Aging takes a toll on our cells, making recovery from illness or injury tougher over time. Enter NAD+ (nicotinamide adenine dinucleotide), a powerhouse coenzyme driving DNA repair, energy production, and cellular health. As NAD+ levels drop with age—by up to 50% in some tissues—researchers and longevity enthusiasts are turning to NAD+ boosting therapies to potentially slow aging and enhance vitality. Here’s the scoop on NAD+, its precursors, and what the science says about their role in longevity.
Why NAD+ Matters
NAD+ is essential for over 500 cellular processes, from powering mitochondria to activating sirtuins, proteins that regulate aging and health. As we age, NAD+ declines due to increased consumption (e.g., DNA repair) and reduced synthesis, contributing to fatigue, metabolic issues, and disease vulnerability. Boosting NAD+ through precursors—molecules the body converts into NAD+—is a hot topic in longevity circles, promising to restore cellular resilience.
Harvard longevity expert David Sinclair is a vocal proponent of NAD+ boosting. He argues that NAD+ decline accelerates aging by impairing sirtuins, which maintain cellular health. His groundbreaking mouse studies show that nicotinamide mononucleotide (NMN) restores NAD+ levels, reversing mitochondrial aging and boosting vascular health and lifespan. Sinclair himself takes 1g of NMN daily, paired with resveratrol to enhance sirtuin activity. However, he acknowledges human evidence is still emerging, and his commercial ties to NAD+-related ventures have sparked debate. More human trials are needed to confirm his findings.
How NAD+ Precursors Work
NAD+ precursors feed into the body’s salvage pathway, efficiently replenishing NAD+. Here’s a quick look at the key players:
Nicotinamide Riboside (NR): Converts to NMN via NRK enzymes, then to NAD+. It boosts muscle NAD+ by ~60%, enhancing energy and reducing inflammation.
Nicotinamide Mononucleotide (NMN): One step from NAD+, NMN rapidly raises levels in the liver and brain, improving insulin sensitivity. It may convert to NR for cell entry.
Nicotinamide (NAM) & Nicotinic Acid (NA): NAM recycles to NMN, but high doses may inhibit sirtuins. NA forms NaMN but causes flushing.
Reduced Precursors (NRH/NMNH): These bypass rate-limiting enzymes for faster NAD+ production but may increase inflammation in some cells.
Precursors restore NAD+ to support metabolism and repair, though excessive doses risk methylation strain or other side effects.
The Science So Far
Mouse studies, including Sinclair’s, show NMN and NR extend lifespan and improve health metrics like endurance and vascular function. Human trials, however, are smaller and less conclusive. NMN (250–500 mg/day) has improved sleep in older adults and insulin sensitivity in prediabetic women, while NR reduces inflammation. Experts like Daniel Craighead and Jonas Thue Treebak caution that evidence for human lifespan extension is thin, with stronger benefits seen in conditions like prediabetes or age-related diseases.
Longevity Supplementation Trends
Popular Choices: NMN (250–1,000 mg/day) or NR (e.g., Tru Niagen, 250–500 mg/day), often paired with resveratrol, metformin, or senolytics like fisetin.
Methods: Oral capsules are most common, with sublingual forms for faster absorption. IV infusions ($200–$500/session) are pricier and less studied.
Lifestyle Boosts: Fasting, exercise, and low-carb diets enhance NAD+ via NAMPT enzyme activity. X users (e.g., @BiohackerX, July 2025) report mixed results, with some feeling energized and others noticing little change.
Risks and Considerations
NAD+ precursors are sold as supplements, often unregulated by the FDA, leading to inconsistent dosages and unverified claims. NMN’s supplement status was questioned in 2022, reclassified as a drug. While short-term use is safe, long-term risks like liver strain or potential cancer promotion (in mice) remain unclear. Side effects include headaches or nausea. Researchers like Eduardo Chini and Joseph Baur suggest NAD+ therapies may better target diseases (e.g., Parkinson’s, heart disease) than general aging, urging caution against overhyped commercial products.
