How To Boost NAD Levels To Fight Inflammation, Improve Recovery, and Slow Aging
These notes were generated by AI and may contain inaccuracies.
NAD co-enzymes are critical for converting fuel, building stuff, and repairing stuff. NAD levels decline with age. Many people take NAD boosting supplements. It was initially Dr. Charles Brenner's technology that turned into the nicotinamide riboside and NAD boosting industry. They published a paper in 2020 with a shocking result. NAD plays a role in exercise recovery. Sports trainers and athletic programs swear by it. The Patriots took Niagen for many years. You can't just supplement with NAD directly; you have to take a precursor.
Dr. Charles Brenner is a professor and chair in the department of diabetes and cancer metabolism at City of Hope. He is well known for discovering the NAD precursor nicotinamide riboside (NR), which has been made into a supplement. He is evidence-based.
NAD Levels Decline with Age?
NAD levels do decline with age. Leading theories: diseases, lifestyle changes. Dr. Brenner is not comfortable accepting every premise from Instagram. There is no evidence that human blood NAD declines with age. Human tissue NAD pools decline or are disturbed with age. Not every human system's NAD declines.
Human blood NAD data shows three types:
- Normal people (male and female): 20 micromolar NAD+ on a volumetric basis.
- Supplementers: maybe twice that.
- People with mitochondrial disease: lower.
In collaboration with University of Helsinki, people with mitochondrial disease (thought to have muscle mitochondrial myopathy) have low blood NAD. Generally, normal people and older people do not have low blood NAD. Alcoholics have disturbed NAD in liver. People with noise-induced hearing loss likely have damaged cochlear NAD.
Blood vs. Tissue NAD
Distinction between blood NAD and tissue NAD. As humans age, they become sedentary, overweight, obese, develop diabetes, metabolic syndrome. Do these disease states lower NAD levels in blood and organs? Clinical trials of older people (not on 12 medications) show largely normal blood NAD. In people with many diseased conditions and polypharmacy, blood NAD may be abnormally low.
Inflammatory processes disturb the NAD system in blood and every organ in diseased conditions.
In March 2020, during COVID lockdowns, Dr. Brenner's lab stayed open because they worked on coronavirus-infected mice from Stanley Perlman's lab (expert on coronaviruses). They did NAD metabolomics and published a 2020 paper on coronavirus effects on mouse liver and human lung samples from morgues/databases.
Five different members of the PARP superfamily were transcriptionally activated by coronavirus infection, consuming NAD. Double-stranded RNA (from virus) is seen as an invader by innate immune system (humans don't make dsRNA or endotoxin). Cells turn on five PARPs as immediate early response. This is common to many infections, not just COVID, including respiratory illnesses.
Measuring blood NAD: substantive precursor intake (300 mg+) changes circulating NAD metabolome. Foods high in NAD precursors (liver, spinach) are high in micronutrients because full of mitochondria (animals) or chloroplasts (plants) containing co-enzymes. Co-enzymes break down to soluble precursors (e.g., NAD to NR/nicotinic acid; CoA to pantothenate), which cells rebuild into stores.
Blood NAD not fully indicative of whole system. Substantial age-related declines in tissues and disease/condition-driven declines in tissues. No one volunteers brain/liver for measurement.
Animal Studies
Animal studies show declines in muscle, liver, brain. Translates to humans. In liver, related to inflammation and microbiome (varies by mouse facility). In disease/conditions: heart failure, central/peripheral neurodegeneration, sun exposure attack NAD system.
Obesity/insulin resistance, chronic inflammation (driver of heart disease, Alzheimer's), chronic sleep deprivation.
- Obesity (2016 mouse study): High-fat diet to type 2 diabetes disturbed liver NAD system; PARP center degraded ability to detoxify reactive oxygen species.
- Not that they can't make NAD, but facing a storm consuming NADPH.
- Multiple mechanisms.
Human data on obesity/metabolic syndrome: fat is accessible (liposuction), could measure adipose tissue NAD. Interested in bariatric surgery livers in Europe.
