Improving NAD Status to Support Cellular Resilience
Nicotinamide adenine dinucleotide (NAD) is critical for cellular function [1-3]. Found in every one of our trillions of cells, NAD catalyzes chemical reactions required to both generate energy and build and repair the molecules that make up our bodies.
Despite being essential for cellular health, NAD is not a constant resource. Fortunately, our cells have several mechanisms in place to create more NAD [4-6] using smaller building blocks from our diet. These building blocks—often called NAD precursors by scientists—include forms of vitamin B3. NAD is so important for our cells that not getting enough vitamin B3 can lead to a deficiency disease called pellagra.
Early research in the first half of the twentieth century helped establish recommended dietary allowances for vitamin B3, helping ensure we get enough dietary NAD precursors to avoid developing pellagra. With access to whole foods and B3-fortified grains, most people living in developed countries no longer need to worry about this disease.
Today we are now aware of a different kind of NAD insufficiency or inadequacy. As NAD research has advanced, we have learned more about how NAD depletion is linked to age, physiologic stress, and a variety of all-too-common disease states [7]. These findings have helped to expand the understanding of the role of NAD from a molecule that drives cells’ energy production to a molecule that is also vital for cellular defense and repair in the face of stress. This, in turn, has led to research examining the potential benefits of boosting NAD with intakes above the traditional B3 recommendations. Scientists are actively investigating the benefits of augmenting cells’ NAD levels to benefit cellular and whole-body health.
Beyond B3: Supporting Intrinsic Capacity by Increasing NAD Status Through Supplementation
Preclinical studies in animal models [8-12] are showing that increasing NAD status provides benefits well beyond prevention of pellagra, including improvements in basic cellular processes to support the health of a wide variety of tissues under stress. The benefits of nutritionally boosting NAD make sense given the fundamental importance of NAD for healthy cellular metabolism and energy production and the wide-ranging physiologic stresses we all face in the modern world.
The World Health Organization (WHO) defines Intrinsic Capacity (IC) as “...the composite of all the mental and physical capacities that a person can draw on and includes their ability to walk, think, see, hear, and remember”. In other words, IC is an indicator of a body’s (or cells’) ability to maintain key functions in the face of stress, whether it be aging, poor diet, lack of exercise, sleep deprivation or viral infection. In the modern world, we are all faced with a variety of these and other stressors each and every day. Our ability to maintain functionality in the face of these stressors, or our IC is a direct indicator of health - the better we respond to stress, the better our IC, the more resilient we are, the better our health. The same is the case at the cellular level, and NAD is a key factor in cells’ IC or resiliency.
IC can be organized into five different functional areas, or domains, including locomotion, cognition, vitality, sensory, and psychological. These five domains embody the basic IC definition from the WHO, but also represent key areas of research focused on NAD and its impact on cellular function and overall health.
As the domain names imply, each covers a core set of functions that collectively reflect the needs for healthspan - the ability to move, think, see, hear, remember, and recover. Locomotion represents physical functions, muscle strength and exercise. Cognition, as the name implies, represents all Intellectual functions, such as thinking and memory. Vitality is a more complex domain encompassing organ, metabolic and hormonal functions. Sensory, as its name implies, represents sight, smell, touch and hearing functions, while psychological represents emotions and feelings.
These IC domains include research aimed at how NAD depletion relates to physiological decline and disease in metabolically active tissues such as the brain, heart, liver, and skeletal muscle [13-16].
Although more clinical research is ongoing in humans to understand how increasing NAD specifically impacts health, results from animal studies provide exciting insights into the potential ways improving NAD status might one day be shown to benefit human health. Many clinical studies are now in progress to test whether any of the results shown in animal models can be translated to humans. This research can be organized according to the five IC domains.
COGNITION
Neurological Health
The brain requires a constant supply of oxygen and glucose to generate the energy required for healthy function. Despite its small size, the brain consumes approximately 20% of the entire body’s oxygen supply. Given its energetic requirements, it should come as no surprise that researchers are increasingly making connections between brain and mitochondrial health (mitochondria are “power horse” organelles found in most cells and are responsible for cellular respiration and energy production). In line with this idea, increasing NAD has been shown to improve mitochondrial function in mouse models of Alzheimer’s disease and a fruit fly model of Parkinson’s disease [17-23].
