What is NAD+? Everything You Need to Know | Qualia

What Is NAD⁺? Everything You Need to Know

NAD+ is a core molecule of cellular function found in every cell in the body. NAD+ is a cofactor for several enzymes involved in cellular metabolic pathways and plays a key role in the production of cellular energy as adenosine triphosphate (ATP). NAD+ also plays a key part in maintaining redox homeostasis—the balance between reducing and oxidizing reactions that influences many critical cellular functions. Furthermore, NAD+ is co-substrate for enzymes involved in key cell signaling pathways essential for cellular survival and health [1,2]. 

How Is NAD+ Made by Cells?

NAD+ is the oxidized form of nicotinamide adenine dinucleotide (NAD), a coenzyme form of vitamin B3. The NAD molecule consists of nicotinamide mononucleotide (NMN) bound to adenosine monophosphate (AMP). Nicotinamide (or niacinamide) is a form of vitamin B3, along with nicotinic acid (or niacin). 

Figure 1. NAD structure

NAD+ is continuously synthesized, metabolized, and recycled in cells through different pathways. NAD+ can be produced from tryptophan (de novo synthesis pathway), niacin (Preiss-Handler pathway), and niacinamide (salvage pathway). 

The de novo synthesis pathway converts L-tryptophan to NAD+ by building a niacin molecule from scratch. De novo synthesis starts with tryptophan and proceeds through the kynurenine pathway (KP) to yield quinolinic acid. The next step converts quinolinic acid to a niacin-containing molecule called nicotinic acid mononucleotide (NAMN). NAMN converges with the Preiss-Handler pathway—it is a common intermediate in both pathways. The Preiss-Handler pathway starts with niacin and its conversion into NAMN. NAMN produced by both pathways is then converted into nicotinic acid adenine dinucleotide (NAAD), which, in the final step of the Preiss-Handler pathway, is converted into NAD+ [3,4].

The salvage pathway starts with nicotinamide and its conversion to nicotinamide mononucleotide (NMN). NMN is then converted into NAD+. This pathway can metabolize nicotinamide obtained from the diet, but its main purpose is to recycle (or salvage) nicotinamide produced as a byproduct in NAD+-consuming reactions back to NAD+. NAD+ can then be used again in NAD+-dependent reactions, regenerating nicotinamide in the process. Therefore, the salvage pathway is a cycle [3,4].

How NAD+ Functions in The Body

NAD is found in cells in two main forms: the oxidized form NAD+ and the reduced form NADH. These two forms are continuously interconverted in redox reactions (i.e., reactions where electron transfer occurs) and have key roles in maintaining cellular redox homeostasis. 

One of the most crucial functions of NAD+ is to carry electrons extracted from nutrients in cell energy pathways (glycolysis, fatty acid oxidation, and the citric acid cycle) and deliver them to the electron transport chain where they are used to power the production of ATP [5]. 

Another important function of NAD+ is to act as a co-substrate for NAD-dependent enzymes that mediate signaling pathways and processes that are essential for cell and tissue health and general healthspan. These include supporting mitochondrial function, DNA repair, genomic stability, cellular senescence, cell differentiation and survival, and metabolic adjustments, among others [6–10]. 

Enzymes that Consume NAD+

There are several NAD-dependent enzymes that consume NAD+ and produce nicotinamide as a byproduct [11]. Among the most impactful are sirtuins, poly(ADP-ribose) polymerases (PARPs), and NADases such as cluster of differentiation 38 (CD38).

Sirtuins

Sirtuins are a family of enzymes involved in cell signaling pathways that regulate key metabolic processes, stress responses, and cellular homeostasis, and consequently, the aging process [12]. Some sirtuins act as metabolic sensors: they respond to NAD+ levels as indicators of the energetic state of a cell and adjust cellular metabolism according to energetic needs [13]. 

Sirtuins are critical regulators of DNA repair and genome stability, mitochondrial metabolism and homeostasis, and autophagy [12]. In mammals, there are seven different sirtuins (SIRT1–SIRT7) with different activities and targets. SIRT1 is a key factor in mitochondrial quality maintenance [13]; it promotes mitochondrial biogenesis through peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activation and promotes mitophagy in response to a high NAD+/NADH ratio [14,15].

Sirtuin activity can be impacted by age-dependent declines in NAD+ levels, leading to poor mitochondrial function, which can cause redox imbalance and oxidative stress, thereby contributing to the progression of aging [8,16]. 

PARPs

PARPs are a family of 17 enzymes involved in many essential cellular processes, including DNA damage repair and preservation of genomic integrity [17]. PARP1, the most studied, is responsible for about 90% of total PARP activity in response to DNA damage. Upon DNA damage, PARP1 binds to DNA and synthesizes ADP-ribose polymers that bind to its own structure and to other proteins, which acts as a signal to recruit and activate other DNA repair enzymes and proteins to initiate DNA repair [18]. Due to high PARP1 activity, DNA damage causes a massive consumption of NAD+ [17]. 

