How does inflammation impact NAD levels in the body?

Both acute and chronic inflammation can disturb the NAD system. For example, viral infections like coronaviruses transcriptionally activate PARP enzymes, which consume NAD, leading to its depletion. Certain inflammatory conditions like COPD also show improved inflammatory markers with NR supplementation.

Can Nicotinamide Riboside (NR) supplementation help with chronic inflammation?

Yes, randomized controlled trials have shown that nicotinamide riboside (NR) at doses around a gram a day is anti-inflammatory, significantly lowering markers like IL6 and IL10 in human subjects, particularly in inflammatory conditions like COPD.

What lifestyle changes have the biggest impact on supporting NAD levels?

Addressing the root causes of chronic inflammation, such as obesity, chronic sleep deprivation, excessive alcohol consumption, and sedentary behavior, provides the biggest benefit for supporting NAD levels. Exercise is also crucial as it boosts NAD biosynthetic enzymes.

Does NR supplementation improve cognitive function and brain NAD levels?

Imaging experiments show that oral NAD precursors can increase brain NAD. Small clinical studies have indicated that NR improves cerebral blood flow in people with mild cognitive impairment, and a study on long COVID patients showed within-group improvements in executive function with NR.

Why is it better to take NAD precursors like NR instead of direct NAD supplements or NMN?

NAD molecules are too large and contain phosphates, preventing them from entering cells. Similarly, NMN (Nicotinamide Mononucleotide) has a phosphate group that blocks cellular uptake, requiring it to be broken down into NR before entering cells. NR, lacking these phosphates, can readily enter cells and then be converted into NAD.

What are the potential benefits of NR for peripheral artery disease?

A three-arm clinical trial for peripheral artery disease showed that NR supplementation improved patients' six-minute walk test performance, while placebo and NR plus resveratrol groups degraded. This suggests NR could be one of the first real medical indications for Niagen in an age-related disease population.

Are there safety concerns or cancer risks associated with NAD precursor supplementation?

Clinical data from Australian nicotinamide trials suggest that NAD boosting is cancer preventative at the population level, lowering the risk of non-melanoma skin cancer. While some animal studies on specific aggressive cancers exist, overall clinical evidence indicates that NR is safe, with testing up to 3g/day, and is listed as 'generally regarded as safe' by the FDA.

How was Nicotinamide Riboside (NR) discovered as an NAD precursor pathway?

Dr. Brener's research began by studying an NAD synthetase enzyme in yeast and humans. Realizing existing NAD synthesis diagrams were incomplete, he hypothesized an alternative pathway through a nucleoside, nicotinamide riboside. Experiments confirmed this NR pathway, uncovering a previously unknown route to synthesize NAD.

What are the primary biological roles of NAD in the body?

NAD co-enzymes are critical for three main biological processes: converting fuel into ATP for energy, building essential molecules like RNA, DNA, and lipids (anabolism), and repairing cellular damage, including DNA and detoxification of reactive oxygen species.

Key Moments

How To Boost NAD Levels To Fight Inflammation, Improve Recovery, and Slow Aging

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Science & Technology5 min read115 min video

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Key Moments

TL;DR

Dr. Charles Brenner discusses NAD, its role in energy, repair, aging, and inflammation, and NAD precursors like NR.

Key Insights

NAD levels are crucial for energy production, cellular repair, and gene regulation.

NAD levels may decline in specific tissues with age or disease, not necessarily in blood.

Inflammation, obesity, and sleep deprivation can negatively impact NAD systems.

Nicotinamide riboside (NR) is a safe and effective NAD precursor with demonstrated anti-inflammatory benefits.

Oral NR can increase NAD levels in the brain and may support cognitive function and cerebral blood flow.

Exercise is a vital support for NAD systems, potentially increasing NAD biosynthetic enzymes.

Sourcing and third-party testing are critical for supplement safety and efficacy.

THE FUNDAMENTAL ROLES OF NAD

Nicotinamide adenine dinucleotide (NAD) is a vital coenzyme essential for life, playing a critical role in three primary biological processes: converting fuel into ATP for energy, synthesizing new molecules (anabolism), and repairing cellular damage. NAD exists in different forms (NAD+, NADH, NADP+, NADPH) that facilitate these functions by transferring high-energy electrons. While often associated with energy production, NAD's involvement in building and repairing cellular components, including DNA and cell membranes, highlights its pervasive importance.

NAD LEVELS: AGE, DISEASE, AND TISSUE SPECIFICITY

Contrary to popular belief, human blood NAD levels may not significantly decline with age. However, NAD pools in specific tissues, such as the liver or brain, can be disturbed by aging, various diseases, or lifestyle factors like alcoholism. Conditions like mitochondrial disease, neurodegeneration, and even noise-induced hearing loss can impact tissue NAD. While blood NAD can be influenced by precursor supplements, tissue-specific declines remain a key area of research.

