The Mouse Source of Youth: Living Long and Happy with NAD or Without NAD

The dream of longevity shaped into NAD (nicotinamide adenine dinucleotide) molecules is becoming an increasingly popular therapy in America, to which celebrities like Hailey and Justin Bieber, Kendall Jenner, and other Hollywood figures who support health trends related to intravenous therapy with ‘miraculous’ preparations are subjected. For instance, in one episode of the reality show ‘The Kardashians’, Kendall Jenner and Hailey Bieber underwent NAD anti-aging therapy. Hailey Bieber stated at the time: ‘I’m going on NAD for the rest of my life and I will never age.’ Additionally, in a documentary about her husband, singer Justin Bieber, there is a scene where Hailey receives an infusion of NAD+ in a doctor’s office to ‘cleanse her body of toxins.’ The famous actress Jennifer Aniston is also enthusiastic about NAD and believes it is the therapy of the future.

NAD therapy is popular as a potential means of extending lifespan, although results obtained from research on mice have yet to be proven in humans. Animal studies have shown that NAD can help repair DNA, leading to longevity. NAD+ has shown positive health effects, such as slowing the progression of Alzheimer’s disease in mice. Results from research conducted on older mice that took NAD+ for six weeks, published in Science in 2016, showed that the mice lived longer, ran faster and further, and had stronger grips in their little paws. However, scientists are still trying to understand the full effects of NAD+ on the human body. Although NAD therapy has attracted attention as a potential means of extending lifespan, caution is advised.

The Disease of Aging

Longevity medicine has been on the rise since the World Health Organization added aging to the list of diseases in 2018. This has spurred research into new therapeutic methods for delaying or slowing aging-related diseases to find a longevity formula that will help people not only live longer but also improve health and quality of life during aging. Peptides like NAD are small chains of amino acids that can help activate vital cellular functions, and they are introduced into the body through infusions, injections, or supplements. Infusions are very expensive, costing between $300 and $2000 for 500 mg of NAD and can be painful.

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Developmental biologist Shin-ichiro Imai from the University of Washington School of Medicine has established NMN as a critical, systemic signaling molecule that maintains the biological resilience of the communication network supporting NAD+. In numerous studies, NMN supplementation has increased NAD+ biosynthesis, suppressed aging-related inflammation of adipose tissue, enhanced insulin secretion and action, and improved mitochondrial and neuronal function in the brain…

– The importance of nicotinamide adenine dinucleotide (NAD+) in human physiology is well known. Since it is believed that the concentration of NAD+ in human skin, blood, liver, muscles, and brain decreases with age, finding ways to increase NAD+ status could impact the aging process and associated metabolic consequences. In middle age, NAD+ levels are at half the value of youth. Numerous studies have shown that NAD+ levels can be increased by activating enzymes that stimulate NAD+ synthesis, as well as by supplementing precursors, including nicotinamide mononucleotide (NMN) among others. Since nicotinamide mononucleotide (NMN) is a precursor for NAD+ biosynthesis, numerous in vitro/in vivo studies have shown that NMN supplementation increases NAD+ concentration and can alleviate age-related disorders such as oxidative stress, DNA damage, neurodegeneration, and inflammation. The promotion of NMN as a health supplement against aging has gained popularity due to such discoveries. However, since most studies assessing the effects of NMN have been conducted on cellular or animal models, there are concerns regarding the safety and physiological effects of NMN supplementation in humans. Currently, about a dozen clinical trials in humans are underway investigating the effects of NMN – explains Prof. Dr. Ruža Frkanec from the Center for Research and Knowledge Transfer in Biotechnology at the University of Zagreb.

Cellular Redox State

According to Frkanec, NAD is nicotinamide adenine dinucleotide, a molecule composed of two nucleotides, adenine and nicotinamide, linked by phosphate groups. Nucleotides are the building blocks of the nucleic acids DNA and RNA. NAD exists in two forms: oxidized and reduced, NAD+ and NADH (H is hydrogen). In cellular metabolism, NAD is involved in oxidation-reduction reactions, transferring electrons from one reaction to another; NAD+ is an oxidizing agent, accepting electrons from other molecules, resulting in NADH, which can be used as a reducing agent to donate electrons. These electron transfer reactions are the main function of the NAD molecule. The balance between the oxidized and reduced forms of nicotinamide adenine dinucleotide is called the NAD+/NADH ratio.

– This ratio is an important component of what is called the cellular redox state, a measure that reflects metabolic activities and cell health. Nicotinamide adenine dinucleotide (NAD) is essential for cellular physiological processes and directly or indirectly affects metabolism and gene expression – emphasizes Frkanec.

She adds that alongside the new synthesis of adenine dinucleotide (NAD+) from vitamin B3, there are several NAD+ precursors, including nicotinamide mononucleotide (NMN) and niacinamide, best known as nicotinamide (NAM). They are vital for human metabolism and an irreplaceable part of the human diet.

In Nature and Artificially

Nicotinamide mononucleotide NMN exists in two structural forms, α and β. α-NMN does not exist in nature, while β-NMN is the natural form found in all organisms and is the active form because specific enzymes within our cells can recognize it to produce the NAD+ molecule.

