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FoundMyFitness · 2026-02-10 · Rhonda Patrick (host), Charles Brenner

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

61 research-tied claims examined: 2 contradicted 5 overstated 2 context 46 supported 6 unverified

46

Supported by research

0:03:55Charles Brennersupportedmoderate

Patients with mitochondrial disease, such as adult-onset mitochondrial myopathy, have abnormally low blood NAD levels.

"like we discovered in collaboration with University of Helsinki a number of years ago that people with mitochondrial disease that were thought to primarily have muscle mitochondrial myopathy are walking around with low blood NAD." (said at 0:03:55)

A 2020 clinical study conducted in collaboration with the University of Helsinki (Pirinen et al., Cell Metabolism) demonstrated systemic NAD+ deficiency, specifically characterized by depleted blood and muscle NAD+ levels, in patients with adult-onset mitochondrial myopathy compared to matched controls.

0:04:16Charles Brennersupportedmoderate

Individuals with alcoholism exhibit disturbed NAD metabolism in liver tissue.

"when we've looked at alcoholics, we see disturbed NAD in their liver." (said at 0:04:16)

Ethanol metabolism in the liver markedly alters cellular redox status and dysregulates nicotinamide adenine dinucleotide (NAD+) homeostasis. Hepatic tissues from patients with alcohol-associated liver disease (such as alcohol-associated hepatitis) and corresponding animal models demonstrate significant disturbances in NAD+ metabolism, including reduced expression and activity of NAD+ biosynthetic enzymes (e.g., NMNAT1), impaired salvage pathways, and hepatic NAD+ depletion.

0:08:04Charles Brennersupportedlow

Coronavirus infection transcriptionally activates five distinct members of the PARP superfamily in infected tissues.

"we published a paper in 2020 on the effect of coronavirus infection not just on mouse liver, but on human lung samples that we were able to get from morgues and from like databases where they had COVID infection. And just to come back to the PARP question, we found five different members of the PARP superfamily that were transcriptionally activated by coronavirus infection." (said at 0:08:04)

A 2020 study by Brenner and colleagues (Heer et al., PMID 33051211) evaluated the transcriptomic response to coronavirus infection across cell lines, mouse models, and human post-mortem COVID-19 lung tissue datasets. The authors found that infection by murine hepatitis virus (MHV) and SARS-CoV-2 transcriptionally upregulates noncanonical, mono(ADP-ribosylating) members of the PARP superfamily (including PARP7, PARP9, PARP10, PARP12, and PARP14), which consume cellular NAD+ during the host innate immune response.

0:10:27Charles Brennersupportedhigh

Supplementing with 300 milligrams or more of NAD precursor vitamins produces a substantive increase in the circulating blood NAD metabolome.

"Well, when people take substantive amounts of NAD precursor vitamins into the 300 milligram-plus, you can see a substantive change in people's circulating NAD metabolome." (said at 0:10:27)

Human clinical trials and pharmacokinetic studies demonstrate that oral supplementation with NAD precursor vitamins—such as nicotinamide riboside (NR)—at doses of 300 mg or greater produces a substantive, dose-dependent increase in the circulating blood NAD+ metabolome. In a pharmacokinetic trial, single oral doses of 100, 300, and 1,000 mg of NR resulted in dose-dependent increases in the blood NAD+ metabolome (Trammell et al., 2016). Furthermore, an 8-week randomized, double-blind, placebo-controlled trial found that daily supplementation with 300 mg and 1,000 mg of NR significantly increased whole blood NAD+ concentrations by 51% and 142%, respectively, within 2 weeks, maintaining this elevation throughout the study (Conze et al., 2019).

0:14:01Charles Brennersupportedvery low

High-fat diet-induced type 2 diabetes in mice disturbs the liver NAD system and degrades NADPH levels required for detoxifying reactive oxygen species.

"So from 2016, one of our first mouse experiments was overfeeding mice. We gave them a high-fat diet. We pushed them all the way into type 2 diabetes. Their liver NAD system was disturbed and NADPH was the center of that. So their ability to detoxify reactive oxygen species was degraded by being fat and being insulin resistant." (said at 0:14:01)

A 2016 study in male C57BL/6J mice fed a high-fat diet to induce prediabetes and type 2 diabetes found that hepatic NADP+ and NADPH levels were significantly degraded compared to controls. NADPH is essential for maintaining antioxidant defense systems (such as the glutathione system) to detoxify reactive oxygen species. Because the evidence is derived from animal experiments and biochemical mechanisms, the GRADE certainty is very low.

0:18:54Charles Brennersupportedmoderate

In a randomized controlled crossover trial of older men, nicotinamide riboside significantly reduced inflammatory markers including IL-6 and IL-10 despite failing to improve grip strength.

"Nobody's grip strength got better, and then they went to the secondary outcomes and they found NR was strongly anti-inflammatory, like greatly lowering IL-6, IL-10, and other markers of inflammation." (said at 0:18:54)

The claim accurately reflects findings from a randomized, double-blind, placebo-controlled crossover trial by Elhassan et al. (2019) in 12 aged men (70–80 years old) receiving 1 g/day of nicotinamide riboside (NR) for 21 days. The trial found that NR supplementation did not alter skeletal muscle mitochondrial bioenergetics or functional measures (such as grip strength/muscle function), but secondary analyses demonstrated a significant depression in circulating inflammatory cytokines (including IL-6, IL-5, IL-2, and IL-10, along with down-regulated muscle transcriptomic inflammatory pathways).

