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Orthomolecular Medicine News Service, March 22, 2024

The Vital Role of NAD+ and Niacin in Longevity and Well-being

Richard Z. Cheng, Sarah Myhill and Atsuo Yanagisawa

OMNS (Mar 22, 2024)


The paper delves into the critical role of NAD+ and its precursor, niacin, in health, aging, and disease management. It highlights the decline in NAD+ levels with aging, associated with age-related diseases, and the potential therapeutic benefits of restoring NAD+ through precursors like niacin. Boosting NAD+ levels have shown significant improvements in cardiovascular health by reducing blood pressure and arterial stiffness. Moreover, niacin supplementation exhibits anti-inflammatory effects and plays a crucial role in neurological health conditions like Alzheimer's and Parkinson's diseases. Studies also suggest that niacin may have a preventive effect on cancer and contribute to longevity by enhancing immune function and metabolic homeostasis. Overall, the research underscores the pivotal impact of NAD+ and niacin on well-being, longevity, and disease prevention, emphasizing the need for further exploration into targeted strategies for maintaining NAD+ availability through supplementation with its precursors including niacin.

NAD+ levels decline with aging

NAD+ decline is a key feature of aging and cancer, and its restoration through precursors may offer therapeutic benefits (Demarest 2019, Khaidizar 2021). NAD+ levels decline with aging, a phenomenon attributed to increased consumption by NAD+-consuming enzymes such as PARPs, SARM1, sirtuins, and CD38 (Schultz 2016, Strømland 2021). This decline has been observed in various species, including humans, and is associated with age-related diseases (Peluso 2021, Clement 2019). The decline in NAD+ levels is accompanied by an increase in the reduced form of NAD+ and NADP+ (Clement 2019). This age-related decline in NAD+ levels is linked to metabolic dysfunction and age-related diseases (Chini 2017). However, the evidence for this decline is limited and often restricted to a single tissue or cell type (Peluso 2021). Further research is needed to better understand the role of NAD+ in aging and to develop targeted strategies to maintain its availability (McReynolds 2020).

Boosting NAD+ levels improve cardiovascular health

A growing body of research suggests that boosting NAD+ levels can improve cardiovascular health. Chronic supplementation with NAD+ precursors, such as nicotinamide riboside, is well-tolerated and effectively elevates NAD+ levels in healthy middle-aged and older adults, potentially reducing blood pressure and arterial stiffness (Martens 2018, Rotllan 2021, Freeberg 2023). NAD+ precursors are safe and can increase NAD+ levels in multiple tissues (Freeberg 2023). Boosting NAD+ metabolism in cardiovascular diseases has the potential benefits (Matasic 2018). NAD+ repletion can induce health benefits in age-related cardiovascular and metabolic disease models (Kane 2018). The positive effects of NAD+ replenishment in preclinical models of cardiovascular diseases were noted (Abdellatif 2021), including the potential of nicotinamide mononucleotide as a nutraceutical against cardiac aging (Wei 2021). Mechanistic evidence, showing that boosting NAD+ levels can improve mitochondrial respiration and reduce proinflammatory activation in heart failure patients was shown (Zhou 2020).

NAD precursors and hallmarks of aging

NAD+ is a critical metabolite that declines with aging and is associated with age-related diseases (Lautrup 2023). Its depletion contributes to mitochondrial dysfunction, a hallmark of aging (McReynolds 2019). NAD+ precursors, such as niacin, nicotinamide riboside and nicotinamide mononucleotide, have shown potential in promoting healthy aging and improving neurodegeneration (Reiten 2021). These precursors have also been linked to lifespan extension and redox homeostasis (Lin 2015, Braidy 2019). Boosting NAD+ levels may counter aging-associated pathologies and age-related diseases (Aman 2018). The NAD+-mitophagy axis, which regulates mitochondrial homeostasis, is a promising therapeutic target for aging and neurodegenerative diseases (Aman 2018). NAD+ precursors have been shown to improve glucose and lipid metabolism, reduce weight gain, and protect the heart from ischemic injury (Bhasin 2023). Age-related changes in NAD+ metabolism in the brain have been linked to Alzheimer's disease (Braidy 2010).

