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NAD+ and Sirtuins: The Dynamic Duo for Aging Well (And We’re Aging Every Day)

What is NAD+?

NAD+ is a signaling molecule and coenzyme – a compound necessary for the functioning of other enzymes throughout the body. It is naturally present in every cell and plays critical roles in numerous cellular processes. It is a very important molecule. Let’s put it this way, without NAD+ we would die. As we age, our bodies’ level of this vital molecule steeply declines. What does this mean to us?

A growing body of research indicates that the systemic decline in NAD+ over our lifespan is not simply an artifact of aging but actually drives the aging process! 

How is NAD+ Made in the Body?

Inside the body, NAD+ is produced either de novo (“from scratch”) from the amino acid tryptophan (from turkey, milk, whole grains) through a biochemical pathway called the kynurenine pathway or from vitamin B3 in the form of nicotinamide (NAM) or nicotinic acid (NA). However, NAMPT, the critical enzyme that converts nicotinamide into NAD+, declines in activity with age, compromising the body’s capacity to create NAD+ from vitamin B3. We, therefore, cannot rely heavily on these pathways for bolstering our NAD+ levels as we grow older.

Fortunately, NAD+ can also be generated through another pathway called the “salvage pathway,” which builds NAD+ from precursor molecules, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). While the aforementioned biochemical pathways require multiple steps to ultimately produce NAD+, administration of NR or NMN provides a rapid means of increasing NAD+ levels. NMN even has a dedicated transporter in cell membranes that transports NMN directly into cells, where it is converted into NAD+. NR, by contrast, requires an extra enzymatic step to be converted into NAD+, making NMN a more direct strategy for increasing cellular levels of NAD+.

Introducing Sirtuins, Crucial Longevity Proteins

One of the most essential roles NAD+ plays is its role as a coenzyme for sirtuins, a crucial family of longevity-promoting proteins. In fact, sirtuins are believed to be the primary biological mediators through which NAD+ exerts longevity benefits. Sirtuins regulate the process of histone deacetylation, whereby small chemical groups called “acetyl” groups are removed from proteins called histones. Histones are small pearl-shaped proteins around which DNA is wrapped inside cellular nuclei. Histone deacetylation by sirtuins promotes genome stability, ensuring that genes are expressed correctly. Proper gene expression is critical as we age.

Along with supporting sirtuin activation, NAD+ plays vital roles in the following:

Controls A Healthy Inflammatory Response. An out-of-control inflammatory response can be the kiss of death for aging well. Sirtuins help control the production of NFκB, a protein complex involved in producing inflammation via the production of cytokines – inflammatory molecules involved in the immune response, and PGC-1α – a protein involved in insulin signaling and mitochondrial biogenesis. The short of it – sirtuins help to regulate inflammatory balance, healthy blood sugar control, and mitochondrial function (which equates to more energy production). (1)

Optimization of Healthspan. As we age, we want to remain as healthy and vital as possible, and NAD+ and sirtuins can do this for us. Visualize sirtuins as the “driver” of a “car,” the car representing your body. Just as the driver determines when to turn the vehicle, increase speed, or pump the brakes, sirtuins similarly drive numerous physiological functions. NAD+ acts as the “gasoline” for sirtuins, fueling them to properly carry out their many vital roles in the body. Just as a sharp driver and sufficient gasoline ensure that a car drives well throughout its lifespan, optimal sirtuin activity and NAD+ levels may optimize our years of living well. 

There’s More! Additional De-Aging Functions of NAD+ and Sirtuins 

Supports DNA Repair

NAD+ is a cofactor for PARPs (poly ADP-ribose polymerase), a family of enzymes involved in DNA repair, the maintenance of genomic integrity, and programmed cell death. We are constantly engaging PARP activity to maintain and safeguard our bodies. And what else is involved in DNA and cellular repair? You guessed it, sirtuins. Upregulation of PARP depletes NAD+, and for sirtuins to be active, they also need plenty of NAD+ at hand. The writing seems to be on the wall with this one – replenishment of NAD+ is a vital aspect of healthy aging when it comes to improving the body’s ability to repair DNA and support genomic integrity.

Supports Cellular Energy Production

NAD+ is found in the mitochondria of every cell of the body, except red blood cells, which are pretty much the only cells that don’t contain mitochondria. Mitochondria health is paramount to optimizing longevity so it’s critical to support our mitochondria every step of the way. Ample amounts of NAD+ will help keep your mitochondria functioning well. Here’s why: Inside the mitochondria, NAD+ carries high-energy electrons in glycolysis and oxidative phosphorylation, allowing for the creation of cellular energy (ATP). A lack of ATP is associated with age-related health declines, thus replenishing NAD+ levels may improve energy availability and contribute to a healthy aging process. (2)

Maintain Healthy Immune Function & Halt Inflammaging

NAD+ is also a cofactor for CD38, also known as “cyclic ADP ribose hydrolase.” CD38 is a glycoprotein found on the surface of many immune cells, including white blood cells and supports a healthy inflammatory response. Because of this, CD38 is a major consumer of NAD+ during the aging process as it is constantly battling the chronic inflammatory process characteristic of aging, referred to as “inflammaging.” (3,4) Sirtuins also support robust immune function. Declines in NAD+ synthesis not only reduce sirtuin activity, but may also contribute to reductions in immune functions that impact healthspan. (5

Help for Sleep via Circadian Rhythm Regulation

NAMPT, the enzyme that creates NAD+ from vitamin B3, is regulated by the body’s circadian rhythm. Your circadian rhythm is an internal set of biochemical processes that follows an approximately 24-hour cycle and controls many aspects of your behavior and physiology. The circadian rhythm is regulated by genes and proteins within our bodies that exhibit rhythmic activity and are referred to as “body clocks.” The decline in NAD+ that occurs with age disrupts the body’s circadian rhythm, in part by dampening sirtuin activity in the hypothalamus, leading to age-associated declines in health. (6) Conversely, restoring healthy NAD+ levels may improve circadian rhythmicity, “synchronizing” the entire body.

How to Support NAD+ Synthesis and Sirtuin Activity 

  • Supplemental NMN: NMN provides a direct, bioavailable precursor to NAD+, allowing the body to rapidly replenish NAD+ levels and support sirtuin activation.
  • Fasting: Our hunter-gatherer ancestors routinely experienced bouts of food scarcity that necessitated fasting. A growing body of research suggests that our biology responds favorably to modest but consistent periods of fasting, upregulating a variety of beneficial processes that include sirtuin activity. (7) The type of fasting that best supports sirtuin activity is unclear at this time; however, a great place to start is aiming for a 13-hour fast between dinner and breakfast the next day. Remember that more fasting is not necessarily better; it’s important to find a balance between intermittent fasting and supporting your body with nourishing food. 
  • Exercise: Exercise increases the expression of sirtuins. (8) Enhancing sirtuin activity in skeletal muscle promotes the production of new, healthy mitochondria and increases ATP production. A combination of aerobic exercise, such as running or cycling, and resistance training may be ideal for supporting sirtuin activity due to its effect on NAD+ levels. (9)
  • Sirtuin-activating compounds (STACs): STACs are compounds that activate sirtuins. One of the most potent STACs is resveratrol, the famous phytochemical found in grapes and red wine. (10) Quercetin is also a sirtuin activator, with milder effects than resveratrol. (11) Quercetin demonstrates multiple benefits for longevity, including antioxidant and metabolic health-promoting effects.

And remember, sirtuins can’t fully do their job without ample amounts of cellular NAD+ making it imperative that we think comprehensively when taking control over the aging process – it’s never too late to start! (12)

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