The NOMIX Take
At NOMIX, we’re excited about NAD+’s potential but grounded in science. Precursors like NMN and NR show promise, especially for metabolic and cognitive health, but they’re not a magic bullet. Pairing supplementation with healthy habits—exercise, fasting, and a balanced diet—maximizes benefits. Stay curious and cautious: consult your biocoach or doctor, choose reputable brands, and start with low doses.
Nicotinamide adenine dinucleotide, or NAD+, is a crucial molecule found in every cell of our body. It’s like a spark plug that helps power various essential processes, such as fixing DNA damage, controlling gene activity, producing energy, and regulating calcium levels. NAD+ levels tend to increase when our energy levels are low, like during fasting, calorie restriction, or exercise.
Let’s dive deeper into the role of NAD+ in our bodies, its decline with age and health issues, and the challenges of oral supplementation.
Role of NAD+ in the body: NAD+ is a crucial molecule that acts as a cofactor and substrate for various cellular processes, including:
DNA repair: NAD+ is essential for repairing damaged DNA, which helps maintain the stability of our genetic information.
Epigenetic regulation: NAD+ plays a role in controlling the expression of genes by modifying their structure. This process is crucial for normal development and cellular function.
Energy production: NAD+ is a key player in the process of oxidative phosphorylation, which generates ATP (the energy currency of our cells).
Intracellular calcium signaling: NAD+ helps regulate calcium levels within our cells, which is important for cellular communication and function.
Immune function: NAD+ is involved in the activation of immune cells, which helps our bodies fight off infections.
Decline of NAD+ with age and health issues: As we age, our NAD+ levels tend to decrease, which can contribute to various age-related issues. Low NAD+ levels have been linked to:
Aging: Reduced NAD+ levels may play a role in the aging process itself.
Cellular senescence: Senescent cells, which are cells that have stopped dividing and are no longer functional, accumulate with age and contribute to tissue dysfunction. Low NAD+ levels may promote cellular senescence.
Inflammation: Decreased NAD+ levels can lead to chronic inflammation, which is a major contributor to various age-related diseases.
Metabolic dysfunction: Low NAD+ levels have been implicated in insulin resistance, type 2 diabetes, and other metabolic disorders.
Challenges of oral NAD+ supplementation: Despite the potential benefits of boosting NAD+ levels, taking NAD+ orally is not a straightforward solution. This is because:
Poor bioavailability: Oral NAD+ supplementation has poor bioavailability, meaning that only a small fraction of the ingested NAD+ is absorbed into the bloodstream.
Gut metabolism: NAD+ is metabolized by enzymes in the gut, which further reduces its availability to the body.
Inefficient conversion: When NAD+ is absorbed, it may be converted back to its inactive form, NAM, by the enzyme NADase.
Alternative NAD+ precursors: Researchers are exploring alternative precursors of NAD+ that might be more effective in boosting NAD+ levels. These precursors include:
Nicotinic acid (NA): NA is a direct precursor of NAD+ and has been shown to increase NAD+ levels in certain tissues.
Nicotinamide riboside (NR): NR is a precursor of NAD+ that is more stable than NAD+ itself and has been shown to increase NAD+ levels in mice.
Nicotinamide mononucleotide (NMN): NMN is another precursor of NAD+ that has been shown to increase NAD+ levels in mice and is currently being studied for its potential benefits in humans.
Nicotinamide adenine dinucleotide ribose (NAR): NAR is a form of NAD+ that contains ribose instead of deoxyribose. It has been shown to increase NAD+ levels in certain tissues.
These alternative precursors are being investigated for their potential to improve NAD+ levels and provide therapeutic benefits. However, more research is needed to understand their efficacy and safety in humans fully. Intravenous infusion of NAD+ remains the most effective way to boost NAD+ levels, but alternative precursors may offer a more convenient and effective option.