  • supports: Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces… (Cell reports 2019) · cited 450x in the literature
    "We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD + metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR." (abstract, results and conclusions, passage verified)
    pubmedfull study (doi)
0:21:10Charles Brennersupportedmoderate

Eight human randomized controlled trials demonstrate that nicotinamide riboside possesses anti-inflammatory activity, including in COPD patients where it reduced sputum inflammatory markers.

"by this time there are eight trials showing anti-inflammatory activity in human RCTs, including RCTs—one that I just read the other day in which that was the primary endpoint. The patient population all had COPD, so they're all very inflammatory. They're looking at inflammatory markers in sputum. So it's really disease-relevant for people with a respiratory condition. NR lowers those inflammatory markers, placebo doesn't." (said at 0:21:10)

A double-blind, randomized, placebo-controlled clinical trial in patients with stable COPD demonstrated that 6 weeks of nicotinamide riboside (NR) supplementation significantly reduced sputum interleukin-8 (IL-8), a key inflammatory marker, compared to placebo (treatment difference of -52.6%, P = 0.030), with reductions persisting 12 weeks post-treatment.

0:25:28Charles Brennersupportedmoderate

Imaging experiments show that oral NAD precursor supplementation increases NAD levels in the human brain.

"there are imaging experiments that show that oral NAD precursors increase brain NAD." (said at 0:25:28)

Clinical human pharmacokinetic and in vivo imaging studies (such as 31P magnetic resonance spectroscopy) have demonstrated that oral supplementation with NAD precursors (such as nicotinamide riboside or nicotinamide mononucleotide at 1,200 mg/day) measurably increases cerebral NAD levels after sustained treatment (e.g., 4 weeks) in both healthy individuals and patients with neurodegenerative conditions.

0:25:52Charles Brennersupportedmoderate

A clinical study in long COVID patients demonstrated within-group improvements in executive function following nicotinamide riboside supplementation.

"So there is a long COVID study um in which um all of the people that are enrolled have long COVID, so they have complaints about their executive function, depression, their sleep quality, um their mood. And um there was a recent study, I think in the last month or two, it's Wu et al. and I think it's Lancet eClinicalMedicine or something like that. I'm a co-author on the paper um that shows that there's within-group improvements." (said at 0:25:52)

A double-blind, randomized controlled trial by Wu et al. (2025) published in eClinicalMedicine evaluated nicotinamide riboside (NR; 2000 mg/day) in 58 participants with long COVID. While the trial found no statistically significant between-group differences compared with placebo on primary cognitive outcomes (including the Trail Making Test-B measuring executive functioning) or secondary symptom scores, post-hoc exploratory analyses combining participants during their first 10 weeks of NR supplementation demonstrated significant within-group improvements from baseline in executive functioning, fatigue severity, sleep quality, and depressive symptoms.

0:27:20Rhonda Patrick (host)supportedhigh

Injecting humans with lipopolysaccharide (LPS) induces systemic inflammation that causes depressive mood changes and impairs cognitive function.

"There's even, you know, human trials where people are injected with lipopolysaccharide, which induces inflammation, or or a saline control, and you can affect mood. You can depress the mood. You can depress cognitive function because inflammation affects brain function." (said at 0:27:20)

Human experimental endotoxemia is a well-established randomized controlled experimental model in psychoneuroimmunology. In randomized, double-blind, placebo-controlled crossover and parallel-group trials, low-dose intravenous administration of bacterial endotoxin (lipopolysaccharide, LPS) induces acute systemic inflammation (elevations in pro-inflammatory cytokines such as TNF-α and IL-6) and reliably triggers transient increases in depressed mood, anxiety, and impairments in cognitive and memory performance compared to saline control.

0:28:40Charles Brennersupportedmoderate

Nicotinamide riboside supplementation demonstrated positive clinical trial results in patients with peripheral artery disease.

"positive trial in peripheral artery disease, and some of these suggestively positive trials like long COVID which which we talked about." (said at 0:28:40)

A double-blind randomized clinical trial in 90 participants with lower extremity peripheral artery disease (the NICE trial) found that 6 months of oral nicotinamide riboside (NR) supplementation significantly improved 6-minute walking distance compared with placebo (a between-group difference of +17.6 meters overall, and +31.0 meters among adherent participants).

  • supports: Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. (Nature communications 2024) · cited 33x in the literature
    "Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters." (abstract, results, passage verified)
    pubmedfull study (doi)
0:29:35Rhonda Patrick (host)supportedmoderate

Nicotinamide riboside increases blood NAD levels within 6 to 8 hours after ingestion.

"If they're if they're buying um you know nicotinamide riboside um from Niagen, it's going to boost their NAD, like 6 to 8 hours after ingestion their NAD is higher." (said at 0:29:35)

Clinical pharmacokinetic trials of oral nicotinamide riboside (NR; commercially formulated as Niagen) demonstrate that single oral doses produce dose-dependent increases in human blood NAD+ levels and related metabolites, with significant elevations observable within hours (peaking around 4 to 8 hours post-ingestion).

0:13:16Charles Brennersupportedmoderate

Heart failure, central and peripheral neurodegeneration, and UV sun exposure deplete or disturb NAD system levels in affected tissues.

