NAD+ stands for Nicotinamide Adenine Dinucleotide. NAD+ is one of the most abundant and critical molecules in life, from single-cell organisms like bacteria to complex multi-cell organisms like primates. Basically, without NAD+, we are on the fast track to death. This molecule is key to the function of the cellular builders - mitochondria. Not only does NAD+ help convert food into energy, but it also plays a crucial role in maintaining DNA integrity and ensuring proper cellular function to protect our bodies from aging and disease.
How does NAD+ work in the body?
NAD+ acts as a shuttle bus, transferring electrons from one molecule to another within the cell to carry out various reactions and processes. Along with its molecular counterpart NADH, this important molecule participates in various metabolic reactions that produce energy for our cells. Without adequate NAD+ levels, our cells would not be able to produce any energy to survive and perform their functions. Other functions of NAD+ include regulating our circadian rhythm, controlling our body's sleep/wake cycle.
NAD+ levels decrease with age
As we age, NAD+ levels decline, suggesting important implications for metabolic function and age-related diseases. DNA damage accumulates and snowballs with age.
Damage to our genetic blueprint activates several proteins, including enzymes called PARPs. By depleting NAD+, PARPs can perform DNA repair functions. During aging, depletion of NAD+ through PARP activation appears to contribute to various diseases. Of all these functions that require NAD+, many scientists believe that PARPs contribute the most.
Enzymes in our immune system also consume NAD+. The more active the immune system, the more NAD+ the enzymes consume. As we age, the levels of enzymes in our immune system increase, depleting the body’s NAD+ levels.
Another class of enzymes that use NAD+ are called sirtuins. These proteins, which are associated with healthy aging and longevity, use NAD+ to regulate metabolism, maintain stable chromosomes, and repair damaged DNA. As DNA damage and chromosomal instability accumulate with age, sirtuins consume more NAD+.
According to the figure above, the decrease in NAD+ is seen as age changes in males (left) and females (right). Here, the red line "a" represents the change in NAD+ levels throughout life, and the blue line "b" only considers the change in NAD+ levels after puberty.
How do our cells make NAD+?
The process by which cells make molecules is called “biosynthesis.” For NAD+, there are three known pathways: the kynurenine (de novo) pathway, the Preiss-Handler pathway, and the salvage pathway.
The kynurenine (de novo) pathway starts with tryptophan, the essential amino acid you often hear about during Thanksgiving because of its association with turkey. Along these lines, tryptophan comes from food sources such as meat, cheese, eggs, and fish. The conversion of tryptophan to NAD+ occurs in the watery portion of the cell, called the cytosol, which is located outside of the cell's components (organelles).
The Preiss-Handler pathway starts with niacin. Normally, niacin is found in food, but it can also be consumed through dietary supplements. This NAD+ precursor molecule is also produced by bacterial flora in the intestine or in the saliva. Niacin is converted to NAD+ in three steps. In the first step, the enzyme NAPRT converts niacin to nicotinic acid mononucleotide (NAMN). In the second step, the enzyme NMNAT converts NAMN to nicotinic acid adenine dinucleotide (NAAD). Then, the enzyme NAD+ synthetase (NADS) converts NAAD to NAD+.
The salvage pathway of NAD+ biosynthesis uses natural compounds related to vitamin B3. These compounds include niacinamide, niacin, niacinamide mononucleotide (NMN), and niacinamide riboside (NR). NAD+ biosynthesis in the salvage pathway involves the conversion of niacinamide to NMN by the phosphoribosyltransferase NMNAT. This enzyme converts NMN to NAD+. NR is converted to NMN by the enzyme NRK. NMN is converted to NAD+ by the enzymatic activity of NMNAT.
What is NAD+ composed of?
NAD+ is made up of two nucleotides connected by a phosphate group. One nucleotide contains an adenine nucleobase and the other contains niacinamide.
NAD+ biosynthetic precursor Supplementation with NAD+ precursors represents a potential therapeutic strategy to slow aging and improve age-related diseases. Oral supplementation with NAD+ has not been shown to provide any benefits for increasing NAD+ levels in the body. However, supplementation with precursors, such as NMN or NR, may provide these benefits.
Studies have shown that supplementing with NMN can protect against various diseases. This effect may be produced by increasing NAD+ levels in the body. NMN supplementation reduces obesity and protects against blood vessel damage in mice. These benefits are also seen in mouse disease models of Alzheimer's disease, cognitive impairment, and neuroinflammation. Supplementing mice with NR has similar beneficial effects.
What happens when NAD+ levels drop?
Numerous studies have shown that NAD+ levels decrease in conditions of disrupted nutrition, such as obesity and aging. Reduced NAD+ levels can lead to metabolic problems. These problems can lead to diseases, including obesity and insulin resistance. Obesity can lead to diabetes and high blood pressure.
Metabolic disturbances caused by low NAD+ levels cascade down. High blood pressure and other reduced cardiac function send damaging stress waves to the brain, leading to cognitive impairment.
Targeting NAD+ metabolism is a practical nutritional intervention to prevent metabolic and other age-related diseases. Studies done by several groups have shown that supplementation with NAD+ boosters can improve insulin resistance caused by obesity. In mouse models of age-related diseases, supplementation with NAD+ boosters improves symptoms of the disease. This suggests that decreased NAD+ levels with aging may contribute to the onset of age-related diseases.
