Why do we talk about NAD+ again? Because it is the most important molecule for life to exist, and our health directly depends on its amount in our body!
This post will help you to understand how your body gets NAD+, how it uses it, and why its level decrease with age based on the latest studies and discoveries. Also…
It contains practical advice on how to measure, maintain and potentially increase your NAD+ levels, including references to useful products and services.
The three recipes below are from the book “The Longevity Diet: Slow Aging, Fight Disease, Optimize Weight” by Dr. Valter Longo; that definitely worth adding to your diet.
How does our body get NAD+?
Just to remind, NAD stands for Nicotinamide Adenine Dinucleotide. It refers to four related compounds (NAD+, NADH, NADP+, and NADPH) that are the central catalysts of metabolism, the process by which the body changes food and drink into energy.
The main difference between NAD and NADP (nicotinamide adenine dinucleotide phosphate) is that NAD is used in cellular respiration, whereas NADP is used in photosynthesis. Both NAD and NADP contain an oxidized and reduced form. The reduced form of NAD is NADH, while the oxidized form is NAD+. In NADP, the reduced form is NADH, and the oxidized form is NADP+.
Here, we will focus on NAD+ since it seems to play a central role. It is a crucial coenzyme that can be found in every cell in your body. NAD+ works as a shuttle bus, transferring electrons from one molecule to another within cells to carry out all sorts of reactions and processes. With its molecular counterpart, NADH, this vital molecule participates in various metabolic reactions that generate our cell’s energy. Without sufficient NAD+ levels, our cells wouldn’t be able to generate any energy to survive and carry out their functions. Other functions of NAD+ include regulating our circadian rhythm, which controls our body’s sleep/wake cycle. Basically, without NAD+, we would be on the fast track to death.
In our previous post, we already showed what food sources provide us with NAD+ precursors for its synthesis inside the cells. There are five major precursors and intermediates to synthesize NAD+: tryptophan (Trp), nicotinamide (NAM), nicotinic acid, also known as niacin (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN).
As shown in the image, NAD+ can be synthesized de novo by the conversion of the amino acid tryptophan (Trp) through multiple enzymatic steps to nicotinic acid mononucleotide (NAMN). This is one of three known pathways to produce NAD+ in a body, called the Kynurenine pathway. You can find more information on how NAD+ is made by this pathway here.
NAD+ can also be made by the Preiss–Handler pathway starting from niacin (NA), a form of vitamin B3. It is known for producing flushing when taken in high amounts. Conversion to NAD+ proceeds in several enzymatic steps. NANM is an intermediate in the pathway, so de novo synthesis from tryptophan shares several steps in this pathway to complete NAD+ synthesis.
But most of our NAD+ we get from the third pathway, called the Salvage pathway. This pathway converts nicotinamide (NAM) to NAD+ with nicotinamide mononucleotide (NMN) as an intermediate.
It is called a salvage pathway because, no matter what precursor (tryptophan or any of the niacins) or pathway produces NAD+ after NAD+ is consumed in a cell, they all result in NAM generation, which is a “salvageable precursor” to re-produce NAD+. So, the salvage pathway is the mechanism used to recycle NAM into NAD+. Nicotinamide riboside (NR) is also used by the salvage pathway. Enzymes exist that can convert NR into NAM or NMN. In either instance, NAD+ formed by NR can be used in NAD+-consuming reactions and ends up as NAM. NMN is also a salvage pathway niacin equivalent.
How is NAD+ consumed in the body?
We already know that NAD+ is a vital coenzyme in redox reactions. It is responsible for accepting “high energy” electrons and carrying them ultimately to the electron transport chain, where they are used to synthesize ATP molecules.
Why is it important? Because ATP, or adenosine triphosphate, is an important “energy molecule” found in all life forms. ATP captures chemical energy obtained from the breakdown of food molecules and releases it to fuel cellular processes, such as transcription, DNA replication, DNA repair, and many others.