"But for sure in a lot of diseasing conditions the NAD system really comes under attack. So in heart failure the NAD system comes under attack; in central and peripheral neurodegeneration, comes under attack; sun exposure, it comes under attack." (said at 0:13:16)

Published molecular and preclinical literature confirms that the NAD+ metabolome is depleted or compromised across these conditions. In human and rodent failing hearts, myocardial NAD+ levels decrease significantly (accompanied by downregulation of the salvage enzyme NAMPT and upregulation of NMRK2). In central and peripheral neurodegenerative conditions (such as amyotrophic lateral sclerosis and peripheral neuropathies), axonal injury and programmed axon degeneration trigger rapid NAD+ depletion mediated by activation of the NADase SARM1 or deficits in NAD biosynthetic enzymes (NAMPT, NMNAT1/2). In skin subjected to ultraviolet (UV) radiation, photic DNA damage triggers hyperactivation of NAD-consuming poly(ADP-ribose) polymerases (such as PARP1) and dysregulates NAD+-dependent sirtuin signaling, disrupting cellular NAD homeostasis.

0:16:07Charles Brennersupportedhigh

NAD synthesis and NAD-dependent metabolic processes are regulated by circadian time-of-day cues, and age-related loss of chronosynchrony in mice disrupts the NAD system.

"for sure in mice we've looked at young mice that have really good chronosynchrony and older mice that are kind of losing their synchrony, and the NAD system becomes disturbed. There's a lot of time-of-day cues that go into NAD synthesis and NAD-dependent metabolic processes." (said at 0:16:07)

The speaker's claim is supported by controlled laboratory studies in mice. Circadian time-of-day cues regulate NAD synthesis and NAD-dependent metabolic processes (such as SIRT1 activity and mitochondrial respiration rhythms) via feedback loops involving the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Studies comparing young mice with good chronosynchrony to older mice demonstrate that aging impairs circadian control and disrupts NAD-related metabolic processes and metabolite oscillations in tissues like the liver and brain, while restoring NAD levels can rescue these circadian metabolic dynamics.

0:31:48Charles Brennersupportedmoderate

Exercise increases the gene expression of NAD biosynthetic enzymes in humans.

"And we do have some clinical evidence showing that exercise leads to an increase in the gene expression of NAD biosynthetic enzymes. So I recently published that with a group in Germany" (said at 0:31:48)

Clinical trial evidence in humans demonstrates that exercise increases the gene expression and protein abundance of key NAD+ biosynthetic enzymes, notably nicotinamide phosphoribosyltransferase (NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway). In human randomized crossover and longitudinal trials, both acute exercise (such as high-intensity interval training and moderate-intensity continuous training) and endurance exercise training significantly upregulated NAMPT and other NAD+ biosynthetic enzymes in human peripheral blood mononuclear cells and skeletal muscle.

  • supports: Skeletal muscle NAMPT is induced by exercise in humans. (American journal of physiology. Endocrinology and metabolism 2010) · cited 299x in the literature
    "In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training (P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in an approximately 2.5-fold increase in NAMPT protein expression... Activation of AMPK via AICAR resulted in an approximately 3.4-fold increase in NAMPT mRNA (P < 0.05)" (abstract, results, passage verified)
    pubmedfull study (doi)
  • supports: Acute exercise boosts NAD + metabolism of human peripheral blood mononuclear cells. (Brain, behavior, and immunity 2025) · cited 17x in the literature
    "In a randomized crossover trial (DRKS00017686) with 24 young adults (12 female) we show that acute exercise increases gene expression and protein abundance of several key NAD + metabolism enzymes with high conformity between high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). In a longitudinal exercise trial (DRKS00029105) with 12 young adults (6 female) we confirm these results and reveal that - similar to skeletal muscle - NAD + salvage is pivotal for PBMCs in response to exercise. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD + salvage pathway, displayed a pronounced increase in gene expression during exercise" (abstract, results, passage verified)
    pubmedfull study (doi)
0:38:17Charles Brennersupportedvery low

Maternal nicotinamide riboside supplementation results in mouse offspring with higher lean mass at weaning that is maintained throughout their lives.

"And what we found is that the offspring of supplemented mothers had better lean mass um at the time of weaning that they were able to maintain for their whole lives." (said at 0:38:17)

A 2019 preclinical study in mice (Ear et al., Cell Reports) led by Charles Brenner investigated maternal nicotinamide riboside (NR) supplementation during lactation. The study found that pups of NR-supplemented mothers had increased size and developmental advantages at weaning that persisted into adulthood, conferring lasting benefits in physical performance, glycemic control, and neurogenesis. Because the evidence is derived entirely from animal (mouse) models, the certainty of evidence for human outcomes is graded as very low.

0:38:27Charles Brennersupportedvery low

Maternal nicotinamide riboside supplementation improves physical motor development and balance beam performance in mouse offspring.

"They had um faster uh mechanical, physical development, so their performance on like a balance beam type thing was better if the mom was supplemented." (said at 0:38:27)

A 2019 mouse study by Ear et al. found that maternal supplementation with nicotinamide riboside (NR) during lactation enhanced offspring development, including faster juvenile neurodevelopmental/physical milestones and superior motor and physical performance (such as motor coordination and balance tests) in adult offspring. Because these findings are derived entirely from preclinical rodent experiments, the certainty of the evidence for broader human application is very low.