The discovery of Sirtuins, a group of enzymes that depend on NAD and are linked to longevity, has opened up a new frontier in aging research. Recently, there has been a surge of interest in using the NAD/Sirtuin pathway to combat brain aging, and therapies based on this principle are expected to become available in the future.
A breakthrough in this field is the identification of nicotinamide riboside (NR) as a vitamin precursor of NAD with excellent oral bioavailability in both mice and humans. Studies have shown that a single daily dose of NR (1000 mg) can increase blood NAD+ levels by 270% within seven days. Additionally, NMN, another NAD+ precursor, is metabolized into NR, which is then converted into NAD+ inside cells.
In mice with metabolic impairments, NR supplementation has been linked to increased SIRT1 expression, reduced oxidative stress, and enhanced mitochondrial function. In a fly model of Parkinson’s disease, NR supplementation has been shown to reduce the loss of dopaminergic neurons and improve motor skills. Furthermore, NR supplementation has been found to reduce tau phosphorylation and enhance cognitive function in a mouse model of Alzheimer’s disease with DNA repair defects.
Another study demonstrated that NMN supplementation promoted mitogenesis in nematode neurons and improved cognitive decline caused by Alzheimer’s disease. In a rat model of Alzheimer’s disease, NMN reduced Aβ aggregation, enhanced spatial memory, and increased neuronal survival, partly by reducing reactive oxygen species (ROS). These findings suggest that NAD+ precursors like NR and NMN may hold promise in treating age-related brain diseases and improving cognitive function.
Longevity research has identified three important signaling pathways in the body that slow down the ageing process and promote health. They act as energy and nutrient sensors in the body and react to changes in our cells. Each pathway has its own mechanism that regulates bodily functions and the ageing process. All three pathways work together synergistically and are essential for our organism. However, they have different effects on the processes that influence our longevity and on different metabolic pathways. AMPK, Sirtuins, mTOR: Pathways to Longevity.
Sirtuins – the switches of longevity Sirtuins are special proteins in the body that play an important role in controlling our genes. To understand how they do this, we first need to visualize how our DNA is packaged in cells. Imagine our DNA as an incredibly long string – if you strung the DNA of all the cells in our body together, it would cover a thousand times the distance from the Earth to the sun! Ultimately, this enormous length has to fit into our tiny cells. To make this possible, our body winds DNA onto tiny “coils” called histones. The DNA packaged in this way is then neatly stowed away in the cells. This is where the sirtuins come into play. They have the ability to modify the histones, which influences which genes can be read and which cannot. They act like switches that can turn certain genes on or off. This is why they are also known as “epigenetic regulators”.
NAD – without this coenzyme, sirtuins are powerless However, in order to operate these switches and activate our longevity genes, the sirtuins require a special coenzyme called NAD (nicotinamide adenine dinucleotide). With increasing age, however, the amount of available NAD in the body decreases. Without this essential cofactor, the sirtuins can no longer work effectively and their activity decreases. It is assumed that this is one of the reasons why we become more susceptible to diseases as we age.
AMPK – the energy conductor of the cell Finally, adenosine monophosphate-activated protein kinase (AMPK) also plays an important role. AMPK is an enzyme in our cells that influences insulin sensitivity and glucose uptake in the cells. It is like a guardian that constantly checks whether our cells have enough energy. When energy becomes scarce, AMPK kicks into action and ensures that more energy is made available.
At the same time, AMPK inhibits the antagonist mTOR (“mechanistic target of rapamycin”), which controls energy production in our cells. If mTOR is too active, the cells use more energy to control anabolic processes. AMPK therefore ensures that our cells use their energy efficiently when food is scarce. However, AMPK does even more for our cells. It helps them extract energy from fats and promotes autophagy, a process in which cells cleanse and rejuvenate themselves.
AMPK and health: the key role in metabolic processes The activation of AMPK can be influenced by various factors, and there are several reasons why many people have difficulty activating AMPK effectively:
Sedentary lifestyle and lack of physical activity: An inactive lifestyle and lack of physical activity can lead to insufficient AMPK activation. AMPK is activated by muscle contractions during exercise, but people who do little or no exercise may have reduced AMPK activity.
