Popular Science Knowledge

NAD+ stands for nicotinamide adenine dinucleotide. From single-celled organisms like bacteria to complex multicellular organisms like primates, NAD+ is one of the most abundant and critical molecules. Essentially, without NAD+, we'd be on the fast track to death. This molecule is crucial for the function of our mitochondria, the cell's powerhouses. NAD+ not only helps convert food into energy, but also plays a vital role in maintaining DNA integrity and ensuring proper cellular function, protecting our bodies from aging and disease.

How does NAD+ work in the body?

NAD+ acts as a shuttle, 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 a variety of metabolic reactions that generate our cells' energy. Without adequate NAD+ levels, our cells would be unable to produce any energy to survive and perform their functions. Other functions of NAD+ include regulating our circadian rhythms and controlling our body's sleep/wake cycles.

NAD+ Levels Decrease with Age

NAD+ levels decline with age, suggesting important implications for metabolic function and age-related diseases. As we age, DNA damage accumulates and snowballs.

This damage to our genetic blueprint activates several proteins, including an enzyme called PARP. By consuming NAD+, PARP performs DNA repair functions. During aging, depletion of NAD+ through PARP activation appears to contribute to various diseases. Of all these NAD+-requiring functions, many scientists believe PARP makes the greatest contribution.

Enzymes in our immune system also consume NAD+. The more active our immune system, the more NAD+ these enzymes consume. As we age, levels of enzymes in our immune system increase, depleting NAD+ levels in the body. 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+. In the figure above, the decrease in NAD+ is seen as men (left) and women (right) age. Here, the red line "a" represents the change in NAD+ levels throughout life, while the blue line "b" only considers changes in NAD+ levels after puberty. How do our cells make NAD+? The process by which cells produce molecules is called "biosynthesis." There are three known pathways for NAD+: the kynurenine (de novo) pathway, the Preiss-Handler pathway, and the salvage pathway. The kynurenine (de novo) pathway begins with tryptophan, an 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 part of the cell, called the cytosol, which is located outside of the cellular components (organelles). The Preiss-Handler pathway begins with niacin. Typically, niacin is found in foods but can also be consumed through dietary supplements. This NAD+ precursor molecule is also produced by bacteria in the gut or 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). The enzyme NAD+ synthase (NADS) then converts NAAD to NAD+. The salvage pathway for NAD+ biosynthesis uses naturally occurring compounds related to vitamin B3. These compounds include nicotinamide, nicotinic acid, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR). NAD+ biosynthesis in the salvage pathway involves the conversion of nicotinamide 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+ through the enzymatic activity of NMNAT. What is NAD+ composed of? NAD+ is composed of two nucleotides linked by a phosphate group. One nucleotide contains an adenine nucleobase, and the other contains nicotinamide. Precursors for NAD+ biosynthesis: Supplementing NAD+ precursors represents a potential therapeutic strategy to slow aging and ameliorate age-related diseases. Oral NAD+ supplementation 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 NMN supplementation can protect against various diseases. This effect may occur by increasing NAD+ levels in the body. NMN supplementation reduces obesity and protects against vascular damage in mice. These benefits have also been shown in mouse models of Alzheimer's disease, cognitive impairment, and neuroinflammation. Similar beneficial effects have been observed in mice supplemented with NR. What happens when NAD+ levels decrease? Numerous studies have shown that NAD+ levels decrease in conditions such as obesity and aging. Reduced NAD+ levels can lead to metabolic problems. These problems can contribute to diseases, including obesity and insulin resistance. Obesity can lead to diabetes and hypertension. Metabolic disturbances caused by low NAD+ levels can cascade down the body. Hypertension and other conditions associated with decreased heart function can 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 by several groups have shown that supplementing with NAD+ boosters can improve obesity-induced insulin resistance. In mouse models of age-related diseases, supplementing with NAD+ boosters improves disease symptoms. This suggests that declining NAD+ levels with aging may contribute to the onset of age-related diseases. Preventing the decline in NAD+ provides a promising strategy for combating the metabolic disorders that occur with aging. As NAD+ levels decrease with age, this may lead to reduced DNA repair, cellular stress responses, and energy metabolism regulation. Potential Advantages: NAD+ is important for mitochondrial maintenance and aging gene regulation across species. However, NAD+ levels in our bodies decline dramatically with aging. "As we age, we lose NAD+. By the time you're 50, your levels are about half what they were at 20," David Sinclair of Harvard University said in an interview. Studies have linked a decrease in this molecule to age-related diseases, including accelerated aging, metabolic disorders, heart disease, and neurodegeneration. Low NAD+ levels, due to reduced metabolic function, are associated with age-related diseases. However, replenishing NAD+ levels has demonstrated anti-aging effects in animal models, showing promising results in reversing age-related diseases and extending lifespan and healthspan. 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 starvation, it dispatches its troops to defend it. Sirtuins maintain genomic integrity, promote DNA repair, and have demonstrated anti-aging properties in animal models, such as extending lifespan. NAD+ is the fuel that drives genes. But just like a car can't run without fuel, sirtuins require NAD+. Research results show that increasing NAD+ levels in the body can activate sirtuins and extend lifespan in yeast, worms, and mice. While NAD+ supplementation has shown promising results in animal models, scientists are still studying how these results translate to humans. Muscle Function As the powerhouses of the body, mitochondria are crucial for our athletic performance. NAD+ is one of the keys to maintaining healthy mitochondria and stable energy output. Increasing NAD+ levels in muscle has been shown to improve mitochondrial health and fitness in mice. Other studies have also shown that mice given NAD+ boosters are leaner, can run farther on a treadmill, and exhibit increased athletic performance. Older animals with higher NAD+ levels outperform their peers.

