THE CRITICAL ROLE OF NAD+ AND NITRIC OXIDE REPLENISHMENT IN ANTI-AGING MEDICINE
By Chris D. Meletis, ND, and Kimberly Wilkes, BS

THE TOWNSEND LETTER, Thursday, December 2, 2021 https://townsendletter.com/article/461-anti-aging-nitric-oxide-and-nad/

 Commentary by Ronald Peters, MD, MPH 

This is a must read article for anyone over 50 years of age as it identifies two key signaling molecules that are essential for health, nicotinamide adenine dinucleotide (NAD+) and nitric oxide.  And, they both decline around middle age.  NAD+ is destroyed by an enzyme called CD38 which increases in response to inflammation.  Aches, pains and stiffness are common features of the aging process and are due to increasing inflammation in the body.  Bacterial toxins from the gut, or endotoxins, are another source of inflammation and is why a healthy microbiome is essential for good health at any age.  Also, the body makes new cells and it recycles dead, or senescent cells.  Basically we need to take out cellular garbage or it will accumulate in the body and contribute to inflammation, especially the inflammation of aging, or inflammaging.  Also, there is a blood test for nitric oxide deficiency.

Degenerative diseases affect a substantial number of people due to the aging of the population. Worldwide, the number of adults 60 years and over is expected to more than double from the years 2013 to 2050.1 Furthermore, the number of people 80 years old and over will more than triple by 2050.1

In attempting to reduce the effects of aging on the human body, instead of merely chasing symptoms of cellular senescence, a more ideal approach is to ensure the cells have the oxygen, circulation, and mitochondrial support they need to remain healthy. In this way, we can get at the root cause of the symptoms of age-related diseases. That’s why the main focus of this article is the critical importance of maintaining healthy circulation and blood flow as we age, as well as keeping the mitochondria functioning efficiently. We’ll also address two of the most important ways to achieve those goals: increasing levels of nitric oxide and nicotinamide adenine dinucleotide (NAD+).

Healthy Blood Flow: A Babbling Brook not a Stagnant Pond

Circulation—in other words blood flow—is important to delivering oxygen and nutrients to bodily tissues. With aging, circulation becomes diminished. This means the brain, heart, GI tract, liver, skin, adrenals, and gonads aren’t receiving the oxygen and nutrients they need to function effectively. It becomes a Catch-22 situation as the decreased circulation caused by aging weakens organs, which in turn causes more damage and additional impairment to healthy circulation. In order to slow down aging, our goal is to sustain a babbling brook of pristine blood flow and to avoid stasis, the stagnant pond phenomenon that leads to metabolite waste and accumulation of deoxygenated blood.

Circulation and the Heart

The heart is one of the hardest working organs in the body. With an average pulse of 72 beats per minute, the heart beats 103,680 times a day. Healthy blood flow through the body’s 60,000 miles of blood vessels is critical to oxygenation of the heart and cardiovascular system. Reducing risk factors for atherosclerosis and heart disease by quitting smoking, exercising, and eating a healthy diet with lots of vegetables is important. However, once the hands of time have turned there are ways to support circulation by meeting the patient where they are in their health journey. In other words, if the patient isn’t eating a perfect diet or exercising enough—or if they started healthy habits after the damage has already been done—enhancing nitric oxide (NO) levels may increase blood flow and improve cardiovascular health.

Nitric oxide is an important molecule to all aspects of healthy aging. It increases perfusion, the flow of blood that delivers nutrients and oxygen to tissues, including heart tissue. It also aids in the removal of waste. NO is a vasodilator, which means it widens the blood vessels to increase blood flow.2 It suppresses coagulation and stops blood platelets from sticking together (platelet aggregation).2

NO is released by the endothelium, the lining of the blood vessels. This is necessary for vasodilation and healthy blood flow. However, during aging, the endothelium undergoes changes that are associated with reduced NO bioavailability.3 This in turn leads to reduced vasodilation, impaired blood flow, and arterial stiffening.3

The endothelium contains a protective layer called the glycocalyx (GCX), which serves as a defense against vascular diseases, including atherosclerosis.4 When GCX breaks down it permits lipids to accumulate on the vessel wall.4 During GCX dysfunction, inflammatory cells are also deposited on the vessel walls.4 One of the most unfortunate consequences of a breakdown in the GCX is a reduced ability of the endothelial cells to synthesize endothelial nitric oxide synthase (eNOS), which produces nitric oxide.4 The lower NO levels in this case lead to vasoconstriction, encouraging the progression of atherosclerosis.4

