NAD+ is a molecule that’s found in every cell of your body that plays many key roles in energy production, health, and longevity. Exciting research has uncovered why NAD+ is so essential and has led to many clinical applications, addressing everything from the signs and symptoms of aging to treating and preventing chronic disease.
In this article, you’ll learn more about:
- What NAD+ is
- The two forms of NAD, namely NAD+ and NADH
- The role NAD+ plays in health and disease
- Why increasing levels of NAD+ is important
- What sirtuins are and how they require NAD+
- The role sirtuins and NAD+ play in vascular aging
- Health conditions that benefit from increasing NAD+
- The three ways the body produces NAD+
- Natural ways to increase NAD+ levels in the body
What is NAD+?
A fair amount of attention has been given to NAD+, particularly for its ability to slow down the effects of aging. NAD+ stands for nicotinamide adenine dinucleotide and it’s used as a coenzyme in many molecular processes that keep your cells and body alive. A coenzyme is like an enzyme helper or assistant and needs to be available for the reaction to take place.
Adequate intracellular NAD+ levels don’t just prevent hastening of cellular aging. They also help to prevent the visible signs of aging that become apparent on the skin. The use of NAD treatment for addiction relies on the speedy delivery of NAD IV therapy and there are numerous NAD+ addiction clinics operational in the United States.
The NAD+ molecule is found in every cell in the body, enabling the conversion of food we eat into energy and chemical products that the body needs to sustain itself. This is very important, since the health and function of every cell relies on this tiny molecule.
NAD+ also plays a critical role with enzymes that regulate gene expression involved in the repair of damaged DNA. Through these pathways, NAD+ influences a variety of processes involved in every cell in your body, improving mitochondrial efficiency, enhancing cell viability, down-regulating inflammation, increasing the antioxidant capacity of cells and tissues, and activating SIRT1, a sirtuin enzyme that plays a role in longevity.
NAD+ and NADH are two different forms of the same molecule, picking up and dropping off electrons. This energy exchange of electrons is what allows the Krebs cycle and electron transport chain to produce ATP, the energy currency in humans. When it picks up an electron, this is NADH, while without the electron it is known as NAD+.
The role of NAD+ in health and disease
Several of these critical roles have already been mentioned, but let’s take a closer look at some of the life-sustaining benefits of NAD+ .
NAD+ is a cofactor for hundreds of enzymatic reactions, such as chromosomal stability and DNA repair. DNA damage is linked to deteriorating chronic health problems, as recently discussed by Robert Naviaux and his theory of the Cell Danger Response.
NAD+ also plays a vital role in energy production, in the Krebs cycle conversion of macronutrients including protein, fats and carbohydrates, and micronutrients such as vitamins and minerals, to ATP. This is the energy molecule that’s crucial to the running of all the body’s essential functions.
In addition, NAD+ is also a cofactor for hundreds of similar enzymatic reactions that are involved in:
- Immune cell signaling and immune strengthening
- Decreasing inflammation
- Decreasing oxidative stress and ‘rusting’ of cells
- Telomere production, with longevity enhanced by longer telomeres
- Neurotransmitter production
- A healthy circadian rhythm and sleep cycle
- Increased activity of sirtuins, which play a role in longevity (see more on this below)
- Prevention of blood vessel damage that reduces the risk of heart disease
- Healthy aging
The importance of increasing levels of NAD+
NAD+ plays a central role in every one of the body’s functions. We simply can’t do without it. In addition, if we boost its levels, we can further optimise cell functions and energy outcome. Unfortunately, as we age levels of NAD+ decline, leading to signs and symptoms of aging.
Low levels of NAD+ are associated with:
- Accelerated aging
- Increased sunburn and skin cancer
- Decreased cellular antioxidants
- Decreased metabolism along with thyroid hormones
- Harmed immune function
- Increased inflammation
- Impaired brain function
- Hypoxia (low levels of oxygen) intracellularly
When NAD+ levels are higher and more robust, we see the following:
- Improved mitochondrial health
- Improved cellular metabolism and energy production
- Improved production of sirtuins
- More NAD anti-aging benefits
- Improved DNA repair and recovery
- Increased immunity, with NAD+ stimulating CD38 that’s present on T-cell immune cells, effectively boosting the immune response
- Stimulation of CD38 activity increasing oxytocin, a hormone associated with social intimacy and bonding
- Increased autophagy or cellular recycling
- Increased redox potential, with more antioxidant action protecting cells
- Improved insulin sensitivity, decreasing the risk of metabolic syndrome and diabetes
- Improved protection of brain cells from oxidative stress, rescuing neuronal loss and improving myelination
- Improved skin health by boosting levels of collagen, keratin, elastin, and hyaluronic acid, a compound found in many skin rejuvenating creams
- Increased stem cells
- Improved exercise performance
NAD+ provides these benefits through several key mechanisms, including:
- Promoting AMPK activity, an enzyme that improves metabolism and helps protect against obesity and diabetes.