NAD+ has a cofactor in the process of ATP synthesis, which is flavin adenine dinucleotide (FAD+). FAD+ is a coenzyme form of vitamin B2. When these electron-carrier molecules (NAD+ and FAD+) accept the electrons, they are reduced into NADH and FADH2 (redox reactions). These electrons usually come in the form of hydride atoms. Reduced forms are oxidized back to NAD+ and FAD+ during ATP synthesis. So, here, NAD+ is in the cycle. But…
NAD+ is also constantly consumed in cells by the action of a number of NAD+ consumers, including sirtuins, PARP enzymes, SARM1, and CD38. Let’s go over with each of these enzymes.
Sirtuins are a family of seven proteins in humans (SIRT1–SIRT7) that are involved in multiple cellular processes. Scientists often refer to sirtuins as “guardians of the genome” for their role in regulating cellular homeostasis, e.i., the exchange of cell materials and energy with its surroundings. Homeostasis involves keeping the cell in balance.
Most importantly, sirtuins affect gene expression.
Our DNA is packaged by special proteins called histones to form chromatin. Histones are molecular spools, and DNA is the thread that wraps around these spools. Sirtuins regulate how much DNA is wound around the histones and how much is open to the surrounding environment. The DNA that is wrapped around the spool can not be expressed (switched off). This way, our genes get switched on or off.
Sirtuins regulate the spooling and unspooling process in response to environmental changes, protecting our DNA from damage. Through this mechanism and others, sirtuins are involved in many biological processes and regulate the cell cycle, DNA repair, and mitochondrial energetics. However….
This group of proteins relies on NAD+ to function and perform cellular functions creating a constant supply of nicotinamide (NAM), which must be recycled back to NAD+ to maintain the balance.
PARPs are proteins similar to sirtuins. PARP is a protein (enzyme) found in our cells. It stands for poly-ADP ribose polymerase. It helps damaged cells to repair themselves by the response to early DNA damage and have a key role in DNA damage repair. The most active in DNA repair is PARP1 through the modification of proteins by linear or branched chains of ADP-ribose units originating from NAD+. This process also releases NAM, which is utilized for synthesis back to NAD+.
Similar post-translational modifications by PARPs have been implicated in many physiological processes, including gene transcription, protein degradation, cell proliferation and differentiation, aging, inflammation, cell death, host–virus interactions, and metabolism.
Stressing the NAD+ pool because of too much demand by PARPs can also have the side-effect of depleting cellular ATP levels, leading to cellular energy failure, which, if left unchecked, can result in cellular dysfunction and, eventually, cell death.
SARM1, or Sterile alpha and TIR motif-containing 1 protein, is an essential mediator of axon degeneration.
Axons, the long protrusions of nerve cells, are programmed to self-destruct under certain conditions that occur during development, stress, or disease states. Mechanisms to destroy and clear neuronal processes are important for the ability of nervous systems to adapt to damage, stress, and viral infection.
The activation of SARM1 is necessary and sufficient to cause axon destruction. It was demonstrated that SARM1 is activated by an increase in the ratio of NMN to NAD+. According to another study, SARM1 activation is triggered by a decrease in the concentration of a cellular metabolite NAD+, rather than depending on the introduction of an activating factor.
In any case, SARM1 initiates a local destruction program involving the rapid breakdown of NAD+ after injury.
CD38 acts as an enzyme in several cellular reactions involved in calcium (Ca2+) mobilization and signaling. One of the CD38 reactions mainly generates ADPR (Adenosine diphosphate ribose) and NAM when it consumes NAD+. As part of the reactions, NAD+ levels get depleted depending on the tissue and the degree of enzyme activity.
Because the majority of activity is extracellular, CD38 is believed to be a significant regulator of extracellular NAD+ pools. With the increasing activity of CD38, depletion of NAD+ increases, while repression of CD38 increases NAD+ levels.