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Sleep disturbance: No exact human study, but mice: young mice have good chronosynchrony, older lose it, NAD system disturbed. Time-of-day cues in NAD synthesis/metabolism. Sleep lack/time zone disruption disturbs NAD.
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Chronic inflammation: Inflammatory stimuli like coronaviruses disturb NAD. RCTs show NR (1 gram/day) is anti-inflammatory in humans.
Trial example: Older men, NR vs placebo crossover, muscle biopsies. Aimed for grip strength improvement in 2-3 weeks (unreasonable without exercise). No grip strength change, but NR strongly anti-inflammatory (lowered IL-6, IL-10, others). Effect persisted 3 weeks post-NR. Carryover effect.
Concern: secondary endpoint (pre-specified primary is grip strength). But 8 RCTs show anti-inflammatory activity, including primary endpoint in COPD patients (lowered sputum inflammatory markers).
NR rebuilds NAD supplies under attack, allowing detoxification of free radicals, better anabolic/repair processes.
For biggest bang in 2-3 months: address inflammation driver (obesity → weight loss; sleep/circadian disruption → fix; stress → manage; drinking/drug use). No one-size-fits-all (e.g., not everyone needs fasting/time-restricted eating; avoid for those with food OCD).
Overweight/obesity: medical options like oral GLP-1 meds + resistance training. GLP-1 helps drinkers too. For sedentary screen time: move body more.
Oral NAD precursors increase brain NAD (imaging). Small studies: oral NR improves cerebral blood flow in mild cognitive impairment.
Long COVID study (Woo et al., recent, Lancet eClinicalMedicine; Dr. Brenner co-author): enrolled with executive function, depression, sleep, mood complaints. Within-group improvements on NR (baseline to on-NR), not in placebo.
Hypothesis: improvement correlates with baseline inflammatory status (e.g., LPS injection trials show inflammation depresses mood/cognition).
High baseline inflammation (alcoholism, obesity, sleep deprivation) → reduce via lifestyle/diet or NR to replenish NAD, affect functional outputs.
For NAD supplement takers: no need for NAD blood testing in individuals (useful in clinical trials). Niagen use case in healthy aging based on 8 RCTs (anti-inflammatory), positive PAD trial, suggestive long COVID.
Dr. Brenner: chief scientific adviser of Niagen (makes Niagen pill) and NADMED (NAD testing company). No use case for individual NAD testing kits.
It's known that buying nicotinamide riboside (NR) from Niagen boosts NAD levels 6 to 8 hours after ingestion. When taking aspirin, no mass spec is needed to confirm ingestion. There's individual variability, but in clinical trials with 50 people, analyzing responders vs non-responders involves checking correlations with inflammatory markers and blood responses. Over-testing in the worried well is unhelpful. Choose battles wisely to avoid driving yourself nuts.
Exercise tops supporting systems for NAD. Exercise increases gene expression of NAD biosynthetic enzymes, as shown in a recent publication with a German group. Any exercise is better than none—the exercise you do beats what you plan. Exercise boosts transcription pathways associated with youth, including mitochondrial biogenesis, improving beta oxidation.
Sports trainers, professional football clubs, college athletic programs buy Niagen by the tub for recovery. Anecdotal evidence is strong; New England Patriots under Bill Belichick and Tom Brady used it for years. Exercise physiology scientists need to study this with rigorous placebo-controlled trials, like bicycle ergometer tests for recovery and performance. Exercise taxes NAD, increasing consumption, then adapts by upregulating genes/enzymes for more NAD production. Supplementing precursors could be synergistic.
Acute sleep loss effects on NAD are not well-studied in humans; mouse experiments with altered lighting/food timing exist but human trials are hard. Chronic sleep deprivation increases inflammatory biomarkers. In new mother mice/rats (2019 study), NR-supplemented control diet moms had fertile pregnancies. Offspring had better lean mass at weaning (maintained lifelong), faster physical development (balance beam), lower fear/anxiety, better Morris water maze performance, and adult hippocampal neurogenesis.
