It’s the magic little coenzyme which keeps our bodies ticking over. Here’s how NAD+ works and why so many people see it as a way to fight aging.

As the antiaging market has picked up pace over recent years, scientists have been searching for any compounds that can slow or even reverse the effects of aging. Often their solutions lie in finding elements that change as we age, and one of the most important of these has been NAD+. This has been featured in a growing number of anti-aging supplements that seek to improve longevity – but once you scrape beneath the hype is there anything to really get excited about? Here is what NAD+ is, how it works and why it’s so important to your body and your health.

What is NAD+?

As we age, our body loses some substances and molecules which can be important in keeping us young. One of these is nicotinamide adenine dinucleotide, better known as NAD+.

Scientists first cottoned onto the existence of NAD+ back in 1906. Since then, our understanding of it has steadily expanded. It’s been found hard at work in the cells of humans, animals, plants and even yeast keeping everything ticking along nicely.

NAD+ is a crucial coenzyme which can be found in every cell in your body. It serves two main functions – to turn nutrients into energy and it is an important player in the metabolic process, serving as a friendly little helper in regulating other cellular functions.

It effectively works like a little transporter moving electrons from one molecule to another to carry out all sorts of reactions and processes. Alongside another molecule, NADH, it takes part in a number of reactions which generate energy within our cells. It also helps to regulate our circadian rhythm that manages our sleep/wake cycle.

It was first discovered in 1906 by Harden and Young as a component to enhance the rate of alcohol fermentation in yeast extracts. Since then, our understanding has expanded dramatically, and it has been used to combat a number of diseases.

One of the first was Pellagra which ravaged through south America after the civil war and was also common in Europe. The condition was found to be caused by a dietary deficiency and could be cured by replacing a corn-based diet with one of meat, milk and vegetables.

In the 1920s it was discovered that Pellagra could be cured by a pellagra preventative (PP) factor, but it wasn’t until 1937 that Conrad Elfehjem identified it as nicotinic acid. He found that a nicotinamide (NAM) enriched fraction from a deproteinized liver and a sample of nicotinic acid (NA) would serve as a successful treatment.

NA and NAM are collectively termed niacin or vitamin B3 and, as we now know, are precursors of NAD+. Since then, precursors of NAD+ have been used to combat a variety of diseases.

Why is NAD+ important

NAD+ is an enabler, or a fuel, for other molecules which help the body to perform at its best. When levels decrease, the activities of any NAD (H) dependant enzymes in oxidative phosphorylation, TCA cycle, and glycolysis are hindered.

This results in lower ATP production. It can also affect levels of PARP and sirtuins and lead to the inactivation of certain downstream molecular pathways which play a role in the repair of DNA.

In other words, without it our body does not function as well as it could, is less effective at repairing itself and leads to a slower metabolic rate. Without NAD+ acting as an important little taxi, your cells will generate less of the energy the body needs to survive and carry out its functions.

The importance of NAD+, therefore, stems not from any magical ingredient, but its ability to help other beneficial molecules do their jobs. If we were looking at the body as a soccer team, NAD+ would be the central midfielder, making the tackles and providing the possession which helps the strikers put the ball in the net.

It’s not flashy, it’s not showy but without it, the entire operation falls apart. Those molecules which are crucial to repairing cells, improving our metabolism and regulating biological functions. Without it we can experience a number of health problems. We’ll look at some of these and detail how NAD+ can be used to mitigate risks below.

Immune systems

The body’s immune system relies on genes called sirtuins. These detect when the body is under stress, such as during exercise, or when you’re hungry. They effectively repair the body as it goes, keeping it in better condition for longer and contributing to a longer lifespan.

NAD+ is the fuel that keeps sirtuins going. They consume NAD, giving them the energy to do their work. High levels of NAD+ have been shown to activate sirtuin activity and to increase life expectancy in yeast and mice. Likewise, when levels are lower, sirtuins are left without the fuel they need. Like a car without any petrol, they grind to a halt. If that happens, their ability to fight disease and repair DNA becomes decreased which can lessen our ability to fight diseases.

This is one of the reasons why the immune systems are less effective in older people. Sirtuins consume NAD+. As we age, they have to work harder, leading to increased NAD+ consumption which naturally depletes levels found in the body.

By maintaining higher levels of NAD+, sirtuins get more of the fuel they need to continue working at a higher function for longer.

