The search for the “fountain of youth” dates back to the 5th century BC. Over time we have evolved from searching for a literal fountain, to making our own injectable form. In today’s post we’ll talk about NAD+, an energy generating molecule that is being hailed as the new miracle supplement, and may even be the real, true fountain of youth.

But at what cost? NAD+ supplements run anywhere from $50 to 100 dollars a month for oral variety all the way to thousands of dollars a month for IV and injectable forms. Not to mention the lack of consistent scientific evidence to support the benefit and safety of long-term supplementation.

What is NAD+

Nicotinamide adenine dinucleotide- it is a coenzyme (a helper molecule that facilitates a chemical reaction) that is found in all living cells, it is involved in cell signaling pathways. NAD exists in two forms in the cell- NAD+ (oxidized) and NADH (reduced).

NAD+ is generated in the body via three main pathways:

1. Preiss-Handler Pathway (uses precursors from food and microbiome to made NAD+)
2. Salvage Pathway (the major pathway- uses NAD byproducts to regenerate NAD+)
3. De Novo Biosynthesis Pathway (mainly in the liver and kidneys, uses tryptophan- an amino acid, as a starting material)

Role of NAD+ in regulating cellular and metabolic signaling pathways – PMC (nih.gov)

What is its role in physiology (normal human functioning)?

The generation of ATP (form of energy used by cells)
DNA repair
Hormone signaling
Circadian rhythm (24-hour body clock)
Regulates inflammation
Involved in immune functioning

What is its role in pathology (disease and injury)?

It is thought that the depletion of NAD+ may be the cause of aging, and may contribute to brain disease (Alzheimer’s, Parkinson’s and Huntington’s) and metabolic dysfunction such as diabetes, obesity, fatty liver and kidney disease.

What happens to NAD+ as we age?

As we mature, the activity of both the salvage and de novo synthesis pathways decline. This is attributed to 2 main causes:

1. A reduction in the rate limiting enzymes responsible for the creation of NAD+ (NAMPT)
2. An increase in the activity of NAD hydrolases (breakdown molecules) such as CD38

What role does it play in cancer growth?

Cancers are notorious for having very high metabolic demands- they grow quickly and need plenty of energy to do so. NAD+ supports the process of energy formation and can contribute to the multiplication of cancer cells. In fact, many caners show an overexpression of NAMPT (an enzyme involved in the regeneration of NAD+).

NAD+ is also important in DNA repair, the depletion of NAD+ my result in aberrant DNA repair mechanisms, and potentially tumor growth.

What does this all mean? Is NAD+ good or bad?

Ultimately, it means there is more research to be done before we all fill up on NAD+ boosting IV’s and pills. When it comes to supplements, they aren’t regulated, so you don’t know how much you’re getting, and what the long-term effects may be.

If you read my post on immune boosting vitamins, you already know how I feel about excessive supplementation. The same is true in this case. I am not saying NAD+ will cause cancer. I am just saying that it may be worth waiting for more concrete, human data, before you decide one way or the other. Most of the information we have is from animal studies.

Here is some helpful information if you do decide to supplement:

NAD precursors, such as nicotinamide, nicotinic acid, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) supplementation may prevent a fall in NAD+ levels. If you are considering NAD+ supplementation, be sure to get a liposomal NAD+, this can help overcome the absorption issues associated with other forms of commercially available NAD+.

“NMN and NR are believed to be orally bioavailable and feed into the NAD salvage pathway directly (NMN) or indirectly (NR via NMN) and thereby bypass a key rate-limiting step determined by the enzymatic activity of NAMPT which decreases with age.” [1]

“It should also be noted that the metabolism of intravenously infused NAD/NADH is currently unclear although it is likely that both metabolites are cleaved into nicotinamide and ADP-ribose by the liver, as has been demonstrated in mice. It is also possible that CD38-expressing cells, such as leukocytes, act to degrade NAD/NADH in plasma.” [1]b (aka break it down before it has a chance to increase your intracellular stores of NAD+)

Here are potential side effects of NAD+ supplementation:

“Based on the human trials conducted to date, NAD pharmacology is a promising treatment strategy that is likely to be safe for human use. However, despite several decades of active investigation, there is still only suggestive evidence, in the form of a few successful and sufficiently powered clinical trials, for NAD upregulation to be effective for any of the many potential indications where it may benefit patients. Further trials are justified. Most of the indications tested require further studies for replication because only a single trial has taken place. In general, it is the case that more and larger studies are required to produce robust data in support of NAD pharmacology. This includes studies in which different forms of NAD upregulation are compared consistently with one another. For example, exercise programs tailored to older individuals may be more effective than all the existing approaches to NAD pharmacology. Whether or not this is the case is one of the more important questions for researchers.” [1]

In the meantime, here are some natural ways to boost your NAD+ levels:
In case you’re wondering why I would suggest natural ways to boost your levels:

A. It’s because these would be physiological, meaning supportive of the processes already going on in your body and are less likely to result in toxic amounts of NAD+

B. Molecular biology is a complex process with multiple concomitant pathways, when we supplement, we aren’t necessarily replicating the entire process, naturally boosting levels may have a better chance of mimicking what is actually going on in your body, including concurrent pathways that are contributing to the benefit, but that we might not have studied yet.

1. Consume a balanced diet: rich in tryptophan (an amino acid) and niacinamide (a form of B3) this is another example of “eat the rainbow.”

Meat, fish, dairy, broccoli, tomato, avocado, cabbage, cucumber

2. Practice portion control: studies show that caloric restriction enhances the conversion of NADH to NAD+ via triggering the “salvage pathway” I mentioned above. Additionally, the ratio of NAD+ to NADH increases. The decreased NADH increases sirtuin proteins- we didn’t talk about these, but they are related to longevity (sirtuins use NAD+ to keep the mitochondria happy and the mitochondria is the powerhouse of the cell). Intermittent fasting may be another way to boost NAD+ levels- the break from digestion allows the gut to secrete key hormones and enzymes involved in repair, as little as 12 hours may be effective.

3. Exercise regularly: It activates the salvage pathway resulting in the conversion of NADH to NAD+

4. Respect your circadian rhythm:  Having a consistent sleep-wake cycle helps to support your body’s internal clock. Sleep is a time for rest and recovery and important hormones and chemical signals are secreted during sleep. Just like your circadian rhythm, the release of NAD+ is cyclical, and your internal clock regulates the secretion of NAMPT (a key rate limiting enzyme in the formation of NAD+)

5. Be mindful of environmental triggers: exposure to extreme heat or cold can generate NAD+, however, repairing cellular damage from the sun depletes our NAD+ stores.

The bottom line:

Manipulating the NAD+ supply in our body shows a lot of promise for anti-aging and in the treatment and prevention of metabolic dysregulation and degenerative brain diseases. The depletion/restriction of NAD+ is even being researched as a target for the treatment of certain cancers. Either way, I think I need a little more data before I can safely recommend NAD+ supplementation as the miracle anti-aging and longevity treatment it is claiming to be. In the meantime, I’ll be doing everything I can to naturally boost my levels!

I hope this information helps you make an informed decision about what you decide to put in your body!

Sincerely,
Corsano MD- your friendly neighborhood PCP

Resources: main.pdf (sciencedirectassets.com)  Cancer Research Points to Key Unknowns about Popular “Antiaging” Supplements | Scientific American longevity collective- natural ways to increase NAD+
[1] Clinical Evidence for Targeting NAD Therapeutically Dina Radenkovic 1,*, Reason 2 and Eric Verdin 3

infographic: Are There Any NAD Supplement Benefits?​ | Healthnews