Nicotinamide adenine dinucleotide (NAD+/NADH) has been implicated in potentially promoting healthspan and lifespan based on extensive research since the 1990s.
During my studies in the 1990s, I explored the function of NAD molecules. I discovered that the NADH coenzyme is critical in regulating metabolism, particularly within the mitochondria, which are the cells' energy factories. NADH provides electrons crucial for converting food into energy. Maintaining an optimal level of NADH is essential for DNA repair and promoting cellular function and health.
I also learned that NADH plays a pivotal role in cellular signaling, with DNA repair and telomere maintenance crucial for optimizing NADH levels. These functions of NADH are closely associated with promoting a healthy lifespan, particularly delaying cognitive decline and impairment, which I covered in previous stories.
Research into NADH is very active and extensive. For example, Pubmed indexed over 94000 scientific and clinical reports on this coenzyme. However, as documented in this 2020 paper, despite several decades of active investigation and numerous possible biochemical mechanisms of action suggested, only a few randomized and adequately powered clinical trials of NAD upregulation as a therapeutic strategy have occurred.
Recent studies suggest that NADH may have neuroprotective effects and could potentially play a role in the prevention or treatment of neurodegenerative diseases like Alzheimer’s and Parkinson’s. NADH is also implicated in the aging process, with some research suggesting that its decline with age may contribute to age-related decline in cellular function.
Without going into too much scientific and technical details, I will introduce the critical function of NAD+ and NADH explaining differences, give valuable insights from the literature, and discuss its safety and supplementation requirements.
What is NAD+ and NADH and What are the differences?
Nicotinamide Adenine Dinucleotide (NAD) is a coenzyme in all living cells. It plays a critical role in cellular energy production. It involves numerous cell metabolic processes.
As documented in this paper, NAD+ is an important metabolite in cell homeostasis that acts as an essential cofactor in oxidation-reduction (redox) reactions in various energy production processes, like the Krebs cycle, fatty acid oxidation, glycolysis, and serine biosynthesis.
High NAD+ levels are required since they also participate in many other non-redox molecular processes, such as DNA repair, posttranslational modifications, cell signalling, senescence, inflammatory responses and apoptosis.
NAD is a critical player in cellular respiration, specifically in oxidative phosphorylation, where it helps transfer electrons from nutrients to the electron transport chain in mitochondria. It is a coenzyme in several enzymatic reactions, including metabolizing carbohydrates, fats, and proteins.
NAD+ refers specifically to the oxidized form of NAD. NAD+ acts as a coenzyme in various metabolic reactions, accepting electrons and becoming reduced to NADH.
NAD and NADH are critical molecules in cellular metabolism and energy production. NAD, in its oxidized form (NAD+), accepts electrons during metabolic reactions, while NADH, the reduced form, donates electrons during cellular respiration, generating ATP.
Their interconversion is tightly regulated and essential for maintaining cellular redox balance. Redox reactions, where molecules undergo oxidation and reduction, are fundamental to biological processes like cellular respiration and photosynthesis, facilitating energy production and nutrient metabolism.
The NADH/NAD+ ratio maintains cellular redox balance and proper cellular function. Disruptions in this ratio have been implicated in various diseases and aging processes.
The role of NADH in cellular metabolism and energy production has led to investigations into its potential as a therapeutic target for metabolic disorders and age-related conditions. Understanding redox reactions is crucial across various fields due to their role in essential chemical processes and reactions.
NADH is involved in DNA repair mechanisms and regulates specific cell signaling pathways. NADH levels have been linked to overall energy levels and vitality. Low levels of NADH may result in decreased energy production and fatigue.
Various health style factors, including diet, exercise, stress, and certain medical conditions, can influence NADH levels. Maintaining optimal NADH levels is necessary for overall health and well-being.
Imbalances in NADH levels have been associated with health conditions, including chronic fatigue syndrome, depression, and metabolic disorders.
Brief Insights from the Literature from the 1990s to 2020s
Low NADH in the body is linked to several metabolic problems. I came across common issues in the medical literature: weight gain, chronic fatigue syndrome, and cardiometabolic issues. In this section, I highlight a few outstanding papers giving us valuable perspectives from last three decades.
Studies in mid 1990s and early 2000s highlighted the crucial roles of NAD+ and NADH in various biological processes, beyond energy metabolism, including cell death, calcium regulation, and gene expression. These molecules exert their effects by controlling numerous enzymes dependent on NAD+/NADH, such as dehydrogenases and sirtuins.
This 1999 clinical study evaluated the efficacy of NADH, like ENADA, the stabilized oral absorbable form, in a randomized, double-blind, placebo-controlled crossover study in patients with chronic fatigue syndrome. It concluded that NADH may be a valuable adjunctive therapy in the management of chronic fatigue syndrome.
While investigating its safety, I found these researchers studied the safety of NADH in 80 rats for 26 weeks in 2002. They gave one group ENADA/NADH 5 mg tablets daily, while the other got fake pills. No rats died or showed side effects from the treatment. Treated female rats gained more weight and ate more, but males didn’t change. Tests showed no differences between the groups in blood, urine, or organ health. The dosage given to rats was much higher than what humans usually take, but ENADA/NADH 5 mg tablets were still considered safe.
As documented in this 2012 review in Endocrinology and Metabolism, several studies have focused on how changes in NAD(+) and NADH levels impact signaling pathways in cells. Proteins like SIRT1, SIRT3, PARP1, PARP2, and CtBP are particularly interesting because they connect cellular redox changes to immediate metabolic effects and long-term transcriptional adaptations to exercise.
