NAD+, NMN and NR: PART 2

?? In this Nexus:

?? Pre-clinical promises vs. clinical research reality

?? Clinical trials with NAD+ boosters

?? Data from NMN and NR clinical trials

??Practical tips on NAD+ boosters

?? How to boost your NAD+ levels naturally?

Found it hard to read my previous Nexus ? Well, as promised, this one is much more down to earth and with practical information on boosting your NAD+ levels. In this Nexus edition I will share clinical evidence behind the effectiveness of Nicotinamide mononucleotide (NMN) and Nicotinamide Riboside (NR) supplementation from the recent clinical trials, and if you decide to take NMN or NR supplements (or if you use it already), how, when and what doses to use, how to choose the right supplements. In addition, I will share what are the natural ways to increase NAD+ levels in your body, which can be even more effective when the pill itself.

Pre-clinical Promises vs. Clinical Research Reality

If you are not a part of the life sciences industry as I am, the first thing you need to understand that clinical research is there for a reason. What works in animals, doesn’t by default have to work in human, or at least not in the same way. Therefore, each time you are buying anything health-related, and it says scientifically proven, don’t be lazy, press on those resource links and check if this data is coming from human.

Similar situation is with NAD+ boosters. Evidence from preclinical studies demonstrating the beneficial effects of NAD+ precursors has rapidly increased, and the results of these studies have prompted the development of clinical trials using NR and NMN. Several studies have demonstrated that the oral administration of NAD+ precursors is safe and significantly increases NAD+ levels in humans. However, the efficacy of NMN and NR is lower than expected from the results of preclinical studies. In addition, the identification of the contribution of the host-gut microbiota interactions to NR and NMN metabolism has added to the complexity of NAD+ metabolism (1 ). The visual below illustrates these differences between the preclinical and clinical data, as the question marks on the human side shows those effects as unknown, not yet proven or the results from different studies are contradicting (2 ).

Worth mentioning, that NAD+ depletion with age is different among species, organ systems and tissues. While it was found that NAD+ levels decline with age in almost every tissue in rodents, we see different results in human, and even the results between different studies are contradicting as shown in the table below (3 ).

The above paragraphs might sound disappointing, but it is actually not. While preclinical results do not translate directly into human, clinical trials are still demonstrating some positive results and I will give you an overview of what was already done in the field as you continue to read this Nexus. But it is also a good reminder, that aging process is complex, as I wrote about the 12 hallmarks of aging in one of the previous editions. This means that there is no single solution (or at least not for now), to address all mechanisms at once. Therefore, your efforts to slow or reverse aging also need to be versatile and boosting NAD+ is only one part of the puzzle.

An important disclosure, I am a believer in NAD+ boosters and I use it myself.

I just think we are not yet there with the most effective molecule, optimal formulation and/or the route of administration. But as with everything in research, we need to start somewhere.

Clinical Trials with NAD+ Boosters

On the day that I write this part of the Nexus edition (18th May, 2024), there are:

• 28 clinical trials registered in www.clinicaltrials.gov with NMN as an investigational product, out of which 14 completed, 12 active, 2 with the status unknown (4 ).
• 98 clinical trials registered in www.clinicaltrials.gov with NR as an investigational product, out of which 43 completed, 44 active, 7 terminated, suspended or withdrawn and 4 with the status unknown (5 ).

Just for your comparison and understanding, there are over 3000 clinical trials registered with Metformin as an investigational product or a comparator in the same database, a drug which is well researched and is used to treat type II diabetes, and which is now gaining interest in the field of longevity as well. Why am I giving this example? To show that clinical data on NAD+ boosters are still not extensive, especially when it comes to long-term studies, which are highly important in the case of longevity and aging.

What Does Science Say?

Data from NMN and NR Clinical Trials

When I read all the reports from recent clinical studies on NMN and NR there are good news and bad news. Let's start from 2 really good ones:

• NMN and NR are safe and well tolerated. The majority of clinical trials have reported NAD+ boosters to be safe and without no serious adverse events, at the doses ranging from as low as 50 mg/day to 2000 mg/day. The period of consumption varied from a single administration, to 6 months (2 ,6 ,7 ). Some studies lasting beyond the 6-month period are still ongoing and the results are pending. As for the safety, I still need to emphasize that longitudinal clinical trials are required to prove the safety of a long-term use of NAD+ boosters.
• NMN and NR increase blood NAD+ levels. Once again, the majority of clinical studies have found that NAD+ boosters were shown to significantly increase blood NAD+ levels and levels of NAD+ metabolites (i.e. intermediate or end products of NAD+ metabolism) (2 ,6 ,7 ). This means that supplementation with NMN or NR is an effective way to increase NAD+ levels, as shown in the tables below (6, 7).

