NAD+ and Longevity: The Essential Molecule for Cellular Health

First discovered in 1906 by scientists Harden and Young, NAD+ (nicotinamide adenine dinucleotide) was originally identified as the compound responsible for enhancing yeast fermentation rates. Now, with over a century and thousands of subsequent experiments later, we know that NAD+ is not just needed for yeast fermentation—it is absolutely vital for human life, too.  

But why is it so important? And why is keeping NAD+ levels elevated so crucial for healthy aging? In this article, we’ll dive into the details about what NAD+ is, how it impacts longevity, and the best ways to support NAD+ levels with age.

The ABCs of NAD 

NAD+ is a molecule known as a coenzyme, meaning it helps other enzymes to function properly. Without NAD+, hundreds of life-giving reactions would not be able to take place—from those on the larger scale, like pumping blood through the body, to the microscopic, like repairing damaged DNA. Essentially, NAD+ is critical to life as we know it. 

Some of the leading functions of NAD+ include helping our cell’s mitochondrial powerplants turn food into energy, regulating our circadian rhythm, ensuring proper cell function, and maintaining DNA integrity. NAD+ works hand-in-hand with NADH, as this pair constantly transfers electrons back and forth within cells to facilitate all of these energy-requiring functions. 

Why Is NAD+ So Important for Healthy Aging? 

NAD+ is not only required for maintaining life but also for having a long life. However, most people experience a drop in NAD+ levels as they age. Some research has found that levels of this crucial coenzyme can drop by as much as 50% between the ages of 40 and 60, with an additional decline upon reaching older age. 

Concurrent with this drop in NAD+ are increases in signs of accelerated aging or physiological decline—the dysfunctional ​​changes that can occur across all organ systems and contribute to disease states and aging. 

So, why do NAD+ levels drop? While there are many potential reasons, many scientists think that the abundance of enzymes and proteins that depend on NAD+ can deplete its levels as we age. For example, a family of enzymes called PARP is known to repair DNA. While this is a beneficial function, we know that DNA damage accumulates with age. This leads to excessive activation of the NAD-dependent PARP enzymes, thereby depleting NAD+ stores. 

Other enzymes that are NAD-dependent include the sirtuin family—a group of proteins commonly dubbed “longevity genes.” Sirtuins also use NAD+ to repair damaged DNA, regulate metabolic function, and support chromosome integrity. But, similarly to PARPs, sirtuins have to work harder to mitigate the accumulation of cellular damage as we age, leading to increased consumption of NAD+. 

With NAD+ depletion, every organ system starts to run at suboptimal levels, leading to metabolic disorders, increases in blood pressure, heart function decline, cognitive impairment, liver and kidney conditions, muscle loss, and even external symptoms, like wrinkles or hair loss. 

NAD+ and Longevity: A Look at the Research

Increasing your NAD+ stores is a surefire way to extend lifespan—if you’re a mouse, roundworm, or cell in a petri dish, that is. As human longevity studies take decades—and millions—to complete, research on NAD+ and lifespan is not easy to complete, which is why we typically use lesser species as model organisms. 

Even though humans obviously aren’t mice or worms, these animals can serve as models for health and longevity research, as they have surprisingly similar anatomy and genetics as us—especially rodents.

In research with yeast and mice, replenishing NAD+ levels has been found to not only reverse age-related organ and tissue damage, but also increase lifespan. Two landmark studies found that the NAD+ precursors NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside) extended the lifespan of mice and roundworms by 4.5% and 10%, respectively. 

In humans, NMN and NR have been found to support aspects of cardiovascular, cellular, and metabolic health. For example, clinical studies have reported that NMN improves blood sugar regulation in postmenopausal women, supports muscle function in older men, and increases aerobic capacity in athletes. Research with NR shows that this NAD+ precursor supports healthy metabolism and muscle function in older adults—plus, more and more clinical trials on these NAD+ precursors are constantly being released and providing us with new information. 

How to Support NAD+ Levels With Age 

Despite the age-related loss of NAD+ that most people see with age, there are fortunately many compounds that act as NAD+ precursors, NAD+ boosters, or both. 