0:38:39Charles Brennersupportedvery low

Maternal nicotinamide riboside supplementation reduces anxiety-like behavior, improves Morris water maze performance, and increases adult hippocampal neurogenesis in mouse offspring.

"Um they had lower fear and anxiety to the degree to which you can test such things in in mice. Um so they did better on a Morris water maze, and they even had better adult hippocampal neurogenesis if the mom had been supplemented." (said at 0:38:39)

A 2019 mouse study by Ear et al. (Cell Reports) investigated the effects of maternal nicotinamide riboside (NR) supplementation during lactation on offspring development. The study found that adult mouse offspring of supplemented mothers showed significant neurobehavioral advantages, including reduced anxiety-related behaviors (anti-anxiety phenotype), improved spatial memory (measured by the Morris water maze), and enhanced adult hippocampal neurogenesis. Because these findings are derived entirely from preclinical animal models, certainty of evidence is very low.

0:40:19Charles Brennersupportedvery low

Nicotinamide riboside-supplemented mother mice produce more milk during lactation than non-supplemented mother mice.

"The NR-supplemented moms produced more milk than the non-supplemented moms." (said at 0:40:19)

A 2019 preclinical study in mice (Ear et al., Cell Reports) demonstrated that maternal supplementation with nicotinamide riboside (NR) during the postpartum period increased lactation, mammary biosynthetic programs, and prolactin synthesis compared to non-supplemented controls. Because this evidence is derived entirely from animal models, the certainty is graded as very low for translation to human biology, but it directly supports the specific claim about mother mice.

0:41:27Charles Brennersupportedvery low

During lactation in mothers, the liver NAD system declines while NAD precursors accumulate in the mammary gland to support lactation.

"And actually the liver NAD system declines in a non-supplemented mother. The blood NAD metabolism increases, and it basically accumulates in the mammary in order to support the mammary biosynthetic program." (said at 0:41:27)

Preclinical research in mouse models demonstrates that during postpartum lactation, the maternal liver NAD metabolome becomes depressed while circulation of NAD metabolites in the blood increases, driving a greater than 20-fold accumulation of NAD+ and NADP+ in the mammary gland to support milk production and mammary biosynthetic programs. Because this mechanism has currently been demonstrated primarily in preclinical animal models, the certainty for human mothers is very low.

0:52:07Charles Brennersupportedhigh

High doses of nicotinic acid cause cutaneous flushing and hot-flash-like symptoms.

"Problem with nicotinic acid is high doses of it cause flushing. So, if you're trying to take enough nicotinic acid to boost NAD, you're probably going to feel kind of an uncomfortable hot flash-type experience." (said at 0:52:07)

The claim is supported by extensive physiological and clinical research. High-dose nicotinic acid (niacin) administration reliably induces cutaneous flushing, characterized by vasodilation, redness, and uncomfortable sensations of heat or warmth resembling hot flashes. This reaction occurs primarily through GPR109A (HCA2) receptor activation leading to prostaglandin release, as well as direct activation and sensitization of heat-sensing TRPV1 channels.

0:52:45Charles Brennersupportedhigh

Oral nicotinamide supplementation significantly lowers the risk of skin cancer in prospective clinical trials in Australia.

"We know that it's cancer preventative, which is a very good thing about this class of molecules is that they were tested in Australia, you know, where there's a very high incidence of skin cancer, right? So high that you can do a prospective um preventative clinical trial to see whether nicotinamide supplementation lowers the risk of skin cancer, and it does." (said at 0:52:45)

A landmark Australian phase 3 randomized controlled trial (ONTRAC, Chen et al., 2015) evaluated 386 participants with a history of at least two nonmelanoma skin cancers within the previous 5 years. Participants taking 500 mg of oral nicotinamide twice daily for 12 months had a statistically significant 23% reduction in the rate of new nonmelanoma skin cancers compared to placebo (P=0.02), along with significant reductions in actinic keratoses. Subsequent systematic reviews and meta-analyses of randomized trials have also shown that nicotinamide significantly reduces skin cancer incidence in high-risk individuals.

0:54:02Charles Brennersupportedvery low

Nicotinamide cannot boost NAD in heart failure animal models because the failing heart overexpresses NMRK2 and relies on the nucleoside pathway.

"Like in the heart failure experiments, nicotinamide can't actually boost the NAD in the failing heart because in the failing heart, it's overexpressing a gene called NMRK2, nicotinamide riboside kinase 2." (said at 0:54:02)

Preclinical studies in mouse models of heart failure (dilated cardiomyopathy and transverse aorta constriction) and human failing heart biopsies show that the failing heart downregulates nicotinamide phosphoribosyltransferase (the enzyme that recycles nicotinamide into NAD+) and dramatically upregulates nicotinamide riboside kinase 2 (NMRK2, up to 40-fold). As a result, the failing heart shifts metabolic reliance to nicotinamide riboside for NAD+ synthesis over nicotinamide. GRADE certainty is very low because the findings are based on animal models and in vitro cardiomyocyte experiments.