Although our body makes NO naturally, especially after eating a diet that’s filled with nitrate-rich green leafy vegetables, NO has only a three- to five-second half life.5 That means almost as soon as it’s made, it’s gone. Therefore, replenishing NO levels through the use of a nitrate-rich supplement, including beetroot is a prudent way to improve blood flow to the heart. Supplementation to increase levels of NO has been shown to reduce blood pressure, modify platelet aggregation, and increase blood flow in the limbs.6,7 NO supplementation is beneficial for both the macrovascular and microvascular systems.8,9

Circulation and the Brain

It is important to remember that healthy circulation is critical for all areas of the body, including the brain. Thomas Edison once said, “The chief function of the body is to carry the brain around.” The brain needs oxygen to function and blood flow delivers oxygen to this important organ. Indeed, the brain consumes 20% of all the oxygen used by the body.10

The decline in cardiovascular function that occurs during aging can reduce cerebral blood flow.1 This can cause problems for the neurons in the brain, especially because the brain is the most metabolically active organ, and yet it has a limited capacity for intracellular energy storage.1 Therefore, it is dependent upon cerebral blood flow to maintain the health of neurons.1

Although Alzheimer’s disease (AD) is usually linked to the cerebral buildup of amyloid-β and hyper-phosphorylated tau peptides l, there’s also evidence that impaired cerebral blood flow is associated with the disease.11 Previously, vascular dementia was thought to be a separate condition from AD. It was thought to occur after a stroke or in conjunction with vascular disease. However, recent evidence suggests that there is a range that includes patients with pure vascular dementia and individuals with pure AD, but that a majority of these patients have both AD and vascular dementia.11

The relationship between impaired blood flow and cognitive dysfunction indicates supplementation with substances that increase NO levels may be especially useful in supporting cognitive health. Preclinical studies indicate a diet rich in nitrate increases perfusion in the frontal white matter of the brain, which is involved in working memory, task-switching, and episodic memory retrieval.12 In a human study, two weeks of daily beetroot juice supplementation, which increases NO levels, led to improved simple reaction time in older adults with type 2 diabetes.13

Circulation and Men’s Sexual Health During Aging

In men, one of the most frustrating manifestations of impaired blood flow during aging is either outright erectile dysfunction or a softening of erections. Optimal blood flow to the penis is critical to healthy erectile function. In order to have an erection, when a man is aroused, vessels leading into the penis relax, leading to a healthy blood flow. The blood flows into the corpora cavernosa, columns of spongy tissue on the shaft of the penis. When the corpora cavernosa is engorged with blood, it triggers an erection.

There are ways in which penile blood flow can be increased in order to improve erectile function. ED pills increase blood flow only temporarily. It is preferable to go after the root cause of impaired penile blood flow, which is an age-related reduction in nitric oxide. Low NO levels are linked to erectile dysfunction.14 Conversely, replenishing NO levels is one of the best ways to improve erectile performance.15 Enhancing NO levels has the added benefit of improving cardiovascular health.15 This is important because if a man is having trouble with erectile function, it is an indicator that circulation throughout his body might be impaired. This serves as a wake-up call to also address cardiovascular issues in the body.

Increasing levels of NO can be accomplished with a nitrate-rich supplement containing beetroot. A source of nitrate, beetroot increases NO availability in the body.16 It has also been shown to decrease vascular inflammation and reduce blood pressure.17 In addition, beetroot enhances exercise tolerance and performance.18 This is advantageous as exercise is an ideal way to increase blood circulation.

Acoustic soundwave therapy, also known as low-intensity extracorporeal shock wave therapy (Li-ESWT), can also be used to enhance blood flow to the penis and increase nitric oxide levels.19 This type of therapy has been shown to be as effective as sildenafil (Viagra) in men with ED.20 Because it promotes the formation of healthy new blood vessels feeding the penis and safely dissolves penile plaque,21 it’s a more permanent solution compared with ED pills. It has been used in doctors’ offices for decades, but recently an at-home device that is equivalent to ones used in clinics was made available to men at home.