Sirtuins, epigenetics and longevity
Sirtuins at the Service of Healthy Longevity
NAD+ consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival
The taming of PARP1 and its impact on NAD+ metabolism
An NAD+/NMN balancing act by SARM1 and NMNAT2 controls axonal degeneration
SARM1 activation triggers axon degeneration locally via NAD+ destruction
CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism
SARM1 activation triggers axon degeneration locally via NAD+ destruction
Why does NAD+ decline with age?
NAD+ levels decline in many tissues with age, and this decline is believed to contribute to the aging process. Multiple factors can play a role in the decline, including dietary deficiencies for NAD+ precursors, changes in the expression levels of enzymes that transform dietary precursors to NAD+, or changes in the activity of enzymes that break down NAD+ (see above).
Diet-induced metabolic damage is related to increased activity of PARPs and CD38 following increased DNA damage and inflammation, and NAD+ consumption. A sedentary lifestyle could be enough to decrease mitochondrial amounts in muscles and, consequently, NAD+ levels, even in the absence of a disease state or changes in NAD+-consuming enzyme activities.
There is also a suggestion that the synthesis of NAD+ declines with age and fails to compensate for its consumption. The constant degradation of NAD+ by enzymes involved in various cellular processes requires a continuous resupply of it by synthesis from dietary precursors or recycling from NAD+ degradation products. As shown above, NAD+ recycling via the NAM salvage pathway is a fundamental step to restore NAD+ levels after irreversible degradation mediated by the different classes of NAD+-consuming enzymes (Sirtuins, PARPs, CD38, and SARM1).
The majority of NAD+ is generated in the salvage pathway (see above), where one of the steps is the conversion of NAM to NMN. This conversion is catalyzed by the protein called NAMPT, and its activity declines with age. A possible mechanism of age-related NAMPT decline is chronic inflammation. The age-related decline in NAMPT expression leads to a reduction of NAD+ levels, which in turn will affect the activities of NAD+-dependent redox reactions and cellular processes.
The balance between NAD+ biosynthesis and consumption at aging
(Source: Yaku et al. Ageing Research Reviews., V.47, 2018)
Other possibilities include increased degradation of NAD+ due to its consumption by PARPs. The longer we live, the more cellular and DNA damage we accumulate, which increases the repair activity of PARPs.
Same with CD38 since it is highly expressed in inflammatory cells. It is possible that the low-grade inflammation occurring during aging may lead to an increase in the expression of CD38. Moreover, the progressive increase in senescent cells with age also increases the activity of CD38, leading to high consumption of NAD+. It was shown that CD38 is the main consumer responsible for the aging-related NAD+ decline.
Sirtuins are continuously active in our cells. SIRT1 and SIRT2 were shown to be responsible for about one-third of the total NAD+ consumption in basal conditions. However, sirtuins seem to operate oppositely to PARP-1 and CD38 in relation to healthspan. Decreasing NAD+ content is more likely to compromise sirtuin activity; thus, sirtuin activity is unlikely to explain the decreases in NAD+ levels observed with aging.
The big picture is that as we get older we don’t make enough NAD+.
NAD+ metabolism and its roles in cellular processes during ageing
NAD + biosynthesis, aging, and disease
Typical NAD+ levels vary considerably by age and unit of measurement. Within cells, it can range between 10 and 1000 μM. Steady-state cellular NAD+ levels in mammals were measured between 200 and 500 μM.
Total NAD+ levels were observed to range between 0.3 and 0.4 μmol/g. These levels gradually decrease with age.
Do you want to know what is your NAD+ levels?
The NAD+ Intracellular Assay by Jinifiti is a blood-based test that targets age-related levels of NAD+ and empowers you to make decisions that most benefit your health.
- Collect a few drops of blood on the test strip | Add fixing buffer to stabilize the NAD+
- Use preaddressed envelope to return sample | Results available in 7-10 days
How to measure NAD+ level?