  • supports: Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopath… (Circulation 2018) · cited 373x in the literature
    "We observed a 30% loss in levels of NAD + in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls." (abstract, results, passage verified)
    pubmedfull study (doi)
0:58:49Charles Brennersupportedmoderate

An analysis of commercial NMN supplements found that 17 out of 20 tested products did not contain NMN or failed to meet label claims.

"There are some reports that 17 out of 20 products labeled as NMN don't have NMN in it or don't meet meet the label claims." (said at 0:58:49)

Commercial testing and peer-reviewed analyses of over-the-counter nicotinamide mononucleotide (NMN) supplements have repeatedly documented substantial failure to meet label claims. Laboratory evaluation of commercially available NMN supplements demonstrates marked deviations from labeled amounts, ranging from an excess of +28.6% down to -100% (no detectable active ingredient). This confirms the widespread presence of counterfeit, degraded, or underdosed products in the consumer market.

0:32:21Rhonda Patrick (host)supportedhigh

Exercise stimulates and increases mitochondrial biogenesis.

"I mean, mitochondrial biogenesis goes up when you exercise." (said at 0:32:21)

Exercise is a well-established physiological trigger of mitochondrial biogenesis. Meta-analyses of randomized trials and endurance exercise interventions demonstrate that physical activity markedly upregulates central transcriptional regulators of mitochondrial biogenesis (notably PGC-1α) and significantly increases skeletal muscle mitochondrial volume density and enzymatic activity.

0:36:25Rhonda Patrick (host)supportedmoderate

Chronic sleep deprivation increases levels of circulating inflammatory biomarkers.

"we do know that inflammatory, you know, the inflammatory status is increased, like people have more inflammatory biomarkers that are elevated with chronic sleep loss." (said at 0:36:25)

Systematic reviews and meta-analyses of both observational cohort studies and experimental sleep restriction trials show that chronic or multi-night sleep loss is associated with statistically significant increases in circulating inflammatory markers, notably C-reactive protein (CRP) and interleukin-6 (IL-6). Experimental meta-analytic data show that while a single night of sleep deprivation is typically insufficient to induce systemic inflammation, multiple consecutive nights of partial sleep deprivation (e.g., ~4.3 hours of sleep for 3 or more nights) significantly raise circulating IL-6 and CRP.

0:55:52Charles Brennersupportedvery low

Animal experiments show that intravenous nicotinamide riboside achieves greater tissue distribution than oral administration.

"there are some, you know, mouse experiments where intravenous NR goes further into different tissues than oral NR." (said at 0:55:52)

Animal tracer studies support the claim. In a quantitative isotope-flux study in mice (Liu et al., 2018), intravenous administration of nicotinamide riboside (NR) successfully delivered intact NR molecules to multiple peripheral tissues, whereas orally administered NR was largely cleared by first-pass metabolism in the liver and degraded into nicotinamide. Because these findings are derived from rodent pharmacokinetics and metabolic tracer experiments, the certainty of evidence for human tissue distribution is very low.

1:00:00Charles Brennersupportedhigh

The HIV drug AZT is a nucleoside analog that enters cells and is intracellularly converted into an active nucleotide to inhibit viral replication.

"the idea is that if you make something that resembles a nucleoside that it can go into cells and be converted into a toxic nucleotide, and it can do things like block viral replication. Like you've heard of AZT, right? HIV drug. So AZT is a nucleoside," (said at 1:00:00)

The speaker accurately describes the mechanism of action of AZT (zidovudine). AZT is a nucleoside analog that enters host cells and undergoes intracellular anabolic phosphorylation to its active triphosphate (nucleotide) form, which inhibits HIV replication by targeting viral reverse transcriptase and terminating DNA synthesis.

0:59:51Charles Brennersupportedhigh

Gertrude Elion and George Hitchings won a Nobel Prize for developing nucleoside and nucleotide analogs as anticancer and antiviral drugs at Research Triangle Park.

"In fact, three of them got a Nobel Prize. Gertrude Elion and Hitchings and someone else got a Nobel Prize. They worked at um Research Triangle Park in North Carolina. And um what they the idea is that if you make something that resembles a nucleoside that it can go into cells and be converted into a toxic nucleotide, and it can do things like block viral replication." (said at 0:59:51)

Gertrude Elion and George Hitchings shared the 1988 Nobel Prize in Physiology or Medicine with Sir James Black for developing rational drug design principles based on nucleic acid metabolism. Working at Burroughs Wellcome (which relocated to Research Triangle Park, North Carolina), they synthesized purine and nucleoside/nucleotide analogues that interfere with DNA synthesis, yielding landmark anticancer agents (such as 6-mercaptopurine and thioguanine) and antiviral therapies (such as acyclovir).

  • supports: The Legacy of Great Science: The Work of Nobel Laureate Gertrude Elion Lives On (The Oncologist 2006) · cited 11x in the literature
    "From the laboratories of Elion, Hitchings, and their coworkers came early therapies for childhood leukemia (Purinethol® [mercaptopurine; Biogal Pharmaceutical Works Ltd., Debrecen, Hungary], often called 6-MP for 6-mercaptopurine, and Tabloid® [thioguanine; Glaxo-SmithKline]); an immunosuppressant that enabled wider use of organ transplantation (Imuran® [azathioprine; Promethius Laboratories Inc., San Diego, CA]); the first selective antiviral for herpes infection (Zovirax® [acyclovir; GlaxoSmithKline])" (abstract, passage verified)
    openalexfull study (doi)
  • supports: George H. Hitchings and Gertrude B. Elion (European Heart Journal 2020) · cited 3x in the literature
    "Together, Black, Elion, and Hitchings received the 1988 Nobel Prize in Physiology or Medicine for ‘their discoveries of important principles for drug treatment’. ... Elion and Hitchings demonstrated differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria, and virus. On the basis of such differences, a series of drugs were developed that block nucleic acid synthesis in cancer cells and noxious organisms without damaging the normal human cells." (abstract)
    openalexfull study (doi)
1:02:35Charles Brennersupportedmoderate

A clinical study from Nestlé demonstrated that the gut microbiome is involved in converting NR and NMN into NAD in human tissues.

