A Brief Introduction to NAD: What It Is and Why It Matters for Your Cellular Health
All living things on our planet are made of cells. While cells come in various shapes, sizes and functions, they have quite a few fundamental characteristics in common. They use a similar genetic code to store information in DNA. They all require energy—be it from food, the sun, or thermal vents deep in the ocean—to survive. And they all contain an important molecule called nicotinamide adenine dinucleotide, or NAD for short.
The human body is made up of trillions of cells, at least 37.2 trillion of them, which all rely on NAD to carry out their day-to-day functions [1, 2]. NAD is so important that we would die without it. The B3 vitamins we consume from whole, fortified foods, and supplements help our cells maintain enough NAD to avoid the vitamin deficiency disease pellagra.
Although pellagra is no longer a major health concern in most developed countries, its existence highlights the critical role NAD plays in our health. Modern research is revealing that declining NAD levels [3] are associated with a wide variety of acute and chronic diseases, as well as age-associated health conditions. Scientists are now eager to investigate strategies for boosting NAD to support overall health [4-9] and optimize resilience.
What is it about NAD that makes it so valuable to our cells and health? We know that NAD is essential, and answering this question is the subject of intense on-going scientific research. Scientists all over the world are working to fully understand all the different ways NAD helps our cells and our health. That’s one of the main reasons we started AboutNAD website—to help track this exciting area of research as it continues to evolve. For now, let’s begin our journey into NAD science by starting with some foundational biology: how your cells use the molecules in your food to keep you alive.
NAD powers metabolism: The role of NAD in catabolism vs. anabolism
We all know that we need to eat to survive and thrive. The nutrients in our food fuel our bodies so we can stay healthy and active. But what exactly happens to the molecules in our food—the fats, sugars, and proteins (these three are also known as macronutrients or macros for short)—once they are digested?
To simplify, let’s consider the fate of a sugar molecule you’ve ingested from your afternoon snack. Once it is digested, this molecule makes its way into one of your many cells. Your cell now has some options. If the cell needs energy, it can break down the sugar into its smallest molecular parts and extract energy. If the cell needs to grow or store energy for later, it can transform the sugar into other types of molecules, such as an amino acid or a fat molecule, to build cellular material and bulk up.
In either case, the cell accomplishes these molecular transformations by carrying out a series of chemical reactions. The term “metabolism” is used to broadly describe all the chemical reactions that occur within our cells and bodies. The trillions of cells that build our tissues and organs are constantly using these chemical reactions to transform molecules from one form into another. Through metabolism, cells break down molecules from our food and create all the molecules—everything from lipids and amino acids to nucleic acids and hormones—that keep our bodies functioning.
Every one of these chemical reactions also involves energy. Some chemical reactions require an input of energy to proceed, while others release energy that can be harnessed for other purposes within the cell. Metabolic processes are categorized based on how they transform molecules and energy. Anabolism is the set of chemical reactions that use stored cellular energy to build small molecules into larger ones, while the set of chemical reactions that break down molecules into smaller pieces and harvest cellular energy is called catabolism.
Cells need a way to productively manage the energy that is required by anabolic processes or released by catabolic ones. Heat energy, like the energy released by a burning flame, is difficult for living things to use and typically dissipates quickly from cells. To keep energy in a more useful form, cells use special molecules to store and manage energy as chemical energy. NAD is a particularly important energy management molecule that acts as a coenzyme, or helper molecule, by transferring energy to and from a variety of chemical reactions.
NAD, along with the closely related molecule nicotinamide adenine dinucleotide phosphate (NADP), is involved in more than 500 chemical reactions in the cell [10]. NAD tends to be involved in catabolic processes, while NADP typically participates in anabolic processes. These two molecules are involved in so many chemical reactions that it’s difficult to find an example of a metabolic process that does not involve at least one of these molecules.
Redox Biochemistry: The difference between NAD, NAD+, and NADH
NAD and NADP help cells manage energy, similar to the way a courier service manages packages. Just like a courier picks up a package in one location and delivers it elsewhere, NAD picks up energetic parcels of electrons from one molecule in one part of the cell and drops them off with a different molecule in another location. When NAD is carrying this parcel of energy, it is referred to as NADH. When it’s not, scientists call it NAD+.
In more technical terms, the packet of energy NAD carries is called a hydride. A hydride is a set of two high energy electrons attached to a hydrogen atom. Because NAD can gain and lose this hydride, it exists in two distinct forms within the cell: NAD+ and NADH. The “+” in NAD+ indicates the molecule has a net positive charge. When it gains a hydride (the “H” in NADH), the negatively charged electrons cancel out the positive charge and the “+” goes away. Same goes for NADP. When it’s loaded up with a package of energy it is called NADPH; otherwise it is called NADP+.
When NAD gains or loses energy, it is participating in an oxidation-reduction reaction, or redox reaction for short. Redox reactions are chemical reactions in which molecules gain and lose high-energy electrons and they are essential for the metabolic processes that cells use to generate energy and build up molecules.
Molecules become oxidized when they lose electrons and become reduced when they gain them. NAD+ is the oxidized form of NAD. It becomes NADH, the reduced form of NAD, when it collects high energy electrons in the form of a hydride from other molecules. NADH can then give away these high energy electrons to become its oxidized NAD+ form once more.
