD may be the key to promoting healthy aging without increasing the risk of cancer. Controlling excess CD38 levels while supplying the nutrient precursors seems to be the best strategy.
Supplements to raise NAD
There are 4 pathways in the body for NAD production. The first, is via dietary intake of an amino acid called Tryptophan. This pathway makes NAD from scratch, or “de novo” as it’s called. It’s an inefficient pathway and not available to all tissues.
Different forms of Vitamin B3 make up the other 3 pathways, including niacin/nicotinic acid (NA), nicotinamide/niacinamide (NAM) and nicotinamide riboside (NR). Each of these can be taken as a supplement, and each seems to raise NAD levels about the same, but there are pros and cons with each.
NA is used to treat high cholesterol and produces the well known “flushing” which is not pleasant, thus limiting it’s appeal. It will raise NAD levels but not in all tissues. NAM is available to all tissues, but will inhibit sirtuin activity, which is not ideal.
Nicotinamide mononucleotide (NMN) is a common intermediary in both NAM and NR pathways. NMN increases NAD and activates SIRT1 pathways. Some research supports the idea that NMN is more effective than NR supplements because it sustains blood levels longer and raises intracellular NAD more.
NR appears to be an ideal precursor with availability in all tissues, no inhibition of SIRT proteins and more safety data. Although, one study showed NMN improves insulin sensitivity and was shown to be safe, albeit in a limited follow up period.
David Sinclair, Ph.D., the founder of Life Biosciences, a longevity startup in Cambridge, Massachusetts is a leading proponent of NMN. Marketed by Alive By Nature, NMN comes in liposomal capsules, sublingual tablets or topical creams.
Charles Brenner Ph.D discovered NR in 2004. Several products for NR include Tru Niagen from ChromaDex, NiaCel from Thorne, and Basis from Elysium.
Direct NAD supplementation
I first discovered NAD as a supplement while researching treatments for Parkinson’s dementia. Decades ago in Austria, the Birkmayer family of physicians began studying NAD. They started a clinic in Austria that is visited by people from all over the world seeking treatment for metabolic and neurodegenerative conditions.
Originally, NADH could be used only intravenously, but over time George Birkmayer, MD, PhD, developed and patented a sublingual form of NADH with the bioavailability and effectiveness of the IV form. The product they market is called ENADA.
We use intravenous NAD in our clinic regularly, especially for conditions that involve chronic fatigue, mitochondrial dysfunction, and for drug and alcohol rehabilitation. NAD is really a “biologic modifier” and by increasing cellular energy it could arguably be used for any condition as well as promoting general health.
Raising NAD by lowering CD38
Controlling excess CD38 levels seems to be a excellent strategy to help raise NAD. There are several compounds that will lower CD38 levels.
Taxifolin or dihydroquercitin, Apigenin and Luteolin are flavonoid antioxidants that are available as CD38 lowering supplements. They also lower inflammation and have anti-cancer properties.
Two others are not available as a supplement, but are found in foods. Callistephin is an anthocyanin, a type of flavonoid that makes foods dark blue, like blueberries, wine grapes and pomegranates. Kuromaninis is also an anthocyanin, found in black currants, red raspberries, lychees, and Peruvian purple corn.
I think your best plan to lower CD38 is to eat lots of the flavonoid and anthocyanin-rich foods noted above, and also include acia, black plums, blackberries, black rice, blood oranges, red cabbage and red onions.
Benefits of Fasting
During times of famine or fasting our bodies are triggered to go into survival mode, leading to the destruction of old and inefficient cells and cellular components, including old worn out mitochondria, via a process called autophagy. This is in line with cellular senescence and is called senolysis. Supplements such as quercitin and fisitin are called senolytics because they selectively eliminate senescent cells.
If food is not readily available then blood glucose levels drop forcing our body to turn to stored glucose, or glycogen as a power supply. Within a few days glycogen runs out so we then turn to fat for energy in a process called ketosis. This is the basis of the ketogenic diet.
Coming out of fasting triggers renewal, including healthy new mitochondria and increased NAD levels. Prolonged fasting, as in 4-5 days, is difficult and isn’t for everyone. The Fasting Mimicking Diet (FMD) developed by renowned anti-aging researcher Valter Longo provides the health benefits of a 5-day fast while still getting some food. Studies show the FMD also decreases gastrointestinal disease, reverses diabetes, and lowers systemic inflammation. I highly recommend his book “The Longevity Diet”.
As an aside, shorter periods of fasting, called intermittent fasting or time restricted eating, is typically fasting for 16-20 hours each day, or 1 day per week, or such. I think the benefits are improved metabolic flexibility between glucose and fats, but I don’t know to what extent this causes autophagy or increases NAD levels.
My plan for NAD support
I’ve taken the sublingual ENADA for years. I only take it after lunch, on days I’m in the office, and note it helps me stay energetic and mentally sharp.
Eat lots of flavonoid and anthocyanin rich foods for lowering CD38 levels plus so many more benefits. Also include plenty of foods rich in niacin, nicotinamide and tryptophan for NAD support. I try to do the fasting mimicking diet a few times each year to stimulate senolysis and activate stem cells.
I don’t get IV NAD treatments as it may be more than enough for someone in good health. Instead, I do get routine ozone / Myers vitamin / glutathione IVs as part of my prevention efforts. I may start taking a NMN or NR supplement, and possibly quercitin or fisitin to stimulate senolysis. One could also add dihydroquercitin, apigenin or luteolin supplements to lower CD38.
Avoiding excess alcohol and not overeating, getting regular exercise and plenty of restful sleep also support healthy NAD levels. Look for new research on NMN and NR supplements as we further define which is best.
Author
Scott Rollins, MD, is Board Certified with the American Board of Family Practice and the American Board of Anti-Aging and Regenerative Medicine. He specializes in bioidentical hormone replacement for men and women, thyroid and adrenal disorders, fibromyalgia and other complex medical conditions. He is founder and medical director of the Integrative Medicine Center of Western Colorado (www.imcwc.com) and Bellezza Laser Aesthetics (www.bellezzalaser.com). Call (970) 245-6911 for an appointment or more information.