This 2018 review examined how filamentous fungi adjust their metabolic mechanisms under hypoxic conditions to maintain NADH and NAD+ balance. It explored how changes in intracellular redox balance influence the production of secondary metabolites, which can be regulated through Nudix hydrolase A (NdxA)-dependent NAD+ degradation, impacting sirtuin A’s HDAC activity.
As pointed out in this review, recent research has sparked renewed interest in NAD+ due to its influence on crucial signaling processes linked to addiction neurobiology. Studies suggest that increasing intracellular NAD+ levels could be a potential strategy for managing addictive behaviors, reducing cravings, and alleviating withdrawal symptoms in individuals with food addiction or substance abuse.
While clinical evidence on NAD+ treatment for addiction is limited, this 2020 review in MDPI highlighted its potential to impact addiction neurobiology and serve as a beneficial intervention against addictive behaviors.
This 2022 paper discussed the possibilities of NAD+ for cancer. To meet the demands for redox and non-redox functions of NAD+ in tumor cells, they must maintain high NAD+ levels, mainly through the salvage pathway, with NAMPT being the key enzyme.
Researchers pointed out that NAMPT, identified as an oncogene in certain cancers, is considered a potential target for cancer treatment. Inhibiting NAMPT reduces NAD+ levels, inhibiting ATP synthesis, decreased tumor cell growth, and apoptosis. Consequently, specific NAMPT inhibitors have been developed and are undergoing clinical trials, highlighting NAD metabolism as a potential target for cancer therapy.
This 2023 paper informed that in 2022, tuberculosis affected 10.6 million people, causing 1.6 million deaths. Current treatment involves lengthy multi-drug regimens, prompting the need for more effective strategies against Mycobacterium tuberculosis infections. Previous research indicated that simultaneous inactivation of type 1 (Ndh-1) and type 2 (Ndh-2) NADH dehydrogenases can kill Mtb.
The paper informed NADH dehydrogenases serve two key roles: NADH oxidation and electron entry into the respiratory chain. This study reveals that the bactericidal effect arises from impaired NADH oxidation. Importantly, researchers demonstrate that synthetic lethality of Ndh-1/Ndh-2 can be achieved through simultaneous chemical inhibition, offering promise for tuberculosis drug development programs.
Do we need to supplement with NADH?
I have always believed that no supplement can replace nutrition from whole foods. However, there may be times when we need supplements. For example, some health conditions may require supplementation based on informed advice from qualified healthcare professionals.
Our bodies can convert niacin (B3) into NAD. Therefore, when we consume adequate amounts of niacin through our diet or supplementation, the body should have sufficient building blocks to produce NAD unless there are underlying health conditions.
NADH supplements are publicly available over the counter in many countries. They are considered safe, but some countries do not allow it. I used it for a while and documented my experience in a story in 2021. It was highly expensive (e.g 30 tablets, around $100) in reliable companies in the US.
I experimented with it because I read exciting reviews in the online health, fitness, and nutrition communities. I found out that it has been used since the 1970s. I studied the molecule for cognitive function in the 1990s. However, the mechanism still needs to be clarified. The problem with supplements is a lack of research. Most of the endorsements are anecdotal.
From my research and discussion with health professionals, NADH supplementation may benefit people experiencing chronic fatigue, seeking cognitive enhancement, coping with age-related decline, or managing certain neurological conditions. NADH supports cellular energy production, cognitive function, and may offer neuroprotective effects.
However, it is crucial to consult with qualified healthcare professionals before starting NADH supplementation, especially for people with underlying health conditions or those taking medications, to determine its appropriateness, dosage, and potential risks. It is also essential to buy them from reliable and trusted sources.
Manufacturing NADH supplements involves careful selection of microorganisms, controlled fermentation, extraction, purification, formulation, and quality control processes to produce high-quality supplements for consumer use. Therefore they are very expensive.
Conclusions and Takeaways
NADH is a critical coenzyme involved in various metabolic processes and cellular functions. Understanding its mechanisms of action, impact on health, implications for disease, and potential therapeutic practices can provide insights into maintaining optimal health and well-being.
Fundamental lifestyle factors like regular exercise, stress management, and restorative sleep help maintain optimal NADH levels for cellular and mitochondrial health. As a pivotal metabolite, NADH naturally occurs in the body. It plays a vital role in every cell’s energy production.
Strategies to support NADH levels include consuming a balanced diet rich in nutrients that support its synthesis, such as niacin (vitamin B3) and other B vitamins. I wrote a detailed article about niacin’s role in the brain and heart.
As a supplement, NADH is the active coenzyme form of vitamin niacin (B3). Some dietary supplements contain NADH precursors or NADH itself, although the efficacy and safety of these supplements are still under investigation. I found NADH’s research and anecdotal testimonials compelling. However, despite all this, I am still unsure whether to supplement with NADH.
Some may need supplements to address nutrient deficiencies and underlying health conditions. Some people can use them for preventative maintenance. It is an individual matter. However, it is vital to discuss supplementation needs with qualified healthcare professionals.
Thank you for reading my perspectives. I wish you a healthy and happy life.
If you found this story helpful, you may also check out my other articles on NewsBreak. As a postdoctoral researcher and executive consultant, I write about important life lessons based on my decades of research and experience in cognitive, metabolic, and mental health.