- Modulating p53, a tumor suppressor gene that repairs damaged DNA and protects against cancer initiation
- Inhibiting NF-kB or nuclear factor-kappa B, a protein that induces the chronic inflammation tied to many diseases and premature aging
- Inhibiting mTOR, a molecular complex whose abnormal activation contributes to many chronic diseases of aging
Sirtuins and NAD
Sirtuin is an acronym for ‘silent information regulator’. This refers to any family of enzymes, made up of proteins, that occur in all living organisms. They’re thought to regulate a wide array of cellular processes such as cellular aging, apoptosis, and stress resistance in more complex organisms. It’s been demonstrated that increasing sirtuin activity leads to longer life and reduction in age-related loss of function. It also protects against DNA damage. NAD levels decline with aging, which also results in reduced sirtuin activity. Boosting NAD+ helps to ramp up this activity.
Seven sirtuins have been identified and play different roles in the body.
- Sirtuin 1 (SIRT1) repairs DNA and vascular tissue and is highly dependent on NAD+ levels
- Sirtuin 2 (SIRT2) reduces body fat and oxidative stress
- Sirtuin 3 (SIRT3) influences longevity
- Sirtuin 4 (SIRT4) can repress tumors and autophagy
- Sirtuin 5 (SIRT5) reduces fatty acids in the liver and oxidative stress
- Sirtuin 6 (SIRT6) regulates blood sugar and decreases insulin resistance
- Sirtuin 7 (SIRT7) benefits the heart
NAD+, sirtuins, and vascular aging
As we age, our small blood vessels die off. This compromises blood flow and the oxygenation of organs and tissues that are fed by these small vessels. Vascular aging is responsible for a constellation of disorders, such as cardiac and neurological conditions, muscle loss, impaired wound healing, and overall frailty.
Dr. David Sinclair, a researcher at the Department of Genetics at Harvard Medical School and a co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School, has discovered a way to reverse vascular aging by boosting the presence of naturally occurring molecules in the body that augment the physiological response to exercise. He states that, “The approach stimulates blood vessel growth and boosts stamina endurance in mice and sets the stage for therapies in humans to address the spectrum of diseases that arise from vascular aging.”
Dr. Sinclair’s study revealed that NAD+ and SIRT1 enable the conversation between endothelial cells in the walls of blood vessels and muscles, but specifically the cells in young mouse muscles, activating SIRT1 signaling generating new capillaries that supply oxygen and nutrients to tissues and organs. Conversely, the study demonstrated that as NAD+/SIRT1 activity diminished over time so did blood flow, which left muscle tissue deprived of nutrients and starved of oxygen.
Dr. Sinclair gave an NAD supplement, as an NAD+ precursor, for two months to a group of mice that were twenty months old, roughly equivalent to seventy in human years, to test its effect on SIRT1 signaling. The treatment worked and restored the number of blood capillaries and capillary density to those seen in younger mice. Blood flow to the muscles also increased and was more significantly higher than blood supply to the muscle seen in mice of the same age that didn’t receive the NAD+ precursor.
The most striking effect emerged in the aging mice’s ability to exercise. These animals showed a 56 to 80 percent greater exercise capacity when compared to that of untreated mice. It was concluded that this observation underscored the notion that age plays a critical role in the crosstalk between blood vessels and muscles. This points to a loss of NAD+ and SIRT1 as the reason behind the reduction in exercise effectiveness after middle age. The researchers believe that their findings might pave the way to therapeutic advances that might be able to help the millions of older people for whom regular physical activity is no longer an option.
“Even if you’re an athlete you eventually decline,” Sinclair says. “But there is another category of people – what about those who are in a wheelchair or those with otherwise reduced mobility?”
Dr. Sinclair’s mouse study suggests that NAD+ may support exercise performance in humans. In a study involving elderly men, supplementation with an NAD+ precursor resulted in improved exercise performance. The men had an 8 percent improvement in peak isometric muscle torque, which is a measure of muscle force, and a 15 percent improvement in lessening of fatigue associated with exercise.
