Nicotinamide adenine dinucleotide, or NAD+ for short, is a coenzyme found in all cells in the body. It plays a vital role in the biochemical reactions within cells, including the metabolism of nutrients to produce energy, immune cell activation, DNA repair, and cell communication.

What does this have to do with healthy aging and longevity?

NAD+ levels decline as we age, which slows cellular metabolism and the ability to repair DNA damage that can lead to age-associated diseases.

Naturally, researchers are investigating whether increasing NAD+ levels is the key to slowing down the aging process in the human body to increase the lifespan and the quality of life as we age.

In this article, we'll look at exactly what NAD+ is, how it functions in the body, and ways to increase NAD+ levels to support healthy aging.

Key Article Takeaways:

• NAD + stands for nicotinamide adenine dinucleotide, and it's involved in many major biological processes, from regulating the body's circadian rhythm to DNA repair and so much more.

• As we age, maintaining NAD+ homeostasis becomes a challenge, and low NAD+ levels have been linked with age-related diseases.

• Increasing NAD+ levels through a healthy diet, better sleeping habits, and dietary supplementation may have beneficial effects. Supplementing NAD+ can be a promising therapeutic strategy for neurodegenerative diseases and other age-related illnesses.

• Much research suggests NAD+ levels play a significant role in ensuring a healthy aging process. Still, more human trials are needed to verify whether supplementing NAD+ or precursor compounds such as nicotinic acid (NA) or nicotinamide mononucleotide (NMN) can truly support longevity.

What Exactly Is NAD+?

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It plays a vital role in many chemical reactions in the body on a cellular level [1].

In more technical terms, NAD+ is a molecule made up of two nucleotides — nicotinamide and adenine.

1. Nicotinamide: is a form of vitamin B3, also known as niacin, an essential nutrient for the human body.

2. Adenine: is one of the four main building blocks of DNA and RNA (genetic material).

NAD+ is involved in all essential cell processes in the body, including:

• DNA repair

• Energy production

• Immune system regulation

• Gene expression regulation.

Throughout this article, we'll mostly refer to NAD+, but it's worth mentioning that NAD+ isn't a substance but a group of related compounds.

ItIt'sike a family with the same last name, but they are all different individuals with unique roles and characteristics.

Two of the most common forms of NAD+ are called NADH and NADPH.

1. NADH: is essential in the body's production system and is involved in the metabolism of carbohydrates, fats, and proteins.

2. NADPH: is used in detoxifying the cell. Just like a city needs to clean up pollution to keep the environment healthy, your cells also need to get rid of toxins to stay healthy.

When Was NAD+ Discovered?

Nicotinamide adenine dinucleotide (NAD+) was first discovered in 1906 by two scientists, Arthur Harden and William John Young, studying sugar fermentation in yeast cells [2].

During their research, Harden and Young found that a substance called "cozymase" "is required for sugar fermentation. Cozymase was later identified as NAD+.

NAD+ was initially thought to be involved only in the metabolism of sugars. Still, it was later discovered to have a much broader role in the body, mediating multiple major biological processes.

With extensive research, NAD+ is thought to have potential therapeutic applications in multiple age-related diseases, including neurodegenerative disorders and cardiovascular disease [3].

The Importance of NAD+ In Cell Metabolism

To understand the importance of NAD+ for maintaining systemic health and balance, let's take a closer look at some of the key cellular functions NAD+ is involved with.

Energy Metabolism

Energy metabolism involves the breakdown of nutrients (carbohydrates, fats, and proteins) to produce adenosine triphosphate (ATP) — the main energy source for cells.

ATP is required to power a wide range of critical cellular processes, including:

• muscle contractions

• muscle regeneration

• the synthesis of proteins

• and the transport of molecules across cell membranes.

Where does nicotinamide adenine dinucleotide (NAD) come in?

NAD+ is involved in the electron transport chain, a series of chemical reactions in the mitochondria (the powerhouse within the cell).

During the electron transport chain, NAD+ accepts electrons from the breakdown of nutrients and transfers them to oxygen. This is one process that produces ATP called oxidative phosphorylation.