And here are some news that are not as good. Even though NAD+ precursors increase NAD+ blood levels, this increase in many cases does not create an extensive, desirable clinical effect, especially not to the level we have seen in animal studies. Here are some highlights on the therapeutic effects of NMN:

? NR has showed no effect on body weight loss, does not improve insulin sensitivity and whole-body glucose metabolism (8 ,9 ,10 ,11 )

? NMN was shown to increase muscle insulin sensitivity, insulin signaling, and remodeling (12 )

?? While one study has demonstrated a borderline decrease in hepatic triglyceride levels (which was not statistically significant) after NR supplementation (13 ), another clinical trial showed no change in hepatic lipid content (14 ). The same study has demonstrated that NR induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.

? It was demonstrated in the clinical setting that NR reduces blood pressure and arterial stiffness in healthy adults (15) . Also, it was shown to enhance oxygen consumption and reduce inflammatory cytokines in peripheral blood mononuclear cells (16 ).

? When researched in Parkinson's patients, NR increased NAD+ levels in brain tissue and decreased levels of inflammatory cytokines in serum and cerebrospinal fluid (17 ).

? Another study have shown that NMN reduces arterial stiffness (18 ).

? While one clinical trial has shown that NMN has improved walking speed and grip strength (19 ), another clinical study of even twice longer use of NMN concluded that NMN did not alter muscular strength, gripping power and walking speed in the elderly subjects (20 ).

? Acute NR intake (2?h prior to exercise) were shown to increase performance in aged individuals (21 ).

To sum up the clinical data, while overall trend looks more positive than negative, the changes induced by the supplementation of NR or NMN are usually very minor comparing to placebo group. Thus further research shall concentrate on:

• Finding the best route of administration. Oral intake vs. intravenous injection.
• Finding the best combination of substances, having synergistic effects.
• Healthy individuals vs. those with disease, as different effects are seen among different study populations.
• Long-term studies, those extending beyond 6 months.
• Different dose regimens, as these supplements seem to be well tolerated even at the higher doses.

Practical Tips on NAD+ Boosters

How to Use NMN or NR?

Food and drinks

Both NMN (22 ) and NR (23 ) are highly water-soluble compounds. Thus, to increase their bioavailability, it is recommended to consume them with a fair amount of water. Taking it with 200 ml glass of water will do in this case. They are not lipid soluble, therefore, fatty foods might decrease their absorption.

Time of the day

Taking into account natural circadian rhythms, metabolic processes of the organism and that both NMN and NR might boost energy levels, it is recommended to take these food supplements in the morning or at least until noon, i.e. in the first part of the day.

Dose

There is a number of clinical trials that are still ongoing and the dose of both NR and NMN is still debatable. My advice would be first to check your NAD+ levels constantly and adjust the use of NAD+ precursors accordingly. From the clinical data is seams that anything up to 1000 mg/daily for either NMN or NR are safe and well tolerated.

Is It Safe to take NMN or NR?

The quick answer is YES. As described in one of the previous paragraphs, both NMN and NR has quite well-established safety profile in a short-term studies up to 6-month period. However, data is still lacking for a long-term use.

Do I Use NMN or NR?

YES. As disclosed before, I am using NR in combination with Resveratrol daily and I tend to do 1-2 months gaps in between a 2-3 month course.

How to Choose NMN or NR Supplements?

My next Nexus edition will be dedicated to discuss overall rules when choosing any food supplement or medical device related to longevity. But until that one shows up, here are 4 simple rules to follow:

1. Check for product quality reports in third party labs if available.
2. NR and especially NMN are expensive to manufacture, therefore, run away from any cheap solutions or 2 for 1 discounts.
3. If you buy from a local e-shop, check, if such food supplement is registered in the national register of a food and veterinary products agency. They are publicly available and I see many brands these days selling illegally.
4. Go for a more established brands, as it will take some time until someone checks the quality and quantity of the active ingredients in a new influencer's white label brand.