Heart disease

According CDC, one person in the US dies from heart disease every 37 seconds. Around 659,000 people die from heart disease in the US every year, which translates to one in four overall deaths. In order to prevent heart disease, arteries need to be in good condition. The elasticity of the arteries acts as a buffer against the pressure waves sent out each time the heart beats. However, these stiffen as we age.

By maintaining the ability of cells to generate energy and repair themselves, NAD+ prolongs elasticity which helps to keep them clear avoiding the risk of cardiovascular problems.

NAD+ can also improve the inflammation response of the heart. Inflammation is a way that the immune system repairs the body, but it can accelerate the process of heart failure. Immune cells can regulate this process, but they are highly dependent on mitochondria which generate the power for the cells. There are suggestions that malfunctioning in the mitochondria in certain immune cells could reduce their ability to function and modulate the impact of inflammation on heart failure.

An article from a research team from the University of Washington shows that inflammation in patients’ hearts was linked to poor mitochondria function. Patients were given a precursor to NAD+, nicotinamide riboside (NR) orally (1,000 mg twice daily). The study showed these patients had enhanced PBMC mitochondrial function and reduced inflammatory responses. Another study also showed than increased levels of NMN, another NAD+ precursor, could reduce inflammation and improve cardiac health in mice.

Dementia and neurodegeneration

A side effect of increased lifespans is rising rates of dementia including conditions such as Alzheimer’s. According to a recent study global dementia rates could triple by 2050 unless risk factors are addressed. It warned that the dementia rates could rise from 57 million to 153 million in 2050. A key pillar of the drive towards longevity will be finding ways to mitigate the impact of neurodegeneration to ensure people not only live longer but enjoy a higher quality of life.

By improving the ability of cells to repair themselves, NAD+ can slow the rate of neurodegeneration preventing the onset conditions. Studies have also suggested that it can also prevent the build-up of proteins which disrupt cell communication and increase cognitive function. Higher NAD+ levels can also stop cells from dying when there is insufficient blood flow to the brain.

Obesity

Evidence suggests reduced levels of NAD+ can also lead to conditions such as obesity and cancer. A study in the Journal of Clinical Endocrinology and metabolism shows that obesity could be linked to low NAD/SIRT NAD+/SIRT Pathway Expression in adipose tissue of BMI-Discordant Monozygotic twins. It also showed higher levels of insulin resistance, inflammation and impaired mitochondria homeostasis.

Impairments to the metabolic system make it less easy to process energy which makes it more likely for patients to gain weight. This in turn can lead to increased risk of other conditions noted here including obesity.

Cancer

A study from Ljubljana, Laboratory of Oxidative Stress Research, Faculty of Health Sciences, Zdravstvena suggested that lower levels of NAD+ may lead to higher risks of cancer. The study found that the NAD+ depletion with age may play a major role in the formation of cancer in three ways:

• Limiting energy production.
• Reducing DNA repair.
• Offsetting genomic stability and signalling.

Disruption of any of these processes, says the report, could increase the risk of cancer due to impaired genomic stability.

NAD+ is a crucial protective factor in early carcinogenesis which means it can hinder the progression of cancer. Therefore, the study suggests NAD+ restoration could ‘prevent or reverse the phenotype of malignant cells at early stages by inducing cellular repair and stress adaptive response as well as regulate cell cycle arrest and apoptotic removal of damaged cells.’

How NAD+ is produced

Ordinarily, NAD+ will be produced in our cells to replenish stocks and keep them doing their job. This is called biosynthesis and it can happen in three different ways.

• The kynurenine (de novo) pathway: This starts up an amino acid called tryptophan that can be found from food sources such as cheese, eggs, meat and fish. Cells convert this into NAD+.
• The Preiss-Handler pathway: For this you need nicotinic acid which is found in food but is also increasingly being added to supplements. It is an NAD+ precursor which can also be produced in your saliva and in your intestines. A three-step process in the cell converts nicotinic acid into NAD+ by firstly converting nicotinic acid into nicotinic acid mononucleotide (NAMN). This is then converted into nicotinic acid adenine dinucleotide (NAAD), which in turn is converted into NAD+.
• Salvage pathway: Using vitamin B3, this uses compounds including nicotinamide, nicotinic acid, nicotinamide mononucleotide NMN, and nicotinamide riboside (NR) to transform nicotinamide’s to NMN into NAD+.