Comparison of NAD+ Precursors in Biological and Therapeutic Effects

NAD+ precursors, including niacin, niacinamide (NAM), and NMN, play crucial roles in cellular processes and have garnered attention for their therapeutic potential. Here is a comparison of these precursors based on their biological effects and FDA approval status:

  1. Niacin (NA):
    1. Niacin has been established as an approved drug for the treatment of certain conditions (Yaku 2023).
    2. It is known for its role in redox reactions and as a signaling molecule that controls key processes like energy metabolism and cell survival (Rajman 2018).
    3. Niacin has been shown to delay the onset of diabetes mellitus type 1 in experimental models and prevent inflammation and atherosclerosis in animals (Rotllan 2021).
  2. Niacinamide (NAM):
    1. Niacinamide has demonstrated neuroprotective effects and reduced infarct size in experimental models (Rajman 2018).
    2. Studies have shown that NAM administration did not cause adverse effects and prevented inflammation and atherosclerosis in animals (Rotllan 2021).
  3. Nicotinamide Mononucleotide (NMN):
    1. NMN has shown promising therapeutic effects, including reducing infarct size in experimental models (Rajman 2018).
    2. Recent evidence suggests that NMN treatment replicated the neuroprotective effects seen with NAM administration (Rajman 2018).

In summary, all three NAD+ precursors have shown beneficial effects in various studies. While niacin is an approved drug with established benefits, niacinamide and NMN have demonstrated neuroprotective effects and potential therapeutic applications. Further research is needed to fully understand the efficacy of these precursors in humans and optimize their therapeutic outcomes.

Comparison of niacin and NAM, NMN on lipid metabolism

Niacin and its derivatives, such as NAM and NMN, have shown effects on reducing LDL-cholesterol and increasing HDL-cholesterol levels. Niacin, in pharmacological doses, acts as a lipid-modulating drug that increases HDL levels, which are crucial for cholesterol scavenging and transport to the liver (Rajman 2018). It has been found to reduce non-HDL cholesterol levels and cardiovascular events (Rajman 2018). Niacin also plays a role in stabilizing ApoA-I and preventing the uptake of HDL in the liver, thereby increasing HDL availability for cholesterol scavenging (Rajman 2018).

On the other hand, NAM supplementation has shown significant effects on improving lipid metabolism, particularly in patients with cardiovascular disease and dyslipidemia (Zhong 2022). While NAM itself may not directly improve lipid metabolism, it is essential in the NAD+ pathway, which influences lipid levels. NMN, another precursor, has been linked to improving muscle performance and increasing NAM levels in the body (Pirinen 2020).

In summary, niacin has a direct impact on lipid metabolism by increasing HDL levels and reducing non-HDL cholesterol, while NAM and NMN play roles in the NAD+ pathway that indirectly affect lipid metabolism. Each of these compounds offers unique benefits in managing cholesterol levels.

Advantages of Niacin Over NAM and NMN

Niacin, a well-known NAD+ precursor, offers distinct advantages over nicotinamide (NAM) and nicotinamide mononucleotide (NMN) based on various studies and research findings:

  1. Metabolic Bypass Therapy:
    1. Niacin serves as a metabolic "by-pass" therapy, providing functional benefits through the suppression of mTOR signaling (Pirinen 2020).
    2. This unique characteristic of niacin highlights its potential in metabolic regulation and cellular processes.
  2. Approved Drug Status:
    1. Niacin has been established as an approved drug for specific therapeutic applications (Yaku 2023).
    2. Its approval status signifies its recognized efficacy and safety profile in clinical settings.
  3. Lipid Modulation and Health Benefits:
    1. Niacin has been shown to increase the use of lipids as energy substrates, improve cholesterol profiles, and promote SIRT1-target gene expression in adipose tissues (Romani 2019).
    2. These lipid-modulating effects of niacin contribute to its potential benefits for cardiovascular health and metabolic functions.

In summary, niacin's unique metabolic effects, approved drug status, and lipid-modulating properties distinguish it from NAM and NMN. While all three precursors play essential roles in NAD+ metabolism, niacin stands out for its established therapeutic benefits and specific mechanisms of action that make it a valuable option in promoting cellular health and metabolic balance.

Niacin supplementation improves cardiovascular health.