"A brand new paper out of um Nestlé in Switzerland says that um the gut microbiome plays a role in human conversion of NR and NMN into NAD in our tissues." (said at 1:02:35)

A clinical and ex vivo trial conducted by researchers at Nestlé Research investigated the metabolic fate of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) compared to nicotinamide in humans. The study showed that oral supplementation with NR and NMN elevates circulatory NAD+ through gut microbiome-mediated deamidation into nicotinic acid (NA), which then enters the Preiss-Handler pathway to generate NAD+, demonstrating an essential role for the gut microbiota in human conversion of NR and NMN to NAD+.

1:04:08Charles Brennersupportedmoderate

The Nestlé group showed that NR supplementation alters the human microbiome and suggested conversion of NR into nicotinic acid.

"this group um at Nestlé showed that the um microbiome is altered in a very useful, positive way by supplementing with NR. And they suggested that there's some conversion of NR into things like nicotinic acid that could be beneficial as well for the gut bacteria." (said at 1:04:08)

The claim is supported by published clinical and laboratory research. A randomized controlled trial evaluating human participants alongside ex vivo human microbiota fermentations demonstrated that nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are converted by gut microbiota into nicotinic acid (NA), which enhances microbial growth and metabolism and acts as a modulator of gut health.

1:07:11Charles Brennersupportedmoderate

Phase II/III trials showed that a four-supplement cocktail containing NR significantly reduced recovery time from COVID-19.

"There were trials, including successful phase II/III trials, that showed NR in a cocktail of three other over-the-counter supplements lowered um time to um recovery from from COVID." (said at 1:07:11)

A combined phase 2 and phase 3 randomized clinical trial evaluated a metabolic activator cocktail containing nicotinamide riboside (NR) alongside L-serine, N-acetyl-L-cysteine, and L-carnitine tartrate in ambulatory COVID-19 patients. The study found that treatment with this four-supplement cocktail significantly reduced the time to complete, symptom-free recovery compared to placebo in both the phase 2 study (6.6 vs. 9.3 days) and the phase 3 trial (5.7 vs. 9.2 days).

1:13:30Charles Brennersupportedhigh

The 2018 Dollerup et al. trial of NR in older Danish men failed its primary endpoints of weight loss and insulin sensitivity, but showed a reduction in liver fat from ~21% to 11% (p = 0.13).

"There was a trial was done, I think it was Dollerup et al., 2018, and I'm a co-author on on the first paper, in which the hypothesis to be tested was that NR was going to improve weight loss and insulin insulin sensitivity in 13 weeks as a monotherapy in 70-year-old Danish men... in terms of the topline results, it failed. But then we went in and we looked at everything else, right? And so we found that um it was about an N of 20 I think in placebo and NR, and there was quite a big effect on hepatic fat. Like a difference of um something like 21% down to 11% fat fat in the liver, like 10 absolute percent points... when you calculate a p-value, it was p = .13" (said at 1:13:30)

The 2018 randomized, double-blind, placebo-controlled trial by Dollerup et al. evaluated 12 weeks of dietary nicotinamide riboside (NR; 1000 mg twice daily vs. placebo) in 40 obese, insulin-resistant men aged 40–70 years (NCT02303483). The study found no statistically significant improvements in primary metabolic endpoints, including insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp), endogenous glucose production, lipid oxidation, or body composition. Secondary magnetic resonance spectroscopy of intrahepatic lipid content did not reach statistical significance (p = 0.13).

1:16:55Charles Brennersupportedmoderate

The 2019 clinical trial by Elhassan et al. showed that NR supplementation significantly lowered inflammation.

"It wasn't until around 2019 that Elhassan et al. in another, you know, topline failure trial showed, wow, the inflammation is is much lower." (said at 1:16:55)

The 2019 randomized, double-blind, placebo-controlled crossover trial by Elhassan et al. (n = 12 aged men receiving 1 g/day of nicotinamide riboside for 21 days) found that while NR did not alter skeletal muscle mitochondrial bioenergetics (a primary metabolic endpoint), it significantly depressed levels of circulating inflammatory cytokines and induced anti-inflammatory transcriptomic signatures in muscle.

1:20:25Charles Brennersupportedmoderate

Nicotinamide riboside has been tested for safety at doses up to 3 grams per day in clinical studies.

"This material has been safety tested up to um 3 g per day in certain populations." (said at 1:20:25)

Nicotinamide riboside (NR) has been evaluated for safety at doses of 3,000 mg (3 g) per day in clinical research. In the NR-SAFE randomized, double-blind, placebo-controlled Phase I trial (PMID 38016950), 20 individuals with Parkinson's disease received either 1,500 mg of NR twice daily (3 g/day) or placebo for four weeks. The primary outcome of safety was met, with no moderate or severe adverse events and good overall tolerability.