NR-supplemented moms had better weight management and produced more milk (higher calorie transfer, possibly richer bioactives like fatty acids or microbiome changes). Epigenetics via histone deacetylases possible. New mothers' livers distribute NAD precursors to mammary glands; supplemented moms had higher mammary NAD, while non-supplemented had declining liver NAD but increased blood NAD accumulating in mammary tissue for lactation.
No human data on NR in pregnancy, but animal studies are positive. UC Davis lactation experts (Dr. Garman et al.) planning large animal and human trials, including for preemie moms (whose mammary systems lag baby needs). Fertility doctors recommend Niagen. Many women take 500 mg–1 g/day NR for fertility/pregnancy, ahead of trials, given strong animal results and safety data. Human equivalent from animal study ~1 g/day (two Tru Niagen).
Shift workers (nurses, doctors, firefighters, police) and jet lag sufferers face health costs from misalignment. Strategies: set calendar to destination time, sleep on their schedule, bright sunlight at 6–7 a.m. local time, time-restricted eating, melatonin. NR supplementation in morning could help, especially with sunlight/activity to reset.
NR boosts circulation hours after intake. Most take it mornings; logical as with food micronutrients rebuilding co-enzymes while macronutrients fuel ATP. Take with breakfast/coffee at start of active cycle—even for night shifters (e.g., wake 9:30 p.m., "breakfast" 10 p.m.). NR not a stimulant, doesn't directly boost felt energy but supports it.
Phosphates prevent NAD/NMN entry into cells. Nicotinamide (NAM) and nicotinic acid (NA) enter; NA causes flushing at high NAD-boosting doses but used for lipids. NAM safe, cancer-preventative (Australian skin cancer trials). NR premium precursor: NR kinase (NMRK1/2) upregulated in stress (failing heart, damaged neurons), so NR boosts NAD where NAM fails (e.g., heart failure overexpresses NMRK2).
NAD IV painful, triggers innate immune response as it/NMN break down extracellularly to NR/NAM/NA for cell entry. Niagen+ IV NR available (non-painful). Mouse data show IV NR reaches tissues better than oral due to pharmacokinetics, promising for future disease trials. Oral Niagen has extensive safety/efficacy data (as of January 2026). Oral NAD breaks down, delivering some NR fraction.
Some people think NMN is one step closer to producing NAD in the cell, so why not supplement with the closer precursor? It doesn't work that way because NMN has a phosphate group that precludes its transport into the cell. In the 1980s, researchers developing nucleotides and bases as anti-cancer and antiviral drugs—Gertrude Elion, Hitchings, and others who won a Nobel Prize at Research Triangle Park in North Carolina—showed that nucleotides resembling those can enter cells and convert to toxic forms, like AZT for HIV, which becomes AZT triphosphate to inhibit reverse transcriptase. Nicotinamide riboside (NR) is a direct NAD precursor that can enter cells, get decorated with phosphates inside, and convert to its final nucleotide form. NMN already has a phosphate, which must be added inside cells. Orally taken NMN is converted back to NR before entering cells.
NR is the most safety-tested NAD booster on the market.
A recent paper from Nestlé in Switzerland shows the gut microbiome plays a role in human conversion of NR and NMN into NAD in tissues. It's hard to detect NR in human blood—it behaves like dark matter, with observable effects (e.g., in cardiac tissue, muscle) but difficult to trace directly due to blood draw artifacts releasing enzymes that break it down. This Nestlé human study showed the microbiome is altered positively by NR supplementation, with conversion to things like nicotinic acid beneficial for gut bacteria.
NR at 500-1,000 mg lowers inflammation, especially in those with higher inflammatory status. The immune system is a major NAD consumer, especially when sick. Human data show NR active in conditions with activated inflammasome (randomized controlled trials). Hypothesis: NR inhibits infection (e.g., wanted trials in high-exposure workers like nurses during COVID). Phase 2/3 trials showed NR in a cocktail of three OTC supplements lowered recovery time from COVID. Logical: provides precursors for cells to fight pathogens, reducing severity/duration of illness.