Unhealthy diet: An unbalanced diet with an excess of calories, especially carbohydrates and fats, can impair AMPK activation. High-calorie intake, especially from poor sources, can lead to an increase in ATP (adenosine triphosphate) and hinder AMPK activation.
Insulin resistance and obesity: People with insulin resistance or obesity often have problems activating AMPK. Insulin resistance can disrupt the signaling pathway of AMPK, leading to decreased activity of AMPK. Obesity can also impair the function of AMPK in fat cells.
Ageing process The aging process tends to lead to a decrease in AMPK activity. This can contribute to older people having difficulty activating AMPK effectively, which can have an impact on metabolism and energy homeostasis. Energy homeostasis describes the balance between supplied and released energy that the body needs for optimal performance.
Genetic factors Individual genetic predisposition can also play a role in AMPK activation. Some people have genetic variations that can affect AMPK function.
Chronic stress Chronic stress can disrupt energy homeostasis and inhibit AMPK activation. Stress hormones can affect AMPK signaling pathways, interfering with normal activation. Insufficient activation of AMPK can accelerate the ageing process and shorten life span and especially health span. The diabetes drug metformin and the natural plant compound quercetin can activate the AMPK signaling pathway in the body and improve insulin sensitivity.
How you can activate AMPK Adenosine monophosphate-activated protein kinase (AMPK) activation can be achieved in a variety of ways, including lifestyle changes, diet, exercise and certain medications. Here are some strategies to activate AMPK:
Regular physical activity
Aerobic training: Endurance training such as running, cycling and swimming can activate AMPK as it affects ATP and AMP levels
Resistance training: Strength training can activate AMPK, especially in the muscular system
Calorie restriction and interval fasting Reduced calorie intake and intermittent fasting (interval fasting) can activate the AMPK signaling pathway as they lead to an increase in AMP relative to ATP.
Healthy diet
Low-fat, high-fiber diet, low in saturated fat and rich in fiber, can support AMPK activation
Foods that promote AMPK: Green tea, curcumin (in turmeric), Resveratrol (in red grapes) and Omega-3 fatty acids (in fish) can activate AMPK
Metabolic stressors Cold or heat therapy and sauna visits can generate metabolic stress and activate AMPK
Dietary supplements Certain supplements can support AMPK, e.g. berberine, alpha lipoic acid and Quercetin. Nicotinamide mononucleotide (NMN) is a chemical that is approved as a dietary supplement in Germany and Europe.
Medications Some medications, such as metformin (a diabetes medication) and AICAR (an AMPK activator), can support AMPK activation.
However, it is important to note that any lifestyle changes, such as taking supplements or medications, should always be made in consultation with a doctor. The individual response to these interventions can vary from person to person and is always dependent on various factors such as health status, genetic predisposition, and current medications.
Is mTOR the bad cop? Longevity requires a fine balance. mTOR, or “mechanistic Target of Rapamycin”, is a key player in our bodies when it comes to cell division and growth. When our body has plenty of energy, mTOR is activated and uses this excess energy to promote muscle and tissue building. An example of the effect of mTOR can be found in people who exercise regularly and consume a lot of animal protein. Through their diet and exercise habits, they increase the activity of mTOR in their bodies, which leads to an increase in muscle mass.
This is particularly important in old age, as maintaining and building muscle mass can protect against sarcopenia, age-related loss of muscle mass, and general frailty. However, as with many things in life, there is a downside. Excessive activity of mTOR can suppress the activity of our longevity genes. From an evolutionary perspective, this makes sense: when there is enough food and therefore energy available, the body focuses on growth and reproduction rather than longevity. In times of abundance, it is more about survival than about the longevity of the individual. It is therefore important to find a balance in mTOR activity to support our health and fitness as well as our longevity.