FACTORS STRESSING THE NAD SYSTEM

Several common health issues and lifestyle choices can negatively affect NAD metabolism. Chronic inflammation, often driven by conditions like obesity and insulin resistance, significantly stresses the NAD system. Sleep deprivation and disruptions to circadian rhythms also impair NAD synthesis and utilization. These factors can lead to increased consumption of NAD as the body attempts to combat oxidative stress and repair damage, potentially depleting available NAD for other essential functions.

NICOTINAMIDE RIBOSIDE (NR) AS AN NAD PRECURSOR

Nicotinamide riboside (NR), a precursor to NAD, has emerged as a promising supplement. Unlike NAD itself or nicotinamide mononucleotide (NMN), NR can efficiently enter cells and be converted into NAD. Clinical trials have shown that NR supplementation can reduce inflammation, a critical factor in many age-related diseases. While NAD itself cannot be effectively supplemented orally due to its poor cell permeability, precursors like NR offer a viable strategy to boost NAD levels.

NR'S IMPACT ON SPECIFIC CONDITIONS

Research indicates NR may benefit various health conditions. Studies suggest it can lower inflammation, potentially aiding in infectious diseases and autoimmune conditions. Promising results have been observed in peripheral artery disease, where NR improved walking distance in clinical trials. For neurodegenerative diseases, preliminary evidence shows NR can improve cerebral blood flow, though more research is needed on cognitive improvements. Furthermore, trials suggest potential benefits for non-alcoholic fatty liver disease, though further studies are warranted.

LIFESTYLE FACTORS AND NAD SUPPORT

Beyond supplementation, lifestyle choices significantly influence NAD levels. Exercise is a cornerstone, with evidence showing it boosts NAD biosynthetic enzymes and supports mitochondrial biogenesis. While rigorous data on NAD and specific exercise types are developing, any physical activity is better than none. For those with existing health issues, addressing root causes like obesity through weight loss or improving sleep quality, alongside lifestyle changes, is paramount. Supplementation with NR may then offer synergistic benefits.

DOSING, SAFETY, AND SUPPLEMENT QUALITY

Clinical trials often use doses of NR ranging from 500 to 1000 milligrams daily, with safety data supporting up to 3 grams per day in certain populations. The quality and source of supplements are critical, as the supplement industry faces challenges with product purity and contaminants. Third-party testing and certifications (like NSF) are recommended to ensure product integrity. While NAD boosting is generally considered safe and even preventative for certain cancers, individuals with existing medical conditions should consult a healthcare provider.

NAD IN CARDIOVASCULAR AND BRAIN HEALTH

NAD plays a role in cardiovascular health, with inflammation being a key driver of conditions like peripheral artery disease. NR supplementation has shown promise in improving exercise capacity in individuals with PAD. In the brain, oral NR has been shown to increase brain NAD levels and improve cerebral blood flow in individuals with mild cognitive impairment, suggesting potential benefits for cognitive function and overall brain health, particularly in the context of inflammation.

THE MECHANISM OF NR IN NAD BOOSTING

Nicotinamide riboside (NR) is recognized as a superior NAD precursor because it can readily enter cells. Once inside, it is phosphorylated to become nicotinamide mononucleotide (NMN), then further converted to NAD+. While NMN is also an NAD precursor, it often requires conversion back to NR to enter cells, making NR a more direct and efficient route. The enzymes involved, like NR kinases, become upregulated in conditions of metabolic stress, highlighting NR's role in supporting cellular NAD levels when demand is high.

NAD PRECURSORS AND FERTILITY

Animal studies, including those in mice, suggest that NR supplementation during pregnancy can improve offspring health. Offspring of supplemented mothers showed better lean mass, faster physical development, reduced fear and anxiety, and enhanced adult hippocampal neurogenesis. This may be related to improved maternal milk production and composition. While human data is limited, some fertility clinics recommend NR, and research into its role in human lactation and fertility is ongoing.

CIRCADIAN RHYTHMS AND NAD

Circadian rhythm disruption, common in shift workers and frequent travelers, can negatively impact the NAD system. The body's internal clock influences NAD synthesis and its utilization in metabolic processes. Maintaining consistent sleep-wake cycles and optimizing light exposure are crucial for supporting NAD. Supplementation with NR, particularly in the morning, might help mitigate some of the negative effects of circadian misalignment, though more research is needed in this area.

THE MICROBIOME'S INFLUENCE ON NAD

Emerging research suggests the gut microbiome plays a role in the human conversion of NAD precursors like NR and NMN into NAD. Studies indicate that NR supplementation can positively alter the gut microbiome. While the exact mechanisms are still being investigated, this interaction highlights the complex interplay between gut health, nutrient metabolism, and NAD status within the body.