10-15% of Americans have PAD (often former smokers): limited exercise ability, fatigue, pain, potential amputation. In a 6-month trial, PAD patients declined (e.g., walked 8m fewer in 6-minute walk test). Mary McDermott at Northwestern ran a three-arm trial (placebo, NR, NR + resveratrol): NR improved 6-minute walk test; placebo and NR + resveratrol arms degraded. Resveratrol blocked NR benefits. Trial had ~40-75 per arm; positive results led to larger trial. Potential first medical indication for Niagen in age-related disease. Eight RCTs show NR lowers inflammation (inflammaging), broadly useful for aging.
Neuroinflammation plays early causal role in Alzheimer's. NR may improve mild cognitive impairment: one paper shows improved cerebral blood flow. Functional metrics (cognition) needed. Increased blood flow correlates with cognition (delivers energy, glucose, oxygen). Prevention easier than treatment in advanced disease.
Liver sees NAD precursors first. Human data: Dollerup et al. 2018 trial (co-author) in overweight, insulin-resistant 70-year-old Danish men with type 2 diabetes. Primary endpoint (weight loss, insulin sensitivity in 13 weeks as monotherapy) failed—unreasonable moonshot (sedentary, smokers). Secondary: NR reduced hepatic fat ~21% to 11% (10 absolute percentage points vs placebo), p=0.13 (close to 0.05, but not randomized for liver fat, high variability). Suggests promise if randomized for fatty liver + exercise/GLP-1. Later trials (e.g., Elhassan 2019) showed inflammation reduction. Pattern: NR aids unhealthy individuals, synergizes with lifestyle changes (not standalone weight loss drug).
Best argument for adding NR: workout recovery (synergizes with exercise). Host takes Niagen (Tru Niagen) since August at 1g/day, notes great recovery despite heavy workouts.
Clinical trials use 500-1,000 mg (up to 2,000 mg studied). 1,000 mg reasonable based on mouse evidence. Safety tested to 3g/day in some populations—don't exceed. Source/safety critical (clinically tested material). Ask doctor for conditions/diseases.
NR + resveratrol negated benefits in PAD. No use case for resveratrol or pterostilbene (not SIRT1 activators, don't increase SIRT1 activity; pterostilbene raises LDL dose-dependently).
Top issue: sourcing—use clinically tested material (e.g., not random Amazon NMN matching hospital study name; may lack active ingredient or have contaminants). Third-party tested/NSF certified recommended industry-wide. Cancer concern: NAD fuels all cells, including tumors. Hierarchy of evidence: Australian nicotinamide trials show it lowers population-level cancer risk (e.g., melanoma)—no signal for causing tumors. Not fuel but wiring for ATP. Population-safe/preventative. Animal studies (e.g., NMN accelerating pancreatic tumors) less relevant (e.g., injecting millions of cells ≠ human cancer development). Ask doctor if active cancer/chemotherapy (potentially contraindicated). Niagen safe per clinical data.
Discussion on a Japanese study where nicotinamide riboside (NR) or similar was injected into mice with pancreatic cancer, accelerating tumor growth. This is expected if tumors already exist, as providing folate, NAD, or similar fuels rapid growth. Concern led to pausing NR supplementation, but resumed later. General advice: if you have cancer, avoid taking many supplements.
Dr. Brenner agrees for the general public, NR is safe. NR is registered with the FDA as a new dietary ingredient under the Food category (F in FDA). Niagen underwent GRAS (generally regarded as safe) process. Any complaints, observations, or clinical trial data linked to NR are tracked, and safety data look excellent.
Honest answer to someone asking if they should supplement with Niagen (NR) alongside healthy diet and lifestyle: Yes, there are use cases beyond aging.
- 20-year-old football players in collision sports recover faster (Sunday game to Tuesday practice).
- People with intense workout schedules.