Niacin supplementation has been shown to improve cardiovascular health through various mechanisms. It inhibits acute vascular inflammation and improves endothelial function, independent of changes in plasma lipid levels (Wu 2010). It also improves the distribution of lipoprotein particle sizes and reduces inflammatory markers in patients with coronary artery disease (Kuvin 2006). Furthermore, niacin has been associated with a reduction in cardiovascular events, including coronary artery revascularization, nonfatal myocardial infarction, and stroke (Duggal 2010). However, the efficacy of niacin in reducing cardiovascular disease events has been challenged by the results of the AIM-HIGH trial (Lavigne 2013. Despite these conflicting findings, niacin has consistently shown benefits in preventing or treating atherosclerotic cardiovascular disease in various clinical trials (Guyton 1998). However, the role of niacin in managing cardiovascular disease outcomes in current practice remains uncertain (D'Andrea 2019, Garg 2017).

Niacin and inflammation

Niacin supplementation has been shown to have anti-inflammatory effects in various studies. Niacin was found to reduce oxidative stress and inflammation in rats with chronic renal failure (Cho 2009), to inhibit acute vascular inflammation and improved endothelial function (Wu 2010, Wu 2012), to alter lipoprotein particle size and distribution, and to reduce inflammatory markers in patients with coronary artery disease (Kuvin 2006). Niacin increased anti-inflammatory markers and decreased pro-inflammatory markers in mice with high-fat diet-induced obesity and rats with ulcerative colitis, respectively (Wanders 2013, Salem 2017). These findings were further supported by the findings that show that niacin downregulated the nuclear transcription factor-κB signaling pathway and attenuated lung inflammation in guinea pigs and rats with sepsis (Si 2014, Kwon 2011).

Niacin improves renal insufficiency

Niacin supplementation has shown promising results in ameliorating oxidative stress, inflammation, proteinuria, and hypertension in rats with chronic renal failure (Cho 2009). It has also been found to improve renal lipid metabolism and slow the progression of chronic kidney disease (Cho 2009b). Furthermore, niacin has been suggested as a potential treatment for dyslipidemia and hyperphosphatemia associated with chronic renal failure (Ahmed 2010). In patients with chronic kidney disease, low-dose niacin supplementation has been found to improve dyslipidemia, lower serum phosphorus levels, and increase glomerular filtration rate (Kang 2013). McConnell and Penberthy (McConnell 2021) reported improvement or reversal of renal insufficiency in more than 2 dozen patients with various stages of renal insufficiency by taking niacin along with sodium bicarbonate.

Niacin's effects on neurological health

Niacin plays a crucial role in neurological health, particularly in conditions like Alzheimer's disease (AD), Parkinson's disease (PD), emotional disorders, and schizophrenia.

  1. 1. Alzheimer's Disease.
    1. Association with AD: Dietary niacin intake has been inversely associated with AD, suggesting a potential protective effect against cognitive decline (Gasperi 2019).
    2. Biological Mechanisms: Niacin influences key biological processes like energy metabolism, mitochondrial functions, and calcium homeostasis, which are vital for brain functions such as neurotransmission, learning, and memory (Gasperi 2019).
    3. Clinical Trials: Studies have shown that niacin supplementation may help limit Alzheimer's progression by modulating microglial activity in the brain (Manjarrez 2022).
  2. Parkinson's Disease
    1. Niacin's Role: Increased niacin intake enhances striatal dopamine synthesis and restores optimal NAD+/NADH ratio in PD patients (Gasperi 2019).
    2. Clinical Trials: Research suggests that niacin enhancement can potentially maintain or improve quality of life in PD patients and slow disease progression (Chong 2021).
  3. Emotional Disorders and Schizophrenia
    1. Symptom Management: Niacin supplementation has been shown to combat symptoms like psychosis, disorientation, memory loss, and confusion in conditions resembling AD (Fricker 2018).
    2. Neuro-Inflammation: Niacin has been found to ameliorate neuro-inflammation in PD through specific receptors like GPR10 (Fricker 2018).

Niacin's effects on cancer

Niacin has been studied for its potential role in cancer prevention and treatment. Niacin supplementation increased the latency of carcinogenesis in rats, suggesting a protective effect (Boyonoski 2002). Niacin intake was found to be associated with reduction of risks of squamous cell carcinoma risks (Park 2017) and leukemia (Bartleman 2008). Niacin seems to have a protective effect on skin cancer in mice, possibly through its role in DNA repair and immune system regulation (Gensler 1999). These findings are consistent with the hypothesis that niacin deficiency may enhance carcinogenesis (Kirkland 2003, Jacobson 1995). Jacobson further developed a biomarker for assessing niacin status, which could be used to evaluate its potential role in cancer prevention (Jacobson 1993).