Measuring your NAD levels was quite difficult and not easily accessible. Up till now, you could do it only in very few laboratories with expensive equipment, using liquid chromatography coupled to mass spectrometry or enzymatic assays. There are some challenges to accurately detecting sub-cellular NAD+ levels because of the high instability of NAD+ and the impossibility of NAD+ detection in live cells/tissues.
The recent development of genetically encoded fluorescent biosensors such as SoNar and a biosensor with a bipartite NAD+-binding domain has enabled imaging of relative levels of free NAD+ in the subcellular compartments. However, these methods do not have public access, even through your doctor or at your local medical facility.
Fortunately, recently a few companies came up with a measuring method based on a blood test.
At-home NAD+ level test kit is now available from a company called Do Not Age. It is a simple blood test where you collect the blood and send it to their laboratory. You will get the results in 4 weeks or so.
Jinfiniti provides its Intracellular NAD™ at-home test kit, which also uses blood samples to measure NAD+ levels.
These tests are not cheap (yet) but give you real-time, actionable data to help you create an effective approach toward your health improvement.
More information on measuring your NAD levels you can find in our other post.
How to increase NAD+ supply?
NAD+ decline at the core of hallmarks of aging.
(Source: Aman et al, Translational Medicine of Aging, V2, 2018.)
As was shown above, increasing the expression and activity of Sirtuins promotes the cellular and mitochondrial processes needed for both healthier aging and longevity. So, in general, we want to have greater amounts of NAD+ available for consumption use, and we want more of it to flow to Sirtuins.
Neither of these appears to occur with aging. Since the consumption users are competing for a finite pool of NAD+, this also means less would be available for sirtuin activity. So, what can we do?
There are many methods that can help you to increase and/or maintain NAD+ levels in your body. According to our current knowledge, they can be divided into three groups in relation to NAD+ biosynthesis pathways and its consumption.
Strategy 3 is related to inhibiting the activity of PARPs, SARM1, and CD38 by limiting DNA damage by sun exposure and alcohol consumption, as well as by special therapies.
Tips for Strategy 1
This strategy is focused on promoting NAD+ synthesis by supplying precursor molecules.
1. Be sure to include food sources of NAD+ precursors in your diet. Our previous post contains details on which precursor is supplied by what food.
- Fermented foods and beverages such as kombucha contain NAD+ and are very beneficial. Fermentation uses NADH to produce lactate, and the byproduct is NAD+. Learn how you can make kombucha drinks at home.
2. The best way to increase NAD+ levels is by taking NAD+ supplements and its precursors. You can take NAD+ in several forms: as an IV treatment, as an injection, as daily oral pills, as a nasal spray, as sublingual tablets, gel, or powder, and as suppositories.
- When taking an orally, you must take a precursor molecule. NAD+ is highly unstable and will break down in your gut without being absorbed.
- NMN and NR, which are NAD+ precursors, have poor bioavailability in capsules and are only partially digested in the stomach, and are almost totally metabolized in the liver and excreted as NAM.
- When it comes to the question of which one you should take, research has shown that certain parts of the body show a “preference” for one over the other because of the presence of transporter molecules specific to that precursor. There are 200 different kinds of cells in the body, from stem to skin to blood cells, and some of them behave differently when it comes to the uptake and utilization of precursors. You may want to try each separately to see which one is a better fit for you and your unique lifestyle.
- We would like to mention that there are some publications linking NR supplementation with the risk of cancer. The data are controversial and are the subject of debate.
- A liposomal version of NMN may well mimic the body’s own transport system, enhancing uptake and delivery. Liposomal supplements are packaged within a liposome, which is a little pocket of fat cells. This format not only helps preserve the nutrient but can also improve absorption within the body.
- When taking NMN, be sure to add resveratrol. A new study shows that such a combination synergistically increases NAD+ levels.