ATP can also be made by breaking down glucose (a type of sugar) in glycolysis.

Some examples of illnesses that can result from dysfunction in energy metabolism include:

• Mitochondrial disease: Mitochondria are the organelles within cells responsible for producing most of the cell's energy. Dysfunction in the mitochondria can lead to various symptoms, including muscle weakness, fatigue, and difficulty with coordination.

• Diabetes: Diabetes is a group of metabolic disorders characterized by high blood sugar levels due to dysfunction in the body's ability to produce or use insulin. Insulin is a hormone that regulates the metabolism of glucose, a sugar that is an important source of energy for cells.

• Metabolic syndrome: Metabolic syndrome is a group of risk factors, such as high blood sugar, high blood pressure, and high cholesterol, that can increase the risk of developing diabetes and heart disease.

• Cancer: Cancer cells have a unique metabolism that allows them to grow and spread rapidly. Dysfunction in energy metabolism in cancer cells can cause them to consume large amounts of glucose and produce lactic acid, leading to acidosis and cell death.

• Neurodegenerative diseases: Some neurodegenerative diseases, such as AlAlzheimer'snd PaParkinson'sare associated with dysfunction in energy metabolism in brain cells.

WeWe'llxplore some of these metabolic diseases in more detail shortly.

DNA Repair

DNA repair is a process by which the human body self-repairs damage to the genetic material.

DNA damage can happen due to various factors, including:

• UV radiation

• Exposure to chemical toxins,

• Oxidative stress.

If left unrepaired, DNA damage can lead to genetic mutations that can potentially cause diseases such as cancer.

NAD+ is involved in DNA repair through base excision repair (BER). During BER, enzymes called DNA glycosylases recognize and remove damaged bases (the building blocks of DNA) from the DNA molecule [4].

These enzymes require NAD+ to function properly. This whole system of repair is crucial in maintaining the integrity and stability of genetic material.

Gene Expression

Gene expression is the process by which the information in a gene is used to make a protein that carries out the body's functions.

Gene expression is important to anti-aging because the expression of certain genes can change as we age. A dysfunction in gene expression can lead to age-related diseases and a decline in the function of cells and tissues.

Now, to touch on the technical part of how NAD+ is involved with this process.

NAD+ is needed in gene expression through sirtuin-mediated deacetylation, a post-translational modification (PTM) that occurs after a protein has been synthesized.

Sirtuins are a family of enzymes that use NAD+ as a cofactor to remove acetyl groups from proteins. The removal of acetyl groups by sirtuins can affect the activity of proteins and the expression of genes.

Researchers hypothesize that by regulating gene expression, it may be possible to promote healthy aging and extend lifespan [5].

Cell Communication

There are several ways that cells can communicate to exchange information and coordinate their activities, including:

• direct contact

• through the release of chemical signaling molecules

• and through electrical signaling.

NAD+ has many roles in the body's metabolic processes — In this case, it casts as a signaling molecule that activates proteins called kinases.

Kinases are enzymes that transfer phosphate groups from ATP to other proteins, and this process is called phosphorylation, a key mechanism for transmitting signals within cells.

One of the key functions of cell communication is to regulate the growth, division, and death of cells, which is known as cell proliferation.

Proper cell proliferation is necessary for the body to maintain healthy tissues, repair damage, and respond to changing needs. As we age, cells may become less able to communicate effectively, leading to a decline in cell proliferation and an increased risk of age-related diseases.

Immune System Regulation

Think of the immune system like a team of soldiers that protect your body from invaders. NAD+ is like the energy supply for soldiers.

Without enough NAD+, the soldiers won't be able to move and fight properly, and they'll inevitably lose the battle against the invaders.

SARM1 (sterile alpha and TIR motif-containing protein 1) is a protein that plays a role in regulating the immune system by breaking down NAD+. SARM1 is like a switch that controls the amount of NAD+ available for the immune cells by breaking down NAD+ when it's not needed.

This can be beneficial in some cases, as it can help prevent the over-activation of the immune system, leading to inflammation and tissue damage when the inflammatory response isn't needed (auto-immune disorders).