Preventing the decline in NAD+ offers a promising strategy for combating metabolic disturbances that occur with aging. As NAD+ levels decrease with age, this may lead to decreased DNA repair, cellular stress responses, and regulation of energy metabolism.
Potential advantages
NAD+ is important for mitochondrial maintenance and aging gene regulation in species. However, as we age, our NAD+ levels drop dramatically. "As we age, we lose NAD+. By the time you're 50, your levels are about half of what you had when you were 20," David Sinclair of Harvard University said in an interview.
Research has shown that a reduction in this molecule is associated with age-related diseases, including accelerated aging, metabolic disorders, heart disease, and neurodegeneration. Low NAD+ levels are associated with age-related diseases due to less functional metabolism. However, replenishing NAD+ levels has shown anti-aging effects in animal models, showing promising results in reversing age-related diseases, extending lifespan and healthspan.
Ageing
Sirtuins, known as "the guardians of the genome," are genes that protect organisms from plants to mammals from degeneration and disease. When the gene senses that the body is under physical stress, such as exercise or hunger, it sends out its troops to defend the body. Sirtuins maintain genome integrity, promote DNA repair, and have shown anti-aging-related properties in model animals, such as extending lifespan.
NAD+ is the fuel that drives genes to work. But just like a car can't run without fuel, sirtuins need NAD+. Research results show that increasing NAD+ levels in the body can activate sirtuins and extend the lifespan of yeast, worms and mice. Although NAD+ supplementation shows promising results in animal models, scientists are still studying how these results translate to humans.
Muscle function
As the powerhouse of the body, mitochondrial function is critical to our athletic performance. NAD+ is one of the keys to maintaining healthy mitochondria and steady energy output.
Increasing NAD+ levels in muscle improved mitochondria and health in mice. Other studies have also shown that mice given an NAD+ boost were leaner, could run farther on a treadmill, and exhibited higher exercise capacity. Older animals with higher NAD+ levels outperformed their peers.
Metabolic disorder
Obesity has been declared an epidemic by the World Health Organization (WHO) and is one of the most common diseases in modern society. Obesity leads to other metabolic disorders such as diabetes, which caused 1.6 million deaths worldwide in 2016.
Aging and a high-fat diet reduce NAD+ levels in the body. Studies have shown that taking an NAD+ booster can slow diet-related and age-related weight gain in mice and improve their exercise capacity, even in older mice. Other studies have even reversed the effects of diabetes in female mice, showing a new strategy to combat metabolic disorders.
Heart function
The elasticity of the arteries acts as a buffer between the pressure waves sent by the heartbeat. But as we age, the arteries become stiffer, leading to high blood pressure, the most important risk factor for cardiovascular disease. The CDC reports that in the United States alone, one person dies from cardiovascular disease every 37 seconds.
High blood pressure can lead to heart enlargement and blocked arteries, which can lead to stroke. Boosting NAD+ levels can protect the heart and improve heart function. In mice, NAD+ boosters have replenished NAD+ levels in the heart to baseline levels and prevented damage to the heart caused by insufficient blood flow. Other studies have shown that NAD+ boosters can protect mice from abnormal heart enlargement.
Neurodegenerative diseases
According to the World Health Organization, by 2050, the world's population aged 60 and over is expected to reach 2 billion, nearly double the number in 2015. People around the world are living longer. However, aging is a major risk factor for many neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, which lead to cognitive impairment.
In mice with Alzheimer's disease, boosting NAD+ levels reduced protein accumulation that disrupts cellular communication and increased cognitive function. Boosting NAD+ levels also protected brain cells from dying when blood flow to the brain was insufficient. Many animal model studies offer new prospects for helping the brain age healthily and resisting neurodegeneration.
Can NAD+ prolong life?
Yes, it is. If you are a mouse. Increasing NAD+ using boosters like NMN and NR can extend the lifespan and healthspan of mice.
Increased NAD+ levels have a modest effect on extending the lifespan of mice. In a 2016 study published in the journal Science, scientists found that supplementing with NR, a precursor to NAD+, extended the lifespan of mice by about 5%.
Boosting NAD+ levels can also protect against various age-related diseases. Preventing age-related diseases means living healthier longer and extending your healthy lifespan.
Indeed, some anti-aging scientists like Sinclair believe the animal studies are so promising that they are taking NAD+ boosters themselves. Others, however, like Felipe Sierra of the National Institute on Aging at the National Institutes of Health (NIH), think the drug isn’t ready yet. “The bottom line is I don’t try any of these things. Why wouldn’t I? Because I’m not a mouse,” he says.
For mice, the search for the "fountain of youth" may be over. For humans, however, scientists agree that we're not quite there yet. Clinical trials of NMN and NR in humans may provide results in the next few years.
Boosting NAD+ levels: The scientific path of NMN and NR
As scientists delve deeper into the mechanisms of aging, they have discovered that NAD+, as a key molecule in cells, plays a vital role in maintaining life activities. In order to naturally increase NAD+ levels, scientists have explored a variety of methods, one of which is through the intake of NAD+ precursor molecules such as NMN and NR. These two precursor molecules effectively promote the synthesis of NAD+ through the "rescue pathway", showing great potential in the fields of health and longevity.
Recent studies have confirmed that NR can significantly increase NAD+ levels in humans, and NMN has shown the same effect in rodent models. Even more striking is that scientists have found NMN transporters in the intestines of mice and corresponding genes in humans. This means that NMN may play a similar role in humans, increasing NAD+ levels through intestinal transporters.