- Both NR and NMN can destabilize over time, especially in an environment of high temperature and humidity, and subsequently convert to NAM (nicotinamide). This intermediary compound may have deleterious effects on health because it reduces sirtuin activation. These precursor need to be stored in a dry cool place. We store them in a fridge.
- Unfortunately, the FDA recently published letters to NMN suppliers saying that NMN can no longer be sold in the U.S. as a supplement. The reason is that NMN “has been authorized for investigation as a new drug.” We are not sure for how long the MNM supplements will still be available.
- Sublingual tablets, gel or powder show a high rate of precursor delivery. Sublingual (under the tongue) delivery can provide rapid absorption via the blood vessels under the tongue rather than via the digestive tract.
- Another effective way is to use suppositories. This way, the supplements are introduced to the dense matrix of capillaries in the colon that allows for very efficient absorption and avoid exposure to the hazards of hydrochloric stomach acid.
- In the case of IV infusion, NAD+ also bypasses the gut and is delivered directly to the bloodstream, where it can enter cells. It is the most effective way so far. Unfortunately, IV therapy with NAD+ is quite expensive.
- You can buy self-administered NAD+ injections online. They have a low toxicity level, and there are no risks of adverse effects or damage to vital organs, as long as the correct dosage is administered.
- The suitable dosage of NAD+ relies on your present health condition and needs, like the type of precursor the supplement is using. It is reasonable to consult a healthcare professional about developing the proper treatment plan.
- Most NMN supplements come with a suggested dosage of around 250 to 300 mg every day, generally equating to one or two capsules. Yet, some dosages have been used between 100 mg and 1,200 mg per day. There have been some substantial side effects for larger dosages of above 6,000mg.
- The upper level, which is by definition “the maximum level of the daily nutrient intake that is likely to result in no adverse effect” , was established for NR intake of 3 mg/kg/day (180 mg/day for a 60 kg/132 lb adult).
- Doses of nicotinic acid (NA) at 50 mg/day and higher are associated with flushing and itching that occur within 30 min after the oral administration . Large doses of 250 mg per day of nicotinamide have induced reversible hepatotoxicity in animals and humans or minor abnormalities of liver enzymes.
- Some supplements will contain just the precursor itself, like NR (nicotinamide riboside). However, some manufacturers may also mix it with additional ingredients like antioxidants, which may have diverse effects.
- Our preferable way to maintain NAD+ levels is to use “NMN with Resveratrol Liposomal Sublingual Gel” from NADlab.
- Whether you’re planning to increase your NAD+ levels naturally or through supplements, speak with your doctor before attempting anything new, especially if you have underlying conditions that may be affected by health-related modifications.
Below are some products that are worth to try (just clock on the images). You may want to consult your doctor, who can help you to choose the right treatment.
NMN with Resveratrol LIPO Gel is designed for sublingual (under the tongue) use for superior bioavailability.
2 pumps provides ▸240 mg liposomal NMN ▸40 mg liposomal Resveratrol
NAD+Max™ Suppository contains the finest and highest potency NAD+, NMN & NR along with the following plant based Polyphenols: Fisetin, Ginkgo Biloba, EGCG, Lutein, Quercetin, Curcumin & Resveratrol.
Tips for Strategy 2
This strategy is based on the fact that our body has a tendency to increase NAD+ synthesis under mild stress or hormesis. The concept relates to the fact that exposure to very low doses of a substance that is toxic at high doses can elicit beneficial effects.
1. One of the simplest ways to naturally increase your NAD+ levels and overall health is to exercise.
- In fact, according to the researchers, their results imply that “most metabolic changes that occur with age in muscle can be reversed with regular exercise training.”
- Regular exercise can enhance the DNA-rebuilding proteins in your body and keep you strong whilst maintaining a healthy weight.
- A recent study in humans finds that aerobic and resistance exercise can restore age-dependent enzymes involved in NAD+ synthesis in muscles.