The right balance of NAD+ is crucial for the immune system to function properly and protect the body from invaders and neurodegenerative diseases [6].

The Link Between NAD+ and Longevity

While the research on the link between NAD+ and longevity is still in its early stages, its thought that increasing NAD+ levels may have potential benefits for healthy aging by improving energy metabolism, enhancing DNA repair, and reducing inflammation — essentially supporting all the metabolic processes we've justt outlined.

Evidence suggests that NAD+ levels decline with age and that increasing NAD+ levels may have potential benefits for healthy aging [7].

For example, animal studies have shown that increasing NAD+ levels can improve energy metabolism and enhance the function of mitochondria [8]. This can lead to improved muscle function, enhanced endurance, and a longer lifespan [9].

LeLet'save a closer look at some age-associated diseases that researchers are studying may be positively affected by increasing NAD+ levels.

Neurodegenerative Disorders

These are conditions involving the degeneration of nerve cells, including conditions such as AlAlzheimer'sisease and PaParkinson'sisease.

Some research suggests that low NAD+ levels may contribute to the development of these disorders by impairing energy metabolism, blood flow, and DNA repair in the brain [10].

This suggests that increasing NAD+ levels can slow the progression of neurodegeneration and prevent the onset of certain conditions.

Cardiovascular Disease

This is a group of conditions that affect the heart and blood vessels, including conditions such as coronary artery disease, heart failure, and hypertension.

Cardiovascular disease is linked with aging because as the body ages, its less able to adapt to changes, and the risk factors for cardiovascular diseases, such as high blood pressure and high cholesterol, become more prevalent.

There's some research that suggests that the disruption of NAD+ homeostasis can contribute to heart failure [11, 12]. Scientists are looking into ways to keep NAD+ levels high in the body as it may help reduce the risk of heart failure.

Diabetes

This is a condition in which the body has difficulty regulating blood sugar levels, and it can lead to serious health complications if left untreated.

Some research suggests that low NAD+ levels may be associated with an increased risk of diabetes, possibly due to impaired insulin signaling and inflammation, although the exact mechanism by which it does so is not fully understood. [13].

Insulin is a hormone produced by the pancreas that regulates blood sugar levels. It helps lower blood sugar levels by promoting glucose uptake by cells, and it helps to prevent high blood sugar levels by inhibiting the production of glucose by the liver.

In more technical terms, NAD+ is thought to play a role in regulating insulin signaling pathways, which transmit signals from insulin receptors to cells.

Cancer

Low NAD+ levels have been linked to the development of certain cancer types, including breast and prostate cancer [14]. Some research suggests that low NAD+ levels may impair DNA repair and enhance the proliferation of cancer cells, which can contribute to cancer development.

Researchers are interested in how NAD+ levels affect various body processes involved in aging and how boosting NAD+ levels could potentially improve health and longevity.

Understanding how NAD+ levels and sirtuins affect the bobody'salance of processes (cellular homeostasis) could help researchers develop therapies to improve quality of life as we age.

Cellular Senescence

Cellular senescence is a process that occurs in our cells as we age.

As cells age, they stop dividing and growing, which can lead to the accumulation of damaged cells in our bodies.

A good analogy would be to imagine you are a car and your cells are the parts that make up the car. As you age, car parts start to wear out and don't as well as they used to. Eventually, the car may not be able to run as well and may break down more often.

Similarly, as our cells age, they can become less effective at their jobs and can start to cause problems in our bodies.

Researchers are studying ways to increase NAD+ levels in cells to help slow down or prevent cellular senescence and aging [15]. One way to do this is by taking supplements that contain precursors to NAD+ or by using drugs that can boost NAD+ levels.

So, NAD+ is like an "energy booster" " for cells, just like how you drink an energy drink before sports. NAD+ helps cells to produce energy and work properly, which can help to slow down the aging process in cells.

How to Boost NAD+ Levels To Regulate Key Metabolic Processes

Several natural ways to boost NAD+ levels include diet, exercise, sleep, stress management, and possibly supplementation.