Metabolic Disorders

Obesity, declared an epidemic by the World Health Organization (WHO), is one of the most common diseases in modern society. Obesity can lead to other metabolic disorders, such as diabetes, which killed 1.6 million people worldwide in 2016.

Aging and a high-fat diet can reduce NAD+ levels in the body. Studies have shown that administering NAD+ boosters can mitigate diet- 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, suggesting a new strategy for combating metabolic disorders.

Heart Function

The elasticity of arteries acts as a buffer against the pressure waves generated by the heartbeat. However, with aging, arteries stiffen, leading to high blood pressure, a significant 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 an enlarged heart and clogged arteries, which can contribute to stroke. Boosting NAD+ levels may protect the heart and improve heart function. In mice, NAD+ boosters have been shown to replenish NAD+ levels in the heart to baseline levels and prevent 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, the world's population aged 60 and over is projected to reach 2 billion by 2050, nearly double the number in 2015. People worldwide 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 is insufficient. Numerous studies in animal models have raised new prospects for promoting healthy brain aging and protecting against neurodegeneration. Can NAD+ extend lifespan? Yes, it does. If you're a mouse. Increasing NAD+ using boosters like NMN and NR can extend lifespan and healthspan in mice. Increasing NAD+ levels has a modest effect on extending lifespan in mice. In a 2016 study published in the journal Science, scientists found that supplementing with the NAD+ precursor NR extended the lifespan of mice by approximately 5%.

Boosting NAD+ levels could also protect against a variety of age-related diseases. Preventing age-related diseases means living healthier lives longer, extending healthy lifespan.

In fact, some anti-aging scientists like Sinclair believe the results from animal studies are so successful that they are taking NAD+ boosters themselves. Other scientists, however, like Felipe Sierra of the National Institute on Aging at the National Institutes of Health (NIH), don't think such drugs are ready yet. "The bottom line is I'm not trying any of these things. Why wouldn't I? Because I'm not a mouse," he says.

The search for a "fountain of youth" may be over for mice. For humans, however, science is Scientists agree that we're not quite there yet. Clinical trials of NMN and NR in humans may provide results within the next few years.

Boosting NAD+ Levels: The Scientific Path of NMN and NR

As research into the mechanisms of aging deepens, scientists have discovered that NAD+, a key intracellular molecule, plays a vital role in maintaining life. To naturally increase NAD+ levels, scientists have explored various methods, including the consumption of NAD+ precursors such as NMN and NR. These two precursors effectively promote NAD+ synthesis through a "salvage pathway," demonstrating significant potential for health and longevity.

Recent studies have confirmed that NR can significantly increase NAD+ levels in humans, and NMN has demonstrated similar effects in rodent models. Even more strikingly, scientists have discovered the presence of an NMN transporter in the mouse intestine and the corresponding gene in humans. This means that NMN may play a similar role in humans, increasing NAD+ levels through intestinal transport proteins.