- Choose workouts that challenge you in order to damage your muscle fibers and prepare them to rebuild themselves stronger than they were before. This is when you feel soreness in the body.
Biphasic dose-response curve toward a hormetic stimulus. Under a certain threshold, the effect of a stimulus/stress on the measured trait is positive (improvement), whereas over this threshold it becomes detrimental/toxic. The range of hormetic doses is indicated as the “hormesis zone.”
(Source: Martucci et. al, Nutr. Rev. 2017, V.75)
- You can also choose HIIT (high-intensity interval training), where you go all out for 30 seconds to a minute, followed by 15 seconds of rest to experience hormesis. During these intense bursts, your muscles are briefly starved for oxygen (hypoxia) which stimulates the production of mitochondria (the powerhouse of the cell.)
2. Mild physical stress to the body by fasting can also stimulate the production of NAD+.
- A study that enrolled participants in a protocol of periodic fasting for five days found that they had elevated levels of SIRT1 and SIRT2 sirtuin expression in humans.
- Another study showed that intermittent fasting might positively stimulate NAD+ concentration and activate signaling pathways that fight aging. However, it is still unclear how much fasting increases NAD+ levels and whether intermittent fasting is safe and beneficial in the long term.
- Nutritional ketosis increases NAD+/NADH ratio. It can be achieved by a ketogenic diet (keto).
3. While direct sunlight causes damage to the body, spending time in natural or artificial heat can certainly help you boost those NAD levels.
- Common heat sources, such as saunas, steam showers, hot tubs, and heated pools, may cause your heart to beat quicker, forcing your body to use more energy to keep cool. This triggers the increased production of NAD+ to supply essential amounts of energy.
- You can put a small sauna or install an affordable steam shower in your home.
4. Cold treatments are expected to have a similar effect.
- A study has shown that cold exposure increases NAD+ and NADH as well as gene and protein expression of key enzymes in the NAD+ salvage and clearance pathways.
- Cryotherapy or ice baths can do the trick. However, cryotherapy is considered to be better because it uses dry cryogenically cooled air to reduce the skin’s temperature, while an ice bath uses wet cold, which can cause muscle tissue to congeal, making them pretty immobile.
- We do not recommend jumping into freezing cold water unsupervised. Experts caution that for some people, shocking the body with cold water could do more harm than good, especially for people with a cardiac history.
5. Some food also has a hormetic effect.
Tips for Strategy 3
This strategy is aimed to suppress the activity of NAD+ -consuming enzymes like PARPs and C38 that relates to any damaging events.
- You are more likely to decrease your levels of NAD+ if you spend too much time in the sun. Direct sunlight may cause your body to use a significant amount of NAD+ to repair damage caused by the sun’s ultraviolet (UV) rays from the sun. To avoid skin damage, try to minimize your time outdoors while the sun is still out, and always remember to cover up with lightweight, loose-fitting clothing.
- The compounds like epigenin, luteolin, quercetin, kuromanin, and luteolinidin have all been demonstrated to enhance NAD+ levels and SIRT1 activity by inhibiting CD38. There are also chemical inhibitors of the NAD+ biosynthesis enzymes, however, little is known regarding their pharmacology and safety for human use to increase NAD+.
- To date, over 200 compounds are listed as CD38 inhibitors in the literature. The therapeutic potential of these inhibitors may be limited due to the inhibitory effect they may have on several other NAD-dependent enzymes, which raises concerns about their specificity.
- With weight loss, SIRT1 expression was observed to increase, whereas PARP-1 activity declines in the subcutaneous adipose tissue of the obese group.
- No clinical trials with PARP-1 inhibitors or CD38 inhibitors that focus on improving metabolic variables have been conducted in humans. This, however, does not imply that this strategy must be abandoned altogether. Exploration of the theoretical metabolic benefit of inhibition of NAD+ consumers may present itself in the future as a valuable therapeutical treatment.