Niacin's effects on longevity

Niacin, a precursor to NAD+ and a key player in cellular metabolism, has been linked to longevity and improved health in several studies. Niacin has important roles in immune function, cellular metabolism and metabolic homeostasis, inflammation, oxidative stress and antioxidant defense, all of which are crucial for aging and age-related diseases (Li 2006, Cho 2009a, Mocchegiani 2008, Yaku 2018). Niacin supplementation can increase lifespan and reduce mortality, particularly in the context of cardiovascular health (Preuss 2011, Canner 1986). Niacin inhibits vascular inflammation and improves endothelial function, independent of changes in plasma lipids (Wu 2010). These findings collectively suggest that niacin supplementation may have a positive impact on longevity and health span, particularly in the context of cardiovascular health and cellular metabolism.

Niacin on energy metabolism, endurance and muscle health

Research on NAD+ boosters, particularly niacin, has shown promising results in improving energy metabolism, exercise endurance, and muscle health. Studies have demonstrated that niacin supplementation can increase NAD+ levels in both blood and muscle, leading to improvements in muscle strength, mitochondrial biogenesis, and body composition (Pirinen 2020, Remie 2020). However, the effects of niacin on insulin sensitivity, mitochondrial function, and other metabolic health parameters are still under investigation (Remie 2020). Niacin has also been found to have anti-inflammatory effects, which could be beneficial for muscle health (Elhassan 2019). Despite these positive findings, some studies have reported no significant effects of niacin supplementation on exercise performance (Stocks 2020, Kourtzidis 2016). Further research is needed to fully understand the potential of niacin as an NAD+ booster in improving energy metabolism, exercise endurance, and muscle health.

Contribution of Drs. Abram Hoffer, Andrew W Saul, and Other Orthomolecular Medicine Experts on Niacin

Dr. Abram Hoffer and Dr. Andrew W. Saul, along with other orthomolecular medicine experts, have made significant contributions to the understanding and utilization of niacin in healthcare. Dr. Hoffer, born in 1917, was a pioneer in the field, emphasizing the therapeutic benefits of niacin in treating various conditions like schizophrenia, arthritis, high blood cholesterol, learning disorders, and more (Passwater 2017). His extensive research and publications have revolutionized medical approaches towards natural healing and reduced reliance on pharmaceuticals.

Abram Hoffer, M.D., Ph.D., founder of the International Society for Orthomolecular Medicine (ISOM.Ca) (Carter 2019), was a pioneer in the field, emphasizing the therapeutic benefits of niacin in treating various conditions like schizophrenia, arthritis, high blood cholesterol, learning disorders, and more (Passwater 2017). His extensive research and publications have revolutionized medical approaches towards natural healing and reduced reliance on pharmaceuticals.

Niacin plays a crucial role in various metabolic pathways in the body. Hoffer's work highlighted the benefits of niacin in preventing atherosclerosis, hyperlipidemia, and related coronary diseases (Smith 2023). He emphasized that niacin is essential for optimal health due to its role as a precursor to NAD, an enzymatic co-factor in metabolic processes (Smith 2023). Hoffer's research suggested that high doses of niacin can be particularly beneficial for individuals with specific genetic backgrounds or health conditions, as it can help prevent and reverse diseases like schizophrenia, depression, cardiovascular issues, and even conditions like Alzheimer's and cancer (Smith 2023).

Moreover, Hoffer's studies indicated that niacin therapy could have positive effects on various health conditions such as arthritis, ADHD, mental illnesses, and even COVID-19 recovery (Smith 2023). He also explored the use of niacin to improve circulatory health and potentially address erectile dysfunction (Smith 2023). Hoffer's approach involved individualizing niacin doses based on each person's needs, with typical daily doses ranging up to 3,000 mg divided into three doses. He noted that niacin is generally safe and not toxic at tolerable doses but can cause flushing in some individuals (Hoffer 2015).