Health conditions that benefit from increased NAD+
Considering what we’ve explored regarding NAD+ energy production in every cell and the importance of this molecule in all aspects of health and longevity, it’s no surprise that NAD+ may benefit a number of health conditions, including chronic disease. Conditions that may benefit from increased levels of NAD+ in the cells include:
- Neurological deficits
- Brain injury
- Cholesterol metabolism issues
- Chronic fatigue syndrome
- Irritable bowel syndrome (IBS)
- Diabesity spectrum, including obesity, metabolic syndrome, and Type 2 diabetes
- Systemic inflammation
- Lyme disease
- Malabsorption syndromes
- Parkinson’s disease
- Alzheimer’s disease
- Huntington’s disease
- Autism spectrum
- Small bowel overgrowth syndrome (SIBO)
- Cardiovascular disease
- Multiple sclerosis
- Hearing loss
- Renal disease
NAD+ pathways of production
There are three major pathways that our body employs to synthesize in NAD+. Influencing and activating these pathways are a way to increase NAD+ within the cells of the body.
The first pathway is the de nova synthesis from the amino acid tryptophan from food protein sources, which also intersects with vitamin B3. This is the long way round.
The second is a salvage pathway, used by the supplement company PRICERA, that our body uses daily to recycle nicotinamide (NAM) according to circadian rhythms. This is the dominant and most robust path for any NAD+ synthesis.
The third pathway is specialized for nicotinamide riboside (NR) reactivation. NR is a shunt product in NAD+ synthesis.
The supplement company claims that PRICERA is the only available compound that utilizes the naturally dominant pathway to generate NAD+ efficiently and robustly. This product is said to improve the tissue distribution of NAD+, maintain and enhance mitochondrial health and creation, and plays a key role in calorie restriction for increased lifespan and exercise response. PRICERA is also said to prevent neurodegeneration and reduce age-related cognitive decline. In addition, it’s claimed that PRICERA increases ATP and maintains antioxidant levels including glutathione, which generally becomes depleted with higher energy requirements or when we’re under stress.
PRICERA differs from other NAD precursor products in that it includes D-ribose, a known source of energy for the mitochondria in the heart, brain, and muscles. Other NAD precursor products need ATP to prime the pathway. However, since PRICERA spares the body’s own energy, one of its key applications may be to serve individuals with compromised mitochondrial function. This can actually hamper performance under oxidative stress.
How To Raise NAD+ Naturally
Fasting, calorie restriction, exercise, and NAD boosters increase the intracellular levels of NAD+, activate SIRT1, and have other physiological benefits. There are a number of ways to boost your NAD+ levels naturally through lifestyle change, diet, and supplementation.
When we exercise, we use up NAD+ and replenish it rapidly. As a result exercise can help us to build up our reserves.
When we burn fat for energy instead of carbohydrates, we preserve adequate levels of NAD+ and increase levels of NAD+ in the brain. This reduces DNA damage in the hippocampus, which is the location of memory storage. Ketosis is achieved by following a ketogenic diet. In addition, ketosis might be enhanced for part of the day through practices such as intermittent fasting, fasting mimicking, or periodic longer fasts. Calorie restriction and intermittent fasting will also increase NAD+ levels.
Vitamin B3 or niacin supplements, along with foods rich in vitamin B3, such as green vegetables, chicken, portabella mushrooms, rice, nuts, tuna, although you need to be careful of mercury, will benefit the body’s NAD+ production. Niacin is believed to act as a building block for NAD+ levels. Lycopene-rich foods, such as tomatoes, also help to prevent NAD+ depletion.
You can take a NAD+ supplement orally or apply it to your skin. When taking an oral preparation you have to take a precursor molecule, as NAD+ will break down in your gut without being absorbed. Nicotinamide riboside (NR) is this type of NAD+ precursor.
NAD IV may be an option for individuals with certain conditions such as addiction, who have access to this type of therapy. NAD+ bypasses the gut and is delivered directly to the bloodstream, where it can enter cells.
NAD repletion strategies, such as those outlined above, have shown therapeutic potential as a means to restore a healthy metabolism and physiological function. Many health conditions are multifactorial and require a root cause approach. Bearing in mind the robust and expanding research on NAD+ I’m often considering NAD+ depletion as a factor in patient’s cases, working with them to restore these pathways and reap all of the physiological and anti-aging benefits.
To work together one-on-one, please contact my office for an appointment.
Dr. Bruce Hoffman, MSc, MBChB, FAARM, IFMCP is a Calgary-based Integrative and Functional medicine practitioner. He is the medical director at the Hoffman Centre for Integrative Medicine and The Brain Centre of Alberta specializing in complex medical conditions. He was born in South Africa and obtained his medical degree from the University of Cape Town. He is a certified Functional Medicine Practitioner (IFM), is board certified with a fellowship in anti-aging (hormones) and regenerative medicine (A4M), a certified Shoemaker Mold Treatment Protocol Practitioner (CIRS) and ILADS trained in the treatment of Lyme disease and co-infections. He is the co-author of a recent paper published by Dr. Afrin’s group: Diagnosis of mast cell activation syndrome: a global “consensus-2”. Read more about Dr. Bruce Hoffman.