Plant-based proteins and intermittent fasting: finding the balance with mTOR and reaping its benefits We all need mTOR to build new cells and maintain our muscle mass. But: excessive mTOR activity has a negative effect on our longevity. An effective way to regulate mTOR activity is to practice moderate calorie restriction or intermittent fasting.
Both strategies can help to temporarily inhibit mTOR and thus maintain balance in the body. It is also important to pay attention to our diet. Animal protein from meat, fish, and dairy products can stimulate mTOR and thus promote cell growth and aging. A healthier alternative is plant-based proteins, which are found in foods such as lentils, beans, and pseudocereals like quinoa. They stimulate mTOR less and should therefore be the preferred main source of protein in our diet.
Conclusion AMPK, sirtuins and mTOR are the three most important longevity players. On a cellular level, their interaction determines whether or not our body is geared towards longevity. Sirtuins are important longevity switches in our cells. They work together with NAD and help to activate our longevity genes. AMPK and mTOR are two enzymes in the body that work as antagonists. Studies have shown that increased AMPK activity leads to an increased lifespan and healthspan, promotes autophagy and improves insulin sensitivity. Its counterpart mTOR, on the other hand, is active when there is an energy surplus and uses this to initiate anabolic processes such as muscle building. While mTOR is essential for the body, a sustained increase in mTOR activity is associated with inhibition of longevity genes.
To promote a balance of AMPK and mTOR, moderate calorie restriction, intermittent fasting or the consumption of plant protein instead of animal protein is suitable. Micronutrients such as Quercetin also help to activate the AMPK pathway, inhibit mTOR and boost longevity processes.
In this episode of the Lifespan Podcast, Dr. David Sinclair and Co-host Matthew LaPlante dive deeply into the science of non-dietary interventions that mimic adversity and promote health. They begin by highlighting how different types of physical activity (i.e., low-intensity aerobic exercise, high-intensity aerobic exercise, and weight training) protect against age-related disease and enhance longevity.
David and Matthew additionally highlight the latest evidence behind hyperbaric oxygen therapy, cold therapy, and heat therapy. As they discuss different adversity mimetics, they also explain how these interventions influence aging at the molecular and physiological levels.
In this episode, Harvard professor Dr. David Sinclair and co-host Matthew LaPlante discuss how frequently we should eat, what food we should avoid, and what food we should pursue. They discuss the science behind how a “low energy state,” which can be induced by a period of fasting, combats aging and promotes health. They also walk through research that points to the benefits of a mostly plant-based diet for slowing aging and offer key insights into when to eat and what to eat to maximize longevity.
In this podcast episode, Dr. David Sinclair and co-host Matthew LaPlante discuss why we age. In doing so, they discuss organisms that have extreme longevity, the genes that control aging (i.e. mTOR, AMPK, Sirtuins), the role of sirtuin proteins as epigenetic regulators of aging, the process of “ex-differentiation” in which cells begin to lose their identity, and how all of this makes up the “Information Theory of Aging”, and the difference between “biological age” and “chronological age” and how we can measure biological age through DNA methylation clocks.
An interview by neuroscientistAndrew Huberman with David Sinclair, Professor of Genetics at Harvard Medical School and an expert researcher in the field of longevity.
In this podcast episode, Andrew Huberman and David Sinclair discuss the cellular and molecular mechanisms of aging and what we all can do to slow or reverse the aging process. They discuss (intermittent) fasting and supplementation with Resveratrol, Metformin, and NMN.
They also discuss the use of caffeine, exercise, cold exposure, along with food choices for offsetting aging and promoting autophagy, the process of clearing the organism of dead cells. And they discuss the key blood markers everyone should monitor to determine their biological versus chronological age.
It rarely happens that top scientists talk in easily understandable words and provide such a wealth of useful advice. We therefore strongly recommend listening to or even watching this podcast episode – these two hours might belong to the best investment of your valuable time, ever! Since – who does not want to stop aging?!