Neurons, the specialized communication cells that make up our brains, are also spread throughout the entire body. These peripheral neurons innervate our organs to deliver messages from central command and collect sensory input from the environment to send back to the brain. Studies in rodents have found that increasing NAD can help these neurons, too. In one study, increasing NAD helped mitigate sensory neuron damage and hearing loss in response to loud noises [24] Another study found that increasing NAD could help protect vision in a model of optic neuritis [25]. Two more studies showed that increasing NAD counteracted the symptoms of peripheral nerve damage caused by chemotherapy and diabetes [26, 27].
LOCOMOTION
Muscle Health
Our muscles, specifically the skeletal muscles that keep us moving, require NAD and healthy mitochondria to generate the energy needed to both contract and relax [28]. Several mouse studies have shown that replenishing NAD in conditions associated with decreased NAD can help maintain muscle function. Replenishing NAD helps improve mitochondrial and skeletal muscle function in aging mice and in mouse models of muscular dystrophy [29-31].
To better understand the relationship between NAD and muscle function, one group of researchers created genetically modified mice with artificially low levels of skeletal muscle NAD. These mice had decreased muscle mass, decreased endurance, and reduced mitochondrial function. These symptoms were attenuated or reversed through supplementation with NAD-boosting molecules [12].
In a recently published human clinical study, [32] researchers examined the effect of raising NAD levels on metabolic health, muscle metabolism, and mitochondrial function in overweight/obese men and women. Increased NAD was associated with minor beneficial changes in body composition (increase in lean mass and decrease in fat mass), as well as a significant elevation in skeletal muscle acetylcarnitine (a molecule that helps bring fuel into the mitochondria) concentrations.
VITALITY
Cardiovascular Health
Always beating, the heart requires large amounts of cellular energy to stay active. It is the most metabolically active organ in the body and contains more mitochondria than any other tissue in the body [3]. An overworked heart can go into metabolic overdrive, degrading the health of the heart’s mitochondria and cells. Several studies have found that boosting NAD improves both mitochondrial and cardiac function in animal models of heart failure [33-41].
A healthy heart is only one part of your overall cardiovascular health. As the heart beats, it forces blood through the vascular system—the extensive network of arteries, capillaries, veins—and delivers blood to all the tissues of the body. Animal studies have shown that increasing NAD can help support a healthy vascular system to help optimize healthy blood flow [42, 43]. An early human clinical trial found that nutritionally boosting NAD decreased blood pressure in some patients and also decreased arterial stiffness [44]. More research is needed to build on these preliminary results, and two clinical trials are in progress to follow up on this work studying larger numbers of subjects.
Past research has also demonstrated that NAD supplementation through NAD+ precursors increases or has a protective effect against declining NAD+ levels in the heart [45, 46]. In a recently published preclinical study, researchers specifically examined the effects of nicotinamide (NAM) and nicotinamide riboside (NR) on cardiac electrophysiology. It was found that both NR and NAM increased NAD and NADH levels. However, only NR indicated a potential antiarrhythmic effect. These results reinforce earlier preclinical findings that suggest increased NAD levels may have a beneficial impact on cardiac conditions and arrhythmias [34, 36].
Metabolic Health
The liver is a metabolically active tissue. The liver filters our blood, detoxifies chemicals, processes medications, and metabolizes nutrients from our food. Metabolism at the cellular level depends on NAD and the liver is one of many tissues that is sensitive to declining levels of NAD. Studies in mice have shown that increasing NAD can support healthy liver function, particularly when metabolically stressed by overnutrition or alcohol overconsumption [8, 11, 47].
Increased NAD also helps improve glucose tolerance in mouse models of diabetes, and more broadly helps counteract the whole-body metabolic consequences of a high-fat diet in mice [9, 27, 48] An early clinical trial found that twelve weeks of oral NR supplementation tended to decrease liver fat in older obese men but did not have any noticeable effects on other metabolic endpoints such as insulin sensitivity [49].
As described in the pre-print of the first ever clinical study evaluating the NAD metabolome (NADome) in human liver tissue, the investigators demonstrated that levels of NAD, NADP, NR, and nicotinic acid (NA) were significantly lower in alcohol related liver disease samples compared to healthy controls. They were also able to show that disease progression resulted in different NAD metabolite signatures that corresponded to other markers of liver dysfunction. The depression of the NADome was also correlated to functional impairment of immune defenses in the liver.