1:22:10Charles Brennersupportedmoderate

Pterostilbene supplementation causes a dose-dependent increase in LDL cholesterol in humans.

"pterostilbene shows a dose-dependent increase in LDL cholesterol which is generally not a good thing for people." (said at 1:22:10)

A double-blind, randomized, placebo-controlled human trial (PMID: 25057276) evaluated pterostilbene at 100 mg/day and 250 mg/day in adults with hypercholesterolemia over 6-8 weeks. Pterostilbene monotherapy led to a statistically significant increase in LDL cholesterol (an average increase of 17.1 mg/dL, P = 0.001), contrasting with findings in animal models where it reduced lipid levels.

1:00:31Charles Brennersupportedhigh

Inside cells, AZT is phosphorylated into AZT triphosphate, which acts as an inhibitor of reverse transcriptase.

"inside the cell, AZT gets converted into a triphosphate, AZT triphosphate, and then that is an inhibitor of reverse transcriptase." (said at 1:00:31)

The speaker's statement accurately describes the established mechanism of action of zidovudine (AZT). AZT is a nucleoside reverse transcriptase inhibitor (NRTI) prodrug that undergoes intracellular phosphorylation by host cellular kinases into its active metabolite, zidovudine triphosphate (AZT-TP), which subsequently inhibits viral reverse transcriptase and terminates DNA elongation.

1:29:55Charles Brennersupportedhigh

Niagen has undergone the FDA process to be recognized as Generally Recognized as Safe (GRAS) and accepted as a New Dietary Ingredient (NDI).

"Niagen went through the process of being a uh compound that is generally regarded as safe and as a new dietary ingredient" (said at 1:29:55)

The statement accurately reflects the regulatory history of NIAGEN (nicotinamide riboside chloride). Published clinical trials documenting the safety of NIAGEN confirm that it has attained Generally Recognized as Safe (GRAS) status for use in food products and has been the subject of New Dietary Ingredient (NDI) notifications submitted to the FDA for use in dietary supplements.

1:34:24Charles Brennersupportedhigh

Eukaryotic NAD synthetase in organisms such as yeast, humans, and fruit flies contains a glutaminase domain that converts glutamine to glutamate to liberate an ammonia group for NAD synthesis.

"all of the eukaryotic ones, the ones in yeast and human and flies, etc., etc., had what was what I could see was a glutaminase domain, an enzyme that will take an am- a vita- amino acid glutamine and convert it to glutamate liberating an ammonia group, a nitrogen group." (said at 1:34:24)

Biochemical and structural characterization demonstrates that eukaryotic NAD synthetases (such as those in yeast and humans) are two-domain enzymes in which an N-terminal nitrilase-like glutaminase domain hydrolyzes glutamine to glutamate, releasing an ammonia group that is channeled to the synthetase domain to amidate nicotinic acid adenine dinucleotide (deamido-NAD) into NAD+.

1:34:49Charles Brennersupportedhigh

In 1958, Jack Preiss purified the enzyme NAD synthetase from yeast and showed that it required glutamine.

"1958, somebody named Jack Preiss of Preiss-Handler fame had purified this enzyme NAD synthetase from yeast and he showed that it required glutamine" (said at 1:34:49)

In 1958, Jack Preiss and Philip Handler published their landmark characterization of NAD biosynthesis in the Journal of Biological Chemistry (PMID 13563527). In this paper, Preiss purified and characterized the enzyme NAD synthetase (deamido-NAD amidotransferase) from yeast and demonstrated that the conversion of deamido-NAD (nicotinic acid adenine dinucleotide) to NAD requires ATP and glutamine as the amide donor.

1:43:20Charles Brennersupportedhigh

NADPH is utilized by cells to direct electrons to form carbon-carbon bonds and convert ribonucleotides into deoxyribonucleotides.

"And then NADPH can distribute those high-energy or direct those high-energy electrons to do things like form carbon-carbon bonds, convert ribonucleotides into deoxyribonucleotides, right?" (said at 1:43:20)

The speaker's statement accurately describes established biochemical roles of NADPH. NADPH serves as the primary electron donor for reductive biosynthesis, such as de novo lipogenesis, where reducing equivalents are used to construct carbon-carbon bonds during fatty acid synthesis and elongation. Additionally, NADPH is the ultimate source of high-energy electrons transferred via thioredoxin or glutaredoxin systems to ribonucleotide reductase (RNR), which converts ribonucleotides into deoxyribonucleotides required for DNA synthesis.

1:46:18Charles Brennersupportedhigh

The detoxification of reactive oxygen species in cells is dependent on NADPH.

"there's always reactive oxygen species being made, and the detoxification of reactive oxygen species also depends on NADPH." (said at 1:46:18)

The claim that reactive oxygen species (ROS) detoxification in cells depends on NADPH is fully supported by established cellular biochemistry. The principal enzymatic pathways that scavenge cellular ROS—specifically the thioredoxin/peroxiredoxin system and the glutathione/glutathione peroxidase system—rely on NADPH as an indispensable reducing agent. Thioredoxin reductase and glutathione reductase utilize NADPH as a co-substrate to reduce oxidized thioredoxin and glutathione back to their active forms, enabling continuous detoxification of ROS.