1. Diet: Some foods may help to increase NAD+ levels in the body. These include foods rich in nicotinamide riboside (NR), a precursor to NAD+. Examples of foods containing NR include milk, brewer's yeast, and certain mushrooms.

2. Exercise: Regular physical activity has been shown to increase NAD+ levels in the body. This may be due, in part, to the fact that exercise increases the production of mitochondria, which are the powerhouses of cells and are involved in the production of NAD+.

3. Sleep: Adequate sleep is important for maintaining NAD+ levels, as sleep deprivation has been linked to decreased NAD+ levels.

4. Stress management: Chronic stress has been linked to decreased NAD+ levels, so managing stress through techniques such as meditation, yoga, or exercise may help to boost NAD+ levels.

5. Supplementation: Some studies have suggested that supplements containing NAD+ precursors, such as nicotinamide mononucleotide (NMN), may help increase NAD+ levels in the body.

How Does Nicotinamide Mononucleotide (NMN) Boost NAD+?

While there are some NAD+ supplements available on the market, its bioavailability — how much of the active compound is absorbed by the body — is scarce compared to precursor enzymes like NMN.

Some scientists believe that the body may not absorb NAD+ supplements, which may limit their effectiveness at increasing NAD+ levels.

This is why taking NMN supplements is often recommended to increase NAD+ levels in the body, and it's thought to have potential therapeutic applications in various age-related diseases. NMN supplements are available in various forms like capsules, gummies, and powders, making it easy to incorporate into your daily routine.

Some studies have suggested that nicotinamide mononucleotide (NMN) may help improve energy metabolism, enhance DNA repair, and reduce inflammation, which could potentially benefit healthy aging [16].

The Takeaway: What Is NAD?

To summarize this article, nicotinamide adenine dinucleotide, or NAD, is a coenzyme that plays a vital role in regulating various metabolic pathways in the body, including energy metabolism, DNA repair, and cell communication.

There is some evidence to suggest that NAD+ levels may decline with age and may be associated with the development of certain age-related diseases.

Increasing NAD+ levels through diet, exercise, sleep, stress management, and possibly supplementation may have potential benefits for healthy aging and the prevention of age-related diseases.

ItIt'smportant to speak with a healthcare professional before starting any regimen to boost NAD+ levels and to continue to learn more about NAD+ and its role in health and longevity.

Resources:

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2. Harden, A., & Young, W. J. (2013). The Alcoholic Ferment of Yeast-juice. In A Source Book in Chemistry, 1900-1950 (pp. 359-365). Harvard University Press.

3. Braidy, N., & Liu, Y. (2020). NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis. Experimental Gerontology, 132, 110831.

4. Krokan, H. E., & Bjørås, M. (2013). Base excision repair. Cold Spring Harbor perspectives in biology, 5(4), a012583.

5. Jaenisch, R., & Bird, A. (2003). Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature genetics, 33(3), 245-254.

6. Figley, M. D., Gu, W., Nanson, J. D., Shi, Y., Sasaki, Y., Cunnea, K., ... & Ve, T. (2021). SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron, 109(7), 1118-1136.

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9. Imai, S. I., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in cell biology, 24(8), 464-471.

10. Kerr, J. S., Adriaanse, B. A., Greig, N. H., Mattson, M. P., Cader, M. Z., Bohr, V. A., & Fang, E. F. (2017). Mitophagy and AlAlzheimer'sisease: cellular and molecular mechanisms. Trends in neurosciences, 40(3), 151-166.

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12. Neubauer, S. (2007). The failing heart—an engine out of fuel. New England Journal of Medicine, 356(11), 1140-1151.

13. Trammell, S. A., Weidemann, B. J., Chadda, A., Yorek, M. S., Holmes, A., Coppey, L. J., ... & Brenner, C. (2016). Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Scientific reports, 6(1), 1-7.

14. Navas, L. E., & Carnero, A. (2021). NAD+ metabolism, stemness, the immune response, and cancer. Signal Transduction and Targeted Therapy, 6(1), 1-20.

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