Innate Immunity
Increasing NAD levels also has positive effects on pro and anti-inflammatory cytokines and has been linked to maintained resilience and defense against stresses, including immune stress. In a recently publicized study, [50] researchers investigated the effects of SARS-CoV-2 infection on NAD levels in cell lines, infected ferrets, and a deceased patient’s lung. It was found that SARS-CoV-2 significantly impacted NAD related genes, thus affecting the production and use of NAD. Decreased NAD levels were conserved across the models and demonstrated induced poly (ADP-ribose) polymerases (PARPs) as part of the innate immune response. Gene expression analysis also indicated that virally exposed cells appear to preferentially seek out NR (as indicated by an increase in the levels of genes related to the NR metabolic pathway) to replenish NAD levels during infection.
SENSORY
Hearing
A study investigated the relationship between NAD levels and an animal model of age associated hearing loss [51]. The investigators used genetically bred Cockayne’s Syndrome (CS) mice with moderate (CSA) and more severe (CSB) symptoms. NAD levels were increased in the mice through NR supplementation, and resulted in hearing improvement, inhibited high frequency hearing loss, restored outer hair cell loss, and improved cochlear health. The improvements were observed to a greater magnitude in the more severe CSB mice than the CSA mice. In both groups, a reduction in inner hair cells was normalized with elevated NAD. This normalization improved neuronal communication and inner hair cell function in response to auditory stimuli, suggesting a rescue of high-frequency hearing loss. The authors suggested that increased NAD levels may also be beneficial in delaying or reducing age related hearing loss in humans.
PSYCHOLOGICAL
In a study investigating the connection of the gut microbiota and brain, the effects of increasing NAD levels through NR supplementation on a mouse model of alcohol-induced depression was examined [52]. NR was found to improve the alcohol-induced depressive behavior in the mice. NR in this study also decreased the levels of pro-inflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10 and TGF-β) cytokines (small proteins involved in cell communication) in the depressive mice brain indicating a potentially anti-inflammatory role of increased NAD. Brain inflammation has been linked to depression and other psychological disorders [53].
Additional research is needed in these areas to understand whether increased NAD status can improve these health outcomes in humans. But collectively, these examples demonstrate how maintaining or increasing NAD status improves cell and tissue resilience under conditions of physiologic stress or disease. By evaluating NAD research from the lens of the IC domains, we can connect complex, but impactful research findings to the WHO’s simple definition of IC, “the indicator of health.”
Is NAD Really an Anti-Aging Molecule?
Despite the sensational headlines you might come across online, NAD is not going to help you defy the inevitable march of time or add countless years to your life. NAD seems to have inherited this reputation, in part, based on mouse studies showing that increased NAD reverses physiological declines associated with aging [29, 31, 54]. Increasing NAD has also been shown to counteract mitochondrial defects associated with premature aging diseases in mice [55, 56]. While impressive, these findings need to be replicated in people before we can start proclaiming NAD to be a fountain of youth.
Instead of an “anti-aging” molecule, think of NAD as a “healthy aging” molecule. Rather than a single stressor, aging represents the accumulation of stress-induced damage over time. It is unlikely that boosting NAD will increase lifespan and make us live longer, but it has enormous potential to improve healthspan—the number of years we spend in good health—by enhancing our IC and resilience.
We know from numerous studies that NAD levels decline with age and this decline has been linked to a variety of age-associated conditions [48]. As a result, our ability to cope with stressors declines as we age, making it more important to nutritionally support our NAD as we mature. At a cellular level, increasing NAD supports mitochondrial health and cell resilience which are also known to decline with age. At the level of tissues and organs, the preclinical studies highlighted above show the potential for increased NAD status to address conditions such as heart failure and cognitive decline that typically become more common as we age. As we learn more about boosting NAD in humans from ongoing clinical trials it will be exciting to see whether the promise of increased NAD we see in animal models will translate to human health as well.
NAD elevation through dietary supplementation may be important throughout life for a variety of conditions. Many chronic health conditions, including obesity, diabetes, cancer, and heart disease are linked to lower NAD levels [7]. Users of NAD precursors have reported benefits with recovery, thus there is a need for rigorous clinical research related to NAD and injury recovery. Additionally, those with cognitive differences, such as autism [57] have also been shown to have either lower NAD levels or impairments in NAD metabolism when compared to their neurotypical counterparts, and thus there is a need for NAD supplementation research for these individuals as well. In many ways, we are just in the infancy in learning about the benefits of NAD. Stay tuned to AboutNAD.com to stay on top of the latest NAD research findings.
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