Mitochondrial Support in Healthy Aging

To slow aging, not only do we need healthy circulation. Of equally critical importance is to make sure we are tending to the health of our mitochondria, our cellular batteries. The moment energy levels in our cells drop to insufficient or suboptimal levels then the peak performance of a cell is diminished. That’s why impaired mitochondrial function impacts every area of the body, including the adrenals, thyroid, brain, and circulatory system. Even sexual organs are involved in a vicious cycle whereby the age-related decrease in gonadal function alters mitochondrial activity while impaired mitochondrial function affects the gonads.22

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Dietary nitrate is an excellent way to rejuvenate mitochondrial health.23 However, this strategy is most effective when also ensuring that nicotinamide adenine dinucleotide (NAD+) levels are continuously being replenished. NAD+ is an essential resource for cellular energy production. The reduced form of NAD+ (NADH) is critical to the mitochondrial production of adenosine triphosphate (ATP), which serves as fuel for the cells of the body.24 Conversely, low levels of NAD+ may make mitochondria more vulnerable to damage.25

Between the ages of 40 and 50, we lose up to 50% of our NAD+ levels.26 This leads to adverse consequences to our health since low NAD+ levels contribute to diminished energy needed to maintain health as we age.24 Low NAD+ occurs in many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, cardiovascular, and muscle atrophy.24 Furthermore, NAD+ depletion affects immunity.27,28

Age-Related Declines in NAD+ in Various Body Tissues29

Muscle 30% – 85%
Liver 40% – 90%
Adipose 55% – 75%
Brain 35% – 90%
Pancreas 80% – 85%
Spleen 35% – 40%
Heart 30% – 70%
Kidney 15% – 98%
Lung 20% – 25%
Cerebrospinal fluid 86%
Skin 40% – 50%
Blood plasma 15% – 92%
Testes 100%

Sirtuins, which increase lifespan, require NAD+ to function properly. Sirtuins are important to increasing longevity and reducing stress responses.30 Enhancing sirtuin activity is linked to the delay of age-related diseases.30 Furthermore, increased sirtuin activity is thought to be the reason why lean diets and exercise lead to cardiometabolic benefits.30 For example, SIRT1 stops the decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion (IR) injury, obesity, and cardiomyopathy.30 However, during aging, NAD+ levels and sirtuin activity progressively decline, an effect made worse by obesity and sedentary lifestyles.30 Activation of sirtuins or increasing NAD+ levels leads to benefits such as improved insulin sensitivity in a number of age-related cardiovascular and metabolic disease models.30

NAD+ and Alzheimer’s

One of the best examples of the protective effect of NAD+ in aging is its role in cognitive function. Mitochondria in neurons synthesize ATP to produce the necessary energy needed for optimal activity. However, dysfunctional or damaged mitochondria build up in the neurons, affected in the brain during AD.31 NAD+ protects the neurons by rejuvenating mitochondrial health.32

How to Increase NAD+ Levels

Evidence indicates that interventions that replenish cellular NAD+ levels may suppress aspects of aging and inhibit some age-related diseases.24 Supplementation with nicotinamide riboside (NR) is an extremely effective way to raise NAD+ levels. NR administered as both a single dose and repeated use has been shown in human research to raise NAD+ levels.33

Research has investigated the use of NR in a number of age-related conditions. In a randomized, double-blind, controlled cross-over study of 30 middle-aged and older healthy male and female adults, 500 mg of NR were given twice per day orally for six weeks.33 NR supplementation tended to lower both systolic and diastolic blood pressure. The decline was more dramatic in subjects who had elevated blood pressure at baseline. Additionally, NR tended to decrease aortic stiffness and increase ATP levels. NAD+ levels increased by an average of 60% after NR supplementation. In another study of peripheral blood mononuclear cells from patients with heart failure, NR reduced inflammation and improved mitochondrial function.34

Preclinical studies in rodents also indicate NR may be of use in type 2 diabetes. In a mouse model of this condition, NR significantly reduced non-fasting and fasting blood glucose and was associated with reduced weight gain.35

Furthermore, NR treatment reduced memory loss in a mouse model of AD.36 In another study that included both mice with AD and aged mice, NR supplementation improved the short-term spatial memory of the aged animals and the contextual fear memory in the AD animals.37 In aged mice, NR also suppressed the activation of astrocytes while in AD mice it reduced the buildup of Amyloid beta.37

Conclusion

Although aging is inevitable, we can slow down the process by concentrating on two important aspects: healthy blood flow and mitochondrial rejuvenation. Maintaining circulation is critical to ensuring all cells of the body are perfused with the nutrients and oxygen they need to function their best. Likewise, our bodies must produce enough energy to fuel healthy cellular function. That’s why maintaining the health of the mitochondria is also important. Tending to these two factors with a nitrate-rich supplement containing beetroot and replenishing NAD+ levels with nicotinamide riboside can help patients feel healthier and more energetic as they age.

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