For simplicity, this site uses the term “NAD” to refer to both the oxidized and reduced forms of the molecule together unless a distinction between NAD+ and NADH is important to the point being made. Even though the difference between NAD+ and NADH is small from a chemical perspective, the difference can have huge implications for how the molecule is used within cells.
NAD and catabolism: breaking down food to generate energy
Catabolic processes involve chemical reactions that break down molecules into smaller pieces. These reactions typically release energy that can be harnessed and used elsewhere in the cell. The most well-known example of catabolism is cellular respiration.
If you remember learning about glycolysis, the citric acid cycle, the electron transport chain, or oxidative phosphorylation in a past science class, then you’re remembering cellular respiration. Without getting into all the details, cellular respiration is the set of chemical reactions and molecular processes that cells use to break down the food we consume to generate cellular energy in the form of adenosine triphosphate (ATP).
This cellular energy is vital for cellular function and powers much of the work cells do every second of every day to keep us alive. It keeps the heart beating. It allows muscles to contract and relax. And it allows neurons in our brain to communicate and process thought.
NAD is a central player in cellular respiration and is required by all types of cells to generate cellular energy. As sugars and fats are broken down, they pass on their stored energy to NAD+ and convert it to NADH. NADH then delivers this energy to the electron transport chain in cellular power stations called mitochondria where it is used to generate ATP. Even cells without mitochondria, such as red blood cells, use NAD to generate very small amounts of ATP from sugar.
NAD and anabolism: making molecules to build cells and tissues
Breaking down molecules for energy is only half of the metabolic story. Anabolic processes involve chemical reactions that make larger molecules from smaller pieces. These reactions typically require energy that has been stored in a useful cellular form. All of the large molecules—fats, carbohydrates, nucleic acids, and proteins—that build our cells and ultimately our bodies are created through anabolic processes.
Not all the foods we eat are broken down completely. Some of that material becomes the raw chemical parts that help our bodies create our essential components. Glucose can be repurposed to other forms of sugar used to make our DNA. Glucose can also be turned into fat, which in turn is used to build up the membranes that define the external barriers for each cell and the smaller compartments within. Glucose can even be transformed into a variety of amino acids to build enzymes that catalyze chemical reactions and proteins that provide structural support to our cells.
NAD and NADP are involved in all of these processes. Instead of extracting packets of energy as molecules are broken down, NADH and NADPH participate in these reactions by donating high energy electrons to drive the formation of larger molecules full of stored chemical energy.
A new frontier in NAD biology: NAD-consuming enzymes
NAD’s integral and ubiquitous role in metabolism is now memorialized in textbooks. For decades, this was the only known role of NAD. But a relatively recent milestone in the history of NAD research forever changed how scientists think about this molecule.
In the 1960s, researchers discovered that NAD could participate in a new kind of chemical reaction [11]. This reaction was very different from the anabolic and catabolic processes scientists were already familiar with and did not involve the transfer of hydrides or high energy electrons. Instead, it changed the chemical identity of NAD by breaking NAD+ into two smaller pieces.
This initial discovery has led scientists to uncover a set of “NAD-consuming enzymes” that break the oxidized form of NAD (NAD+) into pieces instead of using it to facilitate metabolic redox reactions. Some of these NAD-consuming enzymes direct how cells behave by using NAD+ to modify the structures and functions of proteins around the cell. Other NAD-consuming enzymes seem to consume large quantities of NAD to generate signaling molecules or drive changes in overall NAD levels.
Poly-ADP-ribose polymerases, or PARPs for short, are NAD+ consumers. They attach a piece of the broken NAD+ molecule to other molecules in the cell. For example, PARP can attach NAD+ fragments to DNA where it has been damaged to help other components of the cell identify and repair the problem. There are 17 different known PARPs in human cells and scientists are hard at work figuring out all the ways PARPs direct cellular behavior beyond fixing broken DNA [12].
Another group of enzymes called sirtuins use the broken pieces of NAD+ to “deacetylate” other molecules in the cell. This deacetylation removes a small collection of atoms from the structure of a molecule to change its overall shape and activity. For example, sirtuins in the nucleus can deacetylate histone proteins associated with DNA to alter how cells use their genetic information. Sirtuins in the mitochondria can deacetylate enzymes to change their activity and help regulate how cells respond to oxidative stress [13].
Some NAD-consuming enzymes chew up large quantities of NAD and may be involved in driving NAD depletion and cell death. These enzymes are also called “NADases” or NAD degraders to help distinguish their activity from PARPs and sirtuins. An enzyme named SARM1 is a perfect example of this: by consuming large quantities of NAD, SARM1 drives NAD depletion and cellular degeneration in neurons [14].
Another enzyme named CD38 may also be an NAD degrader. Found in immune cells, CD38 can use NAD+ to create the signaling molecule cyclic ADP-ribose—but because CD38 chews up about 100 molecules of NAD+ for every one cyclic-ADP-ribose molecule it produces, scientists tend to focus more on its role as an NAD degrader than an NAD signaling enzyme [15].
Scientists still have a lot to learn about NAD, making this an exciting area of research to watch. As work on NAD continues, we will learn more about how NAD-consuming enzymes relate to our health and we may even discover entirely new ways NAD is used by cells [16, 17]. For now, one thing is clear: NAD is essential for the health of our cells and ourselves.
References
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