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– The classification of aging as a disease opens the way for research into new drugs and therapies for aging-related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegeneration. Numerous strategies have been developed to help reduce aging-related problems. For instance, dietary restriction can significantly aid in finding mutations in nutrient signaling pathways that extend lifespan, as well as physical activity and exercise, and numerous drugs (aspirin, rapamycin, metformin) and anti-aging preparations such as resveratrol, spermidine, and fisetin, which have proven safety and harmlessness – explains Frkanec, adding that the conceptual framework of ‘NAD World’ positions NMN as a critical, systemic signaling molecule that maintains biological resilience to aging. According to her, in all living beings, increasing intracellular NAD+ levels triggers changes that enhance survival, including increased energy production and regulation of cell repair mechanisms.

– NMN has proven to be a mouse source of youth. But what about humans? Numerous scientists studying aging and the impact of NMN on metabolic processes in humans have demonstrated its positive effects. However, nicotinamide mononucleotide (NMN) still provokes considerable controversy. Although the U.S. Food and Drug Administration (FDA) initially approved NMN as a dietary supplement in the spring of 2022, it later changed its stance and stated that NMN cannot be marketed as a dietary supplement because it has been approved for investigation as a new drug and is subject to different regulations. Currently, NMN is not licensed in China either and cannot be produced and marketed as food due to a lack of safety evidence – notes Frkanec.

Dietary Supplement

According to her, in some EU countries, NMN is available as a dietary supplement, including in Croatia, while some countries have stricter regulations that limit its sale and use.

– Safety assessments are conducted based on the dossiers submitted by applicants. The dossiers must contain data on the composition, nutritional, toxicological, and allergenic properties of NMN, as well as data on appropriate manufacturing processes and proposed applications and usage levels. This application process is very costly for the applicant and takes years – emphasizes Frkanec.

She adds that numerous questions remain regarding the use and consumption of NMN in aging prevention, primarily concerning dosages and timing of application, as well as possible interactions between NMN and any other medications someone may be taking.

– Given that NMN can affect various metabolic pathways, it could potentially influence the effectiveness of certain medications, especially those for blood pressure, blood sugar, and hormonal regulation. Some studies have also shown an increased risk of tumor formation due to NMN intake and strong stimulation of NAD+ synthesis – explains Frkanec.

Potential Risks and Side Effects

Short-term studies, according to her, suggest that NMN application is generally safe and well-tolerated, but there is a lack of convincing clinical evidence regarding its long-term safety. Additionally, there are potential risks and possible side effects, and due to the lack of comprehensive human testing, it is important to consume NMN cautiously.

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– Dietary supplements do not require a prescription and can be purchased not only in pharmacies but also in other types of stores and online. More than 50 percent of adults consume various dietary supplements as a substitute for a balanced diet, to improve overall health, enhance appearance, and for anti-aging therapy. It is advisable to avoid purchasing such products online from unknown and unauthorized manufacturers, and when buying in authorized pharmacies and stores, attention must be paid to the product composition and recommended dosages. It is also important to monitor public information regarding possible product recalls due to counterfeiting and potential content of hazardous ingredients – advises Frkanec, emphasizing that consulting a doctor is essential before starting to consume any new dietary supplement, especially NMN.

Moreover, it is unlikely that focusing on NAD therapy without addressing key issues: poor diet, lack of exercise and sleep, and stress, will yield significant benefits. Only when these issues are resolved can one consider taking longevity preparations.

CONTROVERSIES ABOUT MICE, MONKEYS, AND HUMANS: Aging is Just a Curable Disease

Dr. David Andrew Sinclair, a professor of genetics at Harvard Medical School, who stands behind NAD therapy, which the Bieber couple loves so much, recently caused a slight panic among the global elite by resigning from the position of president of the prestigious Academy for Health and Longevity Research just a year after being elected to that position. Wealthy and famous NAD users, as well as the pharmaceutical industry, seem to have begun questioning whether critics of his work, who dispute his claims of achieving ‘age reversal’ in animal models, are right. Or is it perhaps just a battle for profit? This has greatly upset the Australian-American biologist and academic known for his research, controversial claims about aging and epigenetics, and his book ‘Lifespan: Why We Age—and Why We Don’t Have To.’

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Studies on animals have shown that NAD can help repair DNA, leading to longevity. NAD+ has shown positive health effects, such as slowing the progression of Alzheimer’s disease in mice.

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In it, Sinclair explained that aging is a disease, but a curable disease. He has faced criticism since he wrote on X last April that a gene therapy developed in his Harvard lab, which is promoted by the company Life Bioscience, of which he is a co-founder, restored vision and reversed aging in monkeys. He then followed his claim with the words: ‘Next: age reversal in humans.’ Dr. Sinclair is a co-founder of several biotechnology companies (including Sirtris, Ovascience, Genocea, Cohbar, MetroBiotech, ArcBio, Liberty Biosecurity) and is on the board of several others, including Inside Tracker and Life Bioscience. For a non-profit organization like the Academy for Health and Longevity Research, there seems to be no time left.