NAD+ Precursors

NAD+ precursors include the building blocks we need to synthesize NAD+ in the body. As the “N” in NAD+ is nicotinamide—a derivative of vitamin B3, niacin—you can imagine that other niacin-containing compounds are related to NAD+. 

The most well-known NAD+ precursors are:

• Nicotinamide riboside (NR) 
• Nicotinamide mononucleotide (NMN)
• Nicotinamide or niacinamide (NAM)
• Niacin

While they work in different ways, they all participate in the NAD+ biosynthesis pathway. Known as the “NAD salvage pathway,” this internal recycling program produces NAD+ from unused forms of nicotinamide, including NMN and NR.  

NAD+ Boosters 

While all NAD+ precursors are also NAD+ boosters, compounds that are NAD+ boosters are not always NAD+ precursors. NAD+ boosters and NAD+ precursors support different, albeit overlapping, actions in the body. Therefore, most can be used concurrently to support healthy aging and longevity. Although you certainly don’t need to take all of these compounds, some work particularly well together—like NMN and trans-resveratrol, for example. 

There are three main classes of NAD+ boosters, which typically act on specific enzymes that either support NAD+ synthesis or inhibit its degradation: CD38 inhibitors, PARP inhibitors, and sirtuin activators. 

CD38 Inhibitors

CD38 is an enzyme that activates immune cells to produce inflammatory compounds called cytokines. This process is a significant source of NAD+ consumption, so inhibiting CD38 can preserve NAD+ levels as we age.

Some compounds known as CD38 inhibitors include: 

• Quercetin: A flavonoid compound found in several fruits and vegetables, quercetin has been found to inhibit CD38 activity and support healthier inflammatory responses.  

• Apigenin: The active ingredient in chamomile, apigenin is thought to increase antioxidant activity and inhibit CD38 to support healthy aging.

• Luteolin: A flavonoid similar to quercetin, luteolin also inhibits CD38 activity to prevent NAD+ degradation.

PARP Inhibitors 

PARP1 is an enzyme that requires NAD+ to function and helps with DNA repair. PARP1 works as a multifunctional enzyme, repairing single-strand and double-strand breaks in DNA. As mentioned, PARPs are necessary for repairing DNA, but the accumulation of DNA damage that occurs with age or disease requires more and more NAD+ to repair the damage. 

PARP inhibitors can help to prevent this process from going into overdrive, although these compounds are typically marketed as pharmaceutical drugs.  

Sirtuin Activators

Although sirtuins are dependent on NAD+ to function, compounds that activate sirtuins can also be recognized as NAD+ boosters, including: 

• Trans-resveratrol: Found in grapes and red wine, this is the most bioavailable form of resveratrol that activates sirtuins—especially sirtuin-1 (SIRT1)—to support cognitive and cardiovascular health.

• Fisetin: An antioxidant compound found in fruits like strawberries and apples, fisetin activates sirtuins and acts as a senolytic that clears senescent cells that contribute to aging.

• Pterostilbene: Found in blueberries, peanuts, and grapes, pterostilbene is a potent sirtuin activator that promotes longevity by reducing oxidative stress and supporting brain health. 

• Quercetin: A flavonoid compound found in several fruits and vegetables, quercetin has been found to modulate sirtuin activity and support healthier inflammatory responses. 

• Curcumin: As the primary bioactive compound in turmeric, curcumin upregulates SIRT1 and supports cognitive, immune, and cardiovascular health. 

• Berberine: Known for its role in supporting healthy blood sugar levels, berberine also promotes healthy mitochondrial function by promoting SIRT3 activity. 

Key Takeaways

NAD+ is an essential molecule for human life—but its levels decline with age due to an accumulation of DNA damage and cellular or metabolic requirements. With a reduction in NAD+ activity comes increases in signs of aging, including cellular, tissue, and organ dysfunction that lead to disease.

Fortunately, there are many ways to support NAD+ with age, including NAD+ precursors (like NMN and NR) and NAD+ boosters that activate sirtuins or inhibit certain enzymes, including apigenin, curcumin, quercetin, and more.

References: 

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