NMN or NR?

There is no single straightforward answer which one is better. You don't have to be a chemist or a pharmacist to understand from the reaction below that NR is the precursor of NMN, and NMN is the precursor of NAD+ in the NAD+ salvage pathway (shown in the figure; 24 ). This means that if you consume NMN, it is directly converted into NAD+ in the organism, while NR needs to be converted into NMN first. Directly supplementing with NMN bypasses this additional conversion step that NR requires, potentially making it a more efficient way to increase cellular NAD+ levels.

NMN has been suggested to have higher bioavailability compared to NR, meaning it may be absorbed and utilized more efficiently by the body. However, this aspect can vary depending on factors such as dosage, formulation, and individual differences. From the safety perspective, NR is much more researched in a clinical setting, and thus has a better established safety profile in comparison to NMN.

One way or another, both were shown to significantly increase blood NAD+ levels, while therapeutic efficacy is variable depending on the dose, length of use, and overall health condition.

How to Boost Your NAD+ Levels Naturally?

While it may seem that taking food supplements is the easiest way to increase your NAD+ levels, it is important to combine it with the healthy life choices, which can be even more effective than the food supplements themselves. Here are several strategies to boost NAD+ levels naturally:

NAD+ Precursors Rich Food

Here comes the list of foods, where you can find NAD+ precursors and other molecules, involved in NAD+ metabolism:

• NMN is found in a variety of fruits and vegetables including immature soybean pods, cabbage, cucumber, broccoli, tomato, mushroom and avocado as well as in raw beef and shrimp. The NMN content in these vegetables and fruits are 0.25–1.88 mg/100 g and 0.26–1.60 mg/100 g, respectively, whereas raw beef and shrimp contain comparatively lower level of NMN than those plant-based food (0.06–0.42 mg/100 g) (25 )
• NR is found in small amounts in milk, dairy products and yeast-containing products.
• Tryptophan, an amino acid found in turkey, chicken, dairy, nuts, and seeds. Tryptophan is another precursor in the NAD+ biosynthesis pathway.
• Nicotinamide (Vitamin B3) is found in foods like chicken, beef, fish, peanuts, and avocados.
• Nicotinic Acid (Niacin), a precursor of Nicotinamide, is resent in mushrooms, brown rice, whole grains, and green vegetables.

Healthy Lifestyle Choices

Most of the healthy habits can help increase the NAD+ levels. These include:

• Caloric Restriction. Reducing calorie intake without malnutrition has been shown to increase NAD+ levels and activate sirtuins.
• Intermittent Fasting. Cycles of eating and fasting can enhance NAD+ production by promoting metabolic shifts that favour NAD+ biosynthesis.
• Regular physical activity. Physical activity increases the demand for NAD+ in muscle cells to meet energy needs, which can stimulate the body to produce more NAD+. Both aerobic exercises (like running, cycling, and swimming) and resistance training (like weightlifting) are effective in increasing NAD+ levels.
• High-quality sleep. Ensuring at least 6-7 hours of quality sleep per night supports circadian rhythms and can help maintain optimal NAD+ levels. Disrupted sleep patterns can negatively affect NAD+ biosynthesis.

NAD+ Reducing Factors

Chronic stress can significantly deplete NAD+ levels. Anything that increases your resilience to stress can support the increase of NAD+. For some, practices like meditation, yoga, and mindfulness can help manage stress and therefore, support NAD+ levels. For myself, it can be a walk with my dog, playing the piano or listening to the music that I love (usually on repeat).

Excessive alcohol intake can deplete NAD+ levels as our body uses NAD+ for alcohol metabolism. As mentioned in one of my previous Nexus editions, moderation is key when we talk about alcohol consumption, as limiting alcohol intake helps maintaining NAD+ levels.

Hope you enjoyed the read. More on longevity and healthspan is coming in 2 weeks. The next Nexus edition will be even more practical, as I will share some tips and tricks how to be more sharp, how not to believe everything you read about longevity supplements and medical devices on the social media, what are the sources of truth and how to pick the best products for your health benefits. Stay tuned and subscribe!