SAFETY CONSIDERATIONS AND CANCER RISK

Overall, NAD boosting supplements, particularly NR, are considered safe. Long-term studies and population-level data from nicotinamide supplementation in Australia suggest NAD boosting does not increase cancer risk and may even be preventative for certain skin cancers. While some research in cell lines and mice has explored potential tumor growth acceleration with NAD precursors, these findings are not generally considered relevant to human cancer development. However, individuals undergoing cancer treatment should consult their doctor.

Mentioned in This Episode

●Supplements

●Tools

●Organizations

●People Referenced

Boosting NAD for Health and Longevity

Practical takeaways from this episode

Do This

Prioritize lifestyle changes: address obesity, chronic inflammation, and sleep deprivation.

Engage in regular exercise, as any form is better than none for boosting NAD biosynthetic enzymes.

Consider Nicotinamide Riboside (NR) supplementation at 500-1000mg/day, especially for workout recovery.

If taking NR for circadian misalignment (jet lag, shift work), time intake with your desired 'morning' cycle and combine with bright light exposure.

Ensure any NAD precursor supplements are third-party tested and from reputable sources to ensure purity and safety.

For those with overweight/obesity, explore medical options like GLP-1 medications in conjunction with resistance training.

Consult your doctor before taking supplements, especially if you have a pre-existing medical condition or are undergoing chemotherapy.

Avoid This

Do not solely rely on NAD blood tests for personal use; they are primarily useful for clinical trials.

Do not expect weight loss or insulin sensitization from NR monotherapy without underlying lifestyle changes or other medications.

Do not take oral NAD supplements, as NAD itself does not effectively enter cells; instead, opt for precursors like NR.

Do not take NMN orally, as it must break down into NR to enter cells and there are concerns about product purity.

Do not stack NR with resveratrol or tereselbeane, as these compounds have no proven benefit and may even negate NR's effects or raise LDL cholesterol.

Do not exceed 3 grams per day of NR supplementation.

Avoid large doses of nicotinic acid (niacin) due to uncomfortable 'flushing' side effects.

Common Questions

While often stated, there's no strong evidence that human blood NAD universally declines with age. However, NAD pools in certain tissues are likely disturbed with age, and specific disease states linked to aging can lower NAD levels in various organs.

Topics

Nicotinamide Riboside Inflammation Exercise Recovery Mitochondrial Health DNA Repair Cancer Prevention Peripheral Artery Disease Liver Health Supplementation Safety

Mentioned in this video

Organizations

NADMED

An NAD testing company that provides kits and reagents for clinical trial observations, though individual testing for personal use is not recommended by Dr. Brener.

FDA (Food and Drug Administration)

The regulatory body under which nutritional supplements fall. Niagen has gone through the process of being 'generally regarded as safe' and a 'new dietary ingredient' with the FDA.

University of Helsinki

Collaborated with Dr. Brener's group to discover that people with mitochondrial disease often have low blood NAD levels.

Supplements

Nicotinamide

Another NAD precursor vitamin, known to be safe and cancer-preventative, especially for skin cancer, as shown in Australian trials.

Resveratrol

A polyphenol that, when combined with NR in a clinical trial for peripheral artery disease, not only offered no benefit but blocked some of NR's positive effects.

Tereselbeane

A compound sometimes combined with NAD boosters, thought to increase bioavailability, but Dr. Brener expresses no use for it due to potential LDL-raising effects and lack of evidence for SIRT1 activation.

Niagen

A commercially available nicotinamide riboside (NR) supplement, which is a precursor to NAD. It is widely used by sports trainers and in athletic programs, including the New England Patriots.

Nicotinic Acid (Niacin)

An NAD precursor vitamin, but high doses can cause flushing. It is recommended by some cardiologists for lipid regulation.

People

Dr. Charles Brener

Professor and chair in the department of diabetes and cancer metabolism at the City of Hope, known for his contribution to understanding NAD biology and discovery of nicotinamide riboside.

Dr. Garman

A leading expert in human and model system lactation at UC Davis, who is planning large animal and human trials involving NR supplementation for lactation.

Dr. Rudolph Tanzy

A professor at Harvard, mentioned in the context of discussions with Bill Belichick and the New England Patriots regarding Niagen.

Jack Priest of Priest and Handler fame

Purified the enzyme NAD synthetase from yeast in 1958, showing it required glutamine, which puzzled scientists until Dr. Brener's later work.

Bill Belichick

Former coach of the New England Patriots, known to have had his team take Niagen for many years to aid in recovery.

Concepts

PARP

Poly-ADP ribose polymerases, a superfamily of enzymes that are transcriptionally activated by coronavirus infection and consume NAD to help with DNA repair and immune response.

SIRT1

A 'longevity gene' that resveratrol and tereselbeane were thought to activate, but evidence for this is questioned.

Drugs & Medications

GLP-1 medications

Oral medications for weight loss and obesity that can improve health, particularly when combined with resistance training.