NAD+, therefore, plays an extremely important role in helping to keep the body young and functioning. The problem is that as we age, levels of NAD+ become reduced, which has knock on effects that can cause all the problems we commonly experience due to age.

NAD+ depletion occurs due to damage to our genetic blueprint which occurs during the aging process that activates a number of proteins including those called PARPS. This consumes NAD+ to perform cell repair functions. In other words, NAD+ is the fuel that helps these molecules to their jobs.

However, the more our DNA is damaged as we age, the more PARP are created and the more NAD+ they consume. When consumption outstrips the ability of the body to produce NAD+, levels drop and when that happens, they are less able to do the job of repairing cells which can contribute to various disease.

Restoring NAD+

The problem is relatively clear. NAD+ is crucial to the body’s function. It keeps us healthy and young. However, as we age, we need more of it to keep cells repairing and functioning effectively. Levels are consumed, which leads to a host of health problems.

The obvious question for those interested in longevity is, can maintaining higher levels of this coenzyme help to lead to improved health and a longer lifespan? If so, what’s the best way to do it? Oral supplementation with NAD+ has not successfully increased amounts of NAD+ in the body. However, by giving the body these precursors it is possible to give it the fuel it needs to kick start this process.

For this reason, precursors such as NR and NMN are popping up in more and more supplements designed to keep us healthier for longer. The theory is that this gives the body the fuel it needs to make NAD+ itself and so improve the body’s basic functions. Sirtuins are given the fuel they need to keep up with the increasingly busy task of repairing cells and regulating function.

Problems such as inflammation, lower metabolisms and reduced immunity, neural degeneration and many others can be avoided for longer. The result is that people can effectively keep themselves younger, enjoying not only enhanced lifespans but an improved quality of life.

There is some evidence to support this idea. A 2017 study by Elysium Health found that a daily dose of NAD+ precursors increased NAD+ levels by around 40%. This, in theory, should improve the function of the body which in turn should improve the prospects of longevity.

As a result, the NAD+ supplement market has grown considerably and is expected to grow much faster over the coming years. New products have been hitting the market as Longevity.Technology has reported.

For example, Elevant has recently introduced a new NAD+ boosting daily dietary supplement called Prime. It contains a high purity form of nicotinamide mononucleotide called NMN-C, works “within cells to power immunity, deliver daily energy and fight aging.”

Does NAD+ supplementation increase lifespan?

The key question for customers, though, will be, does NAD+ supplementation increase lifespan? Getting an answer to that is not entirely straightforward. There have been some positive results in animal trials including mice. For example, a 2016 study shows that NAD+ supplementation can improve mitochondrial and stem cell function as well as enhancing lifespan in mice.

The study states: “Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibiting proteins, and this rejuvenated MuSCs in aged mice.” However, in humans it’s a more difficult question to answer.

Providers of such supplements will point to examples such as Elysium’s study that supplements successfully increase NAD+ levels. This is certainly promising and shows that it does have the intended benefits – namely using precursors to lead to a real increase in NAD+ levels.

However, it is more difficult to see what is happening at a cellular level. Are those heightened NAD+ levels actually doing the job of improving muscle regeneration and biological health? There will also be questions about which precursor will be better in generating NAD+.

In addition to supplementation there are other, more natural ways to increase NAD +. Leading a healthy lifestyle, with regular exercise, eating a low-fat diet and fasting can all have an impact. High fat content can reduce NAD+ levels accelerating depletion and, in turn, accelerating the aging process. By being healthy and avoiding weight gain people can do a great deal to avoid this issue.

Studies also show the benefit of aerobic exercise in increasing NAD+ levels in the body. A 2019 study showed that aerobic and resistance exercise can increase NAD+ levels and contribute to improved skeletal mass and muscle strength.

NAD+, therefore, deserves its reputation aa a miracle molecule, in keeping bodily functions going. It can be enormously beneficial in providing the fuel to crucial operations including our metabolism, cell repair and immune responses which keep our body in good condition for much longer. Having higher levels, therefore, is an indicator of a healthier and longer lifespan.

What will be open to question is what’s the best way to increase levels. Supplements containing NAD+ precursors have been found to increase levels of NAD+ in the body which should, in theory, improve bodily function. However, this is just one among many factors which can influence longevity.

Photograph: Ready Made/Pexels