One of the 12 hallmarks of aging is genomic instability due to a reduced capacity to repair DNA damage [19]. Accumulation of DNA damage results in prolonged PARP1 activation that leads to a depletion of NAD+ pools. This in turn affects the activity of other NAD+-dependent processes, including sirtuin activity, resulting in an impairment of cells’ DNA repair capacity, mitophagy, and mitochondrial metabolism and homeostasis [20]. 

CD38

CD38 is a multifunctional enzyme whose products include ADP-ribose (ADPR), cyclic ADPR (cADPR), and nicotinic acid adenine dinucleotide (NAAD), which are all key calcium-mobilizing second messengers. CD38 can therefore affect calcium-dependent activities, such as cell proliferation, muscle contraction, and immune cell activation for example [21,22].

CD38 plays an important role in immune responses, regulating immune cell recruitment and cytokine release, for example [23]. Large amounts of NAD+ are consumed by CD38 during immune responses. With aging, changes in immune signaling and responses promote an increase in CD38 levels and activity in immune cells that increases the consumption of NAD+, contributing to a depletion of NAD+ levels as we age [24,25].

CD38 levels increase in multiple tissues with aging, contributing to NAD+ decline [25]. This can alter the activity of sirtuins, PARPs, and other NAD+-consuming enzymes, and affect cellular signaling and metabolism [26]. 

NAD+ Levels Decrease with Age

Healthy cellular function requires that higher levels of NAD+ than NADH be maintained in cells (i.e., a high NAD+/NADH ratio) [27,28]. To do so, cells have several pathways and processes to ensure that NAD+ is continuously synthesized, metabolized, and recycled to sustain stable levels of NAD+. 

But despite all these backup plans, during aging, the balance between NAD+ consumption and production can shift, and NAD+ use can exceed the ability of cells to synthesize NAD+ de novo or salvage nicotinamide to recycle NAD+. As a consequence, NAD+ levels in cells and tissues decline as we age, which contributes to the aging process and age-related physiological decline [20,29–31]. 

Effects of Lower NAD+ Levels

Low NAD+ levels and the consequent low NAD+/NADH ratio can affect the myriad cellular functions in which NAD+ plays a crucial role. Decreases in NAD+ levels can impact cellular energy production and consequently affect all the cellular growth and repair processes that require ATP. Lower NAD+ levels can also affect redox balance and tip it towards an oxidative cellular environment that can drive oxidative stress and oxidative damage to proteins, DNA, cellular membranes, and other molecules and cellular structures. Furthermore, it can compromise cells' ability to respond to those changes by weakening adaptive cellular stress responses, mitochondrial quality, and DNA repair, for example [2,20,32].

Figure 2. NAD+ depletion and replenishment. Source: Amjad et al. Mol Metab, 49:101195, 2021. License: CC BY 4.0

Potential Benefits of NAD+ Boosting

Owing to the functions of NAD+ in cells, the benefits of boosting NAD+ levels can help to support cellular metabolism, redox homeostasis, DNA repair, and mitochondrial fitness, thereby helping to preserve cellular function as we age. Many age-related features can be slowed down and even reversed by restoring NAD+ levels. Boosting NAD+ levels through supplementation with NAD+ precursors or intermediates, such as niacin, niacinamide, NMN, and nicotinamide riboside (NR, which can be converted into NMN and thereby enter the salvage pathway to yield NAD+), has therefore emerged as a promising approach to restore the NAD+ pool and support cell and tissue function and healthy aging [4,20]. 

Support Healthy Aging

Studies with aged animals have shown that restoration of NAD+ levels mitigates many age-related changes by enhancing mitochondrial function and energy metabolism, restoring cellular defenses against oxidative stress, promoting DNA repair, and modulating cellular senescence. By doing so, restoring NAD+ can promote healthspan [33,34]. 

Support Cognitive Function

Age-related decreases in NAD+ in the brain can affect mitochondrial function and energy metabolism, impairing the production of the high amounts of ATP the brain requires to support its function. Decreases in NAD+ levels can also trigger oxidative stress in neurons, compromise neuronal stress responses and DNA repair, and affect neuronal communication and synaptic plasticity [35]. Consequently, low NAD+ levels can significantly impact brain function and cognition. Replenishing NAD+ levels can help to mitigate these age-related changes and help to maintain healthy brain function and cognition [35].