Durasage Lightweight Portable Personal Steam Sauna Spa for Relaxation at Home, 60 Minute Timer, 800 Watt Steam Generator, Chair Included (Gray)
BOTARO Maxxus Saunas MX-J206-01 Seattle Carbon Far Infrared Sauna for 2 Persons, Hemlock Wood, Size 74.8 X 47.2 X 41.3 inches
Mesa 803A Steam Shower, 54″ x 35″ x 85″ with bench seating for two, a chrome interior control panel, a sliding glass door, and a foot massager.
(an example of supplement arrangement from an expert)
David Sinclair is a professor at Harvard University who has been researching the aging process for the duration of his career as a scholar with an extraordinary emphasis on epigenetic programming of the aging process, NAD+ metabolism, and sirtuins NAD+ precursors, such as NMN.
He is committed not to recommending or endorsing any supplement products. But…
Based on a variety of recent interviews as well as his book “Lifespan: Why We Age – And Why We Don’t Have To,” his supplements list could look like the following:
- Nicotinamide Mononucleotide (NMN): 1 gram daily, usually in the morning.
- Resveratrol 1 gram a day, usually in the morning.
- Metformin 800 mg late at night or evening.
- Vitamin D3 sometimes 4,000-5,000 IU daily
- Vitamin K2 sometimes 180-360 micrograms daily
- Low-dose aspirin: at about 83 mg daily
- Alpha lipoic acid (ALA): we are not sure if he takes this currently
- Coenzyme Q10 (CoQ10): we are not sure if he takes this currently
- Spermidine 1 mg daily, usually in the morning.
- Quercetin 500mg and fisetin 500 mg, usually in the early morning
- TMG (trimethylglycine or betaine): we think (not sure) between 500 mg to 1,000 mg daily
The Future of NAD+
Despite the considerable advances that have been made in the past decade, little is known about the pharmacokinetics, efficacy, safety, and potential side effects of long-term supplementation with NAD+ precursors. There are many unanswered questions due to the limited number of human trials and lack of clinical data. Perhaps, among the most pressing questions, the molecular mechanisms and pathways linking NAD+ and aging have so far remained elusive and not understood.
- NAD+ repletion strategies, such as those outlined above, have shown a therapeutic potential to restore a healthy metabolism, a physiological function, and to maintain cellular health, NAD+ has shown various potentials in treating heart diseases, diabetes, Alzheimer’s, and obesity in animal models. However, understanding how studies in animals can translate to humans is the next step for scientists to ensure the safety and efficacy of the molecule.
- Currently, a number of clinical trials are underway in which NAD+ precursor supplementation is being used to improve (often disturbed) metabolic health variables.
- Supplementation with NR has shown some promise in clinical trials, and numerous other trials are ongoing or planned.
- NMN supplementation clinical trials have only been initiated, but their results will be of great interest.
- All NAD+ precursors: NMN, NR, nicotinic acid, and tryptophan increase the availability of NAD+. As noted above, the precursors differ in their ability to enhance NAD+ synthesis via their position in the NAD+ assembly pathway and differ in the number of steps required to form NAD+ in the biochemical pathways. There is a need for more data on precursor differences in absorption, bioavailability, distribution, metabolism, excretion, tissue specificity, and efficacy in increasing NAD+ levels in humans. Currently, there are no studies that directly compare the efficiency of the different precursors to conclude which of the NAD+ boosters has the best therapeutic prospects.
- Recent studies implicate NAD+ biosynthesis as a potential target for preventing and treating age-associated diseases. The coming years will prove whether the promising results observed in preclinical studies can indeed find a human translation.
- Further, we might have overseen how multiple NAD+-related molecules might enzymatically and non-enzymatically react and transform before reaching their target tissues.
- Future work and clinical trials also focus on activators and inhibitors of NAD+ biosynthesis and NAD+ degradation, respectively. The work in mice models has revealed encouraging effects.