Hoffer's work on megavitamin therapy and orthomolecular medicine, although controversial in mainstream medical circles, has contributed significantly to understanding the potential benefits of high-dose niacin therapy for various health conditions (Wikipedia). While his ideas have faced criticism and skepticism from some quarters of the medical community, his research laid the foundation for exploring the therapeutic potential of niacin and other nutrients in treating diseases like schizophrenia and cancer (Wikipedia).

Abram Hoffer's research on niacin underscores its importance in maintaining overall health and its potential therapeutic benefits for a range of conditions. His work has shed light on the significant impact of niacin supplementation on disease prevention and treatment.

Dr. Saul, a prominent figure in orthomolecular medicine, has collaborated with Dr. Hoffer on several books, including "Niacin: The Real Story," (Saul 2023) which delves into the healing properties of niacin and its role in cardiovascular health (Saul 2023, Passwater 2017). Their work highlights the effectiveness of niacin in lowering cholesterol levels and preventing heart disease, emphasizing lifestyle changes alongside niacin supplementation for optimal health outcomes (Passwater 2017).

The research conducted by these experts underscores the importance of niacin as a vital nutrient with diverse health benefits. Their advocacy for natural healing approaches and the therapeutic potential of niacin has significantly impacted medical practices and continues to offer valuable insights into holistic healthcare solutions (Saul 2017).

Summary and Conclusion

In the realm of integrative medicine, the significance of NAD boosters like niacin in chronic disease management and anti-aging protocols cannot be overstated. The research presented underscores the pivotal role of NAD+ and niacin in promoting health, combating age-related diseases, and enhancing longevity. Niacin's ability to boost NAD+ levels, improve cardiovascular health, exhibit anti-inflammatory effects, impact neurological health positively, and potentially prevent cancer aligns seamlessly with the principles of integrative medicine. Incorporating NAD boosters like niacin into integrative medical management protocols offers a holistic approach to addressing chronic diseases by targeting underlying metabolic dysfunctions and age-related pathologies. The therapeutic potential of niacin in maintaining redox homeostasis, enhancing cellular metabolism, and modulating inflammation underscores its importance in anti-aging medicine. Therefore, integrating NAD boosters like niacin into integrative medical protocols can be a valuable strategy for optimizing health outcomes, managing chronic diseases, and promoting healthy aging.

Niacin stands out as a superior NAD booster compared to other alternatives due to its extensive history of research, FDA approval status, and well-documented health benefits. With a long-standing legacy in medical research, niacin has been extensively studied and endorsed by prominent figures in integrative and orthomolecular medicine like Abram Hoffer, MD. Niacin's FDA approval status and established safety profile further solidify its position as a reliable and effective NAD booster. The wealth of evidence supporting niacin's efficacy across various health domains positions it as a cornerstone in holistic approaches to health and longevity.

Niacin has been part of the integrative protocols for orthomolecular medicine practitioners such as one of the authors (RZC) for chronic disease management and anti-aging medicine on hundreds if not thousands of patients with excellent results. The usual dosages RZC recommends are between 500-2,000 mg/day. The dosage may be increased on certain conditions such as emotional or psychiatric disorders such as depression, anxiety, or schizophrenia. First, no significant side effects have been reported, except "niacin flush" which is expected and probably desired response. Improvements ranging from anxiety, depression even improvement in schizophrenia have been observed. Not being a trained psychiatrist, RZC was pleasantly surprised to be able to help psychiatric patients. RZC has also seen several cases of improvement of renal insufficiency. Niacin is also part of RZC's standard integrative cancer protocol and RZC has many cancer patients happily maintained on the integrative cancer management protocol, with at least improved quality of life and probably prolonged survival. RZC has a high number of autoimmune disease patients under his care. Reversal or significant improvement of autoimmune diseases with niacin as part of the integrative protocol is common among RZC's patients.

Atherosclerotic cardiovascular disease (ASCVD) is one of the most interested areas for RZC simply because it's the world's No. 1 killer. RZC has improved/reversed 6 cases ASCVD so far (Cheng 2023). RZC himself personally takes between 2,000 - 3,000 mg of niacin (the plain instant release form) with a meal, as part of his own nutrition supplement package. He has seen his lipid profile improving and insulin resistance markers (HOMA-IR, T/HDL, TyG) completely reversed to normal levels. Very importantly, his physical strength and endurance have improved significant which allows him (a 64-year man) to be able to compete with young men often 10-30 years younger on badminton courts for 2-3 hours each time and 3 times a week.


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