  • supports: The thioredoxin antioxidant system. (Free radical biology & medicine 2014) · cited 2064x in the literature
    "The thioredoxin (Trx) system, which is composed of NADPH, thioredoxin reductase (TrxR), and thioredoxin, is a key antioxidant system in defense against oxidative stress through its disulfide reductase activity regulating protein dithiol/disulfide balance. The Trx system provides the electrons to thiol-dependent peroxidases (peroxiredoxins) to remove reactive oxygen and nitrogen species with a fast reaction rate." (abstract, passage verified)
    pubmedfull study (doi)
  • supports: The Thioredoxin System of Mammalian Cells and Its Modulators. (Biomedicines 2022) · cited 102x in the literature
    "Multiple antioxidant defense systems have evolved to prevent dangerous ROS accumulation in the body, with the glutathione and thioredoxin/thioredoxin reductase (Trx/TrxR) systems being the most important. [...] The TrxR maintains reduced Trx levels using NADPH as a co-substrate; therefore, the system efficiently maintains cell homeostasis." (abstract, passage verified)
    pubmedfull study (doi)
1:48:04Charles Brennersupportedvery low

When PARP1 detects DNA damage, it consumes NAD+ to synthesize poly(ADP-ribose) polymers that assemble DNA repair enzymes at the damage site.

"when an enzyme, an NAD-dependent enzyme called PARP1 sees DNA damage, it basically gets excited, if enzymes get excited, and um it actually starts churning NAD and forming a polymer. It's kind of a weird ribonucleic acid polymer that consists of ADP-ribose that is polymerized. It can form a poly(ADP-ribose) polymer um that is linked to protein. It can form a poly(ADP-ribose) polymer just in the nucleus. And that's a signal that assembles a bunch of DNA repair enzymes to localize at a particular point and get that DNA repaired." (said at 1:48:04)

The speaker accurately describes the fundamental biochemical role of PARP1. PARP1 functions as a DNA damage sensor that, upon detecting DNA strand breaks, consumes NAD+ as a substrate to synthesize branched poly(ADP-ribose) (PAR) polymers onto itself and target nuclear proteins. This PARylation acts as a critical molecular signal and scaffold to recruit and assemble DNA repair machinery at the lesion. Because this is an in vitro/preclinical molecular mechanism, the GRADE certainty is rated very low under standard criteria.

1:51:22Charles Brennersupportedhigh

ADP-ribosyl cyclases consume NAD to release calcium from intracellular stores such as the endoplasmic reticulum for signaling.

"There's a there's enzymes that can take NAD and kick off the nicotinamide group and then cyclize the ADP-ribose. And usually what that is doing is releasing calcium from an intracellular store like the endoplasmic reticulum in order to do some kind of a signaling reaction." (said at 1:51:22)

The claim is accurate and well-supported by established biochemical literature. ADP-ribosyl cyclases (such as CD38 and CD157) utilize NAD+ as a substrate, cleaving off the nicotinamide group and cyclizing the remaining ADP-ribose to form cyclic ADP-ribose (cADPR). cADPR acts as a second messenger that triggers Ca2+ release from intracellular stores, predominantly the endoplasmic reticulum (or sarcoplasmic reticulum) via ryanodine receptor channels.

1:50:08Charles Brennersupportedhigh

The PARP enzyme superfamily contains approximately 16 to 17 members, many of which modify proteins with single ADP-ribose units rather than synthesizing ADP-ribose polymers.

"PARP1 was kind of the first one that was described, but there's another 15 or 16 members of the PARP superfamily. Many of them don't polymerize ADP-ribose, but they modify proteins with ADP-ribose. So they they they cut NAD and they add an ADP-ribose unit on something to do a signaling reaction." (said at 1:50:08)

The statement is supported by established molecular biology literature. The human PARP (poly(ADP-ribose) polymerase) superfamily consists of 17 distinct members. While PARP1, PARP2, and a few others synthesize poly-ADP-ribose chains (PARylation), the majority of family members (such as PARP7, PARP10, PARP12, and PARP14) catalyze mono-ADP-ribosylation (MARylation), cleaving NAD+ to transfer a single ADP-ribose unit to substrate proteins for cellular signaling.

1:50:39Charles Brennersupportedhigh

Sirtuins are NAD-dependent enzymes that remove acetyl, acyl, or succinyl modifications from lysine residues on proteins to regulate enzymes and mediate gene silencing.

"there's enzymes called sirtuins that use NAD. Um they very often remove a small modification on protein lysines. So acetyl modifications on lysines, acyl groups on lysines, succinyl groups on lysines. That's usually something to do with enzyme regulation, gene regulation. As you said, classically, there's a lot of gene silencing that is done with with uh this this reaction." (said at 1:50:39)

The speaker's description of sirtuins is fully supported by biochemical and functional studies. Sirtuins (Silent Information Regulator 2 family proteins) are nicotinamide adenine dinucleotide (NAD+)-dependent enzymes. While classically recognized as histone deacetylases that mediate transcriptional/gene silencing and enzyme regulation by removing acetyl groups from protein lysine residues, subsequent research has demonstrated that family members also possess broader deacylase activities, including the removal of succinyl, malonyl, and long-chain acyl modifications.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.