Support Muscle Function

Muscles require great amounts of cellular energy to maintain their activity, which requires a constant supply of NAD+ and healthy mitochondrial function. NAD+ depletion with aging affects mitochondrial activity and ATP production, leading to poorer muscle metabolism that contributes to poorer function and muscle weakening and degeneration. Poor mitochondrial activity also plays a huge part in aging-induced muscle stem cell senescence, which can impair muscle regeneration. Therefore, loss of muscle mass, strength, and function is a common consequence of aging [32,36]. 

Healthy muscle function is associated with NAD+ abundance [37]. Boosting NAD+ levels in muscles may help to preserve mitochondrial function, stem cell function, and the regenerative capacity of muscles, thereby helping to maintain muscle function as we age [32,36,38,39]. In clinical studies, boosting NAD+ supported mitochondrial biogenesis in muscles [40], muscle remodeling in overweight women [41], and enhanced physical performance in healthy middle-aged and older adults [42–44]. 

Support Heart Function

The heart requires a constant supply of NAD+ to maintain its activity, and consequently, keep us alive. Decreases in cardiac NAD+ levels are associated with several aspects of heart function decline. NAD+ depletion with aging can impair cardiac mitochondrial activity and cell energy production, DNA repair, and redox balance, resulting in a progressive weakening of cardiac muscle function [32,45–47]. Boosting NAD+ levels in the heart may help to support cardiac muscle function and maintain heart muscle health and strength as we age [32,38,45,48,49]. 

5 Ways to Increase NAD+ Levels

Eat Healthy

NAD+ is the coenzyme form of vitamin B3, which can be obtained from the diet in different forms. Niacin equivalents (or vitamin B3 equivalents) is a term used to describe all dietary molecules that can contribute to vitamin B3 status in the body, consequently supporting NAD+ production. These include nicotinamide, niacin, NMN, NR, and L-tryptophan. Niacin equivalents are found in all dietary animal, plant, and fungal foods (these organisms require NAD+ for life). Meat, eggs, fish, dairy, some vegetables, and whole grains are considered good sources of vitamin B3 [50].

Reduce Caloric Intake

What and how much we eat also influences NAD+ bioavailability by altering energy metabolism in mitochondria. For example, a diet high in fat and/or sugar causes energy overload in cells and seizes NAD+ as an electron carrier, converting it into NADH. Because ATP expenditure can’t keep up, NADH can’t feed its electrons to the electron transport chain and accumulates, leading to reduced NAD+/NADH ratio and decreased NAD+ levels [51]. Conversely, calorie restriction reduces the conversion of NAD+ to NADH, but NADH continues to be converted back to NAD+ after being used for ATP production. This increases the NAD+/NADH ratio and triggers an adaptive metabolic stress response that upregulates the salvage pathway and increases NAD+ availability [51].

Exercise 

Exercise or any kind of physical activity increases the demand for ATP, which in turn increases the flow of electrons through the electron transport chain and the conversion of NADH to NAD+. Similarly to caloric restriction, this increases the NAD+/NADH ratio and stimulates an adaptive metabolic stress response that increases NAD+ availability by upregulating the salvage pathway [51]. Studies have shown that regular exercise can reverse the age-dependent decline in NAD+ salvage capacity in the human skeletal muscle [52].

Sleep

NAD+ levels and sirtuin activity are involved in circadian clock regulation and in modulating the circadian rhythm of sleep and wakefulness. Simultaneously, NAD+ levels are regulated by circadian rhythms and oscillate with a 24-hour rhythm. Circadian rhythms are coordinated by the central pacemaker of the circadian timing system—the suprachiasmatic nucleus of the hypothalamus—and by intracellular proteins called “circadian clocks.” These proteins are regulated by the activity of transcriptional activators CLOCK and BMAL1 and repressors CRY and PER. CLOCK and BMAL1 balance the circadian expression of NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway. The activity of NAMPT is reduced by light and upregulated by darkness and night, meaning that NAD+ levels can be modified by sleeping time [51,53,54]. Therefore, keeping good sleep habits helps to support a rhythmic elevation of NAD+ through the salvage pathway. 

Take NAD+ Boosting Supplements

NAD+ boosting supplements are an additional form to supply building blocks for NAD+. The NAD+ molecule is so important that cells evolved multiple ways to create it. With Qualia formulations we believe a better approach for long-term health is to support the functional redundancy inherent in the human body for NAD+ maintenance. So rather than supporting only one pathway of NAD+ production, we developed Qualia NAD+ to support different ways to make it. This entails providing several substrates for NAD+ biosynthesis (NIAGEN® Nicotinamide Riboside, niacinamide, and niacin), as well as supporting rate-limiting steps in the different pathways. This has been our approach in designing Qualia NAD+. You can learn more about our approach in our article Qualia NAD+ Ingredients.*

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

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