- Inhibition of CD38 can also promote NAD+ levels and improve glucose and lipid metabolism, which protects against age- and diet-induced diabetes and obesity. However, due to the reported important neuroprotective activities of CD38, further stringent and comprehensive evaluation of the procedures of CD38 inhibition as a safe anti-aging strategy.
- A potential therapeutic counter for depleted NAD+ pool in aging and age-related diseases could be the inhibition of its consumer, PARPs, which will enable the activity of sirtuins that plays a pivotal role in regulating cellular processes. Identification, evaluation, and testing of such inhibitors are in process.
- The combination of strategies to increase NAD+, such as exercise, caloric restriction, or CD38 and PARP-1 inhibitors, with NAD+ precursor supplementation also needs to be considered to evaluate added efficacy of such approaches.
- The discovery of NRH (Dihydronicotinamide riboside) as a new NAD+ precursor has clearly illustrated that the NAD+ universe might expand far beyond the boundaries established in the early 2000s. It is a reduced version of NR, but despite their structural similarity, the biological properties of NRH turned out to be particularly surprising. NRH can sharply increase NAD+ levels in cultured cells, being far more potent than any other NAD+ precursor described to date.
- Another novel approach whereby NAD+ levels could potentially be boosted via genetic manipulation. In order to understand the fundamental molecular mechanisms in models of aging and age-related diseases, corresponding research and development are ongoing.
From a future perspective, the strategy for healthier aging should not be to just increase NAD+ levels; it should be to increase NAD+ while influencing how it is being distribute and used.
Recipes from Dr. Valter Longo
Dr. Valter Longo is the Edna M. Jones Professor of Gerontology and Biological Sciences and Director of the Longevity Institute at the University of Southern California –Leonard Davis School of Gerontology, Los Angeles, one of the leading centers for research on aging and age-related disease. Dr. Longo is also the Director of the Longevity and Cancer Program at the IFOM Institute of Molecular Oncology in Milan, Italy.
Below are three recipes from his book “The Longevity Diet: Slow Aging, Fight Disease, Optimize Weight”.
Brussels sprouts with garlic, pine nuts, and Parmesan cheese
- Brussels sprouts – 250 g (0.5 lb)
- Garlic – 2 cloves, sliced
- Pine nuts – 1 tsp
- Hot pepper – optional
- Olive oil – 1 tbsp
- Parmesan cheese – 1 tbsp
- Salt and pepper
- Boil the brussels sprouts in salted water.
- Drain, reserving a little of the cooking water.
- Transfer sprouts and reserved water to a heated pan.
- Add the garlic, one nuts, and hot pepper, stirring for 2-3 min.
- Let the dish set.
- Add the olive oil, salt, and pepper.
- Sprinkle with Parmesan cheese.
Garbanzo bean salad with vegetables
- Garbanzo beans – 150 g (0.3 lb), cooked or canned, drained
- Onion – 1 medium, chopped
- Olive oil – 2 tbsp
- Spinach – 200 g (0.4 lb)
- Lemon juice
- Salt and pepper
- Season the garbanzo beans with onion, olive oil, salt and pepper.
- Boil the spinach separately in salted water.
- Add spinach to the seasoned garbanzo beans.
- Add lemon juice and olive oils as needed.
Fennel salad with tomatoes, carrots, onions and olives
- Fennel bulbs – 150 g (0.3 lb)
- Cherry tomatoes – 150 g (0.3 lb)
- Carrots – 1 medium,
- Onion – 1 medium
- Olives – 4 0r 5
- Olive oil – 1 tbsp
- Chope and mix ingredients.
- Add Olive oil and salt.
- Serve with chicory (200 g /0.4 lb), boiled and seasoned with olive oil and lemon juice.
Can add whole-wheat dried focaccia (40 g / 1.5 oz) with extra virgin olive oil on a side.
What is next?
In our upcoming posts, we will keep you updated on the research and development in relation to NAD+, as well as new information on human trials.
Be sure to check back!
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