- Those entering crowded rooms where 5% have flu or 2% have COVID, to avoid frequent illness.
Proud of developing safe, useful Niagen. Future trials: peripheral artery disease, fatty liver, fertility—multiple potential use cases.
Thanks to Dr. Charles Brenner. Active on X as Charles M. Brenner—asks questions there, responds when possible. Lab website: brenerlab.net.
Dr. Brenner's decades studying NAD. Early career as enzymologist, postdoc discovered superfamily of nucleotide-binding proteins. Around 2003, found amino acid sequence in yeast and humans with NAD synthetase domain (converts nicotinic acid adenine dinucleotide (NAAD) to NAD) plus glutaminase domain (converts glutamine to glutamate, liberating ammonia).
1958, Jack Preiss and Philip Handler purified NAD synthetase from yeast, showed it requires glutamine—no prior explanation why eukaryotic versions (yeast, human, flies) use glutamine for ammonia. Given NAD's role as central metabolic catalyst, pursued this bifunctional enzyme with glutaminase site shuttling ammonia to NAD synthesis site.
Realized diagrams from MIT, Harvard, Washington University incorrectly showed NAD pathways (tryptophan via NAD synthetase, niacin/nicotinic acid from 1938, nicotinamide). Knocking out the gene in yeast should block NAD production, but tested for NR pathway—discovered it, expanding from enzyme to full pathway.
NAD as rechargeable molecule for energy: Analogy to electric vehicle (Ford F-150 Lightning) with battery storing high-energy electrons, copper wires distributing to drivetrains, wipers, AC. In biology, NAD coenzymes are the wiring: NAD+ captures high-energy electrons from food (protein, fat, carbs) as hydride (proton + 2 electrons) forming NADH.
NADH passes electrons via electron transport chain to lower-energy carriers, enabling work (e.g., proton pumping for ATP synthesis). Electrons flow downhill like waterfalls. Unlike burning food (electrons lost as smoke/heat), biology couples oxidation to ATP, muscle, memory, heart without waste.
NAD forms: NAD+/NADH (catabolism: fuel to ATP); NADP+/NADPH (anabolism: making stuff). Metabolism converts food to body/components/actions/maintenance.
NADPH directs electrons for carbon-carbon bonds, ribo- to deoxyribonucleotides (RNA/DNA synthesis), lipids, proteins—all self-made and repaired in cells.
Biggest NAD roles:
- Convert fuel to ATP.
- Build stuff.
- Repair stuff.
Repair includes resynthesis (e.g., cuts/scrapes need lipids, nucleic acids via NADPH for new membranes/cells). Oxygen environment produces reactive oxygen species (ROS), detoxified by NADPH. Oxidation byproducts damage mitochondria/DNA; DNA damage (double-strand breaks) risks oncogenic mutations/cancer.
PARP1 (poly-ADP-ribose polymerase 1): Major NAD consumer. On DNA damage, PARP1 polymerizes ADP-ribose from NAD into poly-ADP-ribose (PAR) polymers/linked to proteins, signaling DNA repair enzymes to site. If irreparable, signals cell death (preferable in 37 trillion-cell organism).
First time using 'consumer'—classic coenzyme cycle reoxidizes NAD+/NADP+, but NAD-dependent enzymes like PARP1 cleave NAD without recycling.
PARP superfamily (15-16 members): Modify proteins with ADP-ribose for signaling. Sirtuins: Remove acetyl/acyl/succinyl from lysines (enzyme/gene regulation, e.g., gene silencing). ADP-ribosyl cyclases: Release nicotinamide, cyclize ADP-ribose, release Ca2+ from ER for signaling.
If NAD limiting, full triage unknown. Liver robustly makes NAD from tryptophan, NR, nicotinamide, nicotinic acid; disturbed by aging, alcohol, overnutrition—but generous, distributes to other tissues.
Neurons: High energy needs, lack tryptophan/nicotinic acid pathways. Losing NR/other pathways causes dysfunction. Many diseases disturb NAD system.
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