madman
Super Moderator
01:30:55 Is NR worth supplementing for healthy individuals?
Many symptoms attributed to aging are also consistent with chronic inflammatory stress and impaired NAD metabolism. Dr. Charles Brenner explains the mechanisms, the human data, and what interventions actually move the needle. He also cuts through the crowded world of NAD boosters, including oral NAD pills, NMN, NR, and NAD IV drips, clarifying what actually raises NAD in humans and what emerging research suggests about NR for lowering inflammation and improving recovery.
CHAPTERS:
00:00:00 Introduction
00:01:58 Why disease states disrupt NAD levels
00:06:42 How coronavirus infection impacts NAD levels
00:09:55 Can diet and supplements artificially inflate NAD levels?
00:11:49 Why blood NAD might not show the full picture
00:13:20 How obesity and insulin resistance drain NAD resources
00:16:01 Does poor sleep disrupt NAD levels?
00:16:53 The anti-inflammatory effects of nicotinamide riboside (NR)
00:21:38 Can a single lifestyle change restore NAD?
00:24:22 Cognitive benefits of NAD precursors
00:27:58 Should you measure your NAD levels?
00:30:59 Does exercise boost NAD—and if so, which type?
00:33:01 Can NAD precursors speed exercise recovery?
00:35:35 Is acute sleep loss enough to lower NAD?
00:37:07 Does NR supplementation during pregnancy benefit offspring?
00:41:42 Safety of nicotinamide riboside during pregnancy
00:43:48 Could NR supplementation support fertility?
00:44:58 Shift work and jet lag—can NAD precursors help?
00:47:41 Morning or night—when should you take NR?
00:50:41 NAD supplements vs. precursors—what actually boosts NAD?
00:54:28 NAD IV drips—real benefits or just hype?
00:55:36 Oral vs. IV nicotinamide riboside—what’s more effective?
00:57:06 Do oral NAD supplements genuinely raise NAD levels?
00:58:58 NMN vs. NR—does being ‘one step closer’ really matter?
01:02:06 Does the gut microbiome influence NAD production?
01:04:44 Could NR supplementation enhance immune function?
01:08:02 Can NR supplementation improve peripheral artery disease?
01:12:26 Can NR realistically reduce liver fat?
01:17:33 Does NR supplementation give athletes a recovery edge?
01:19:18 What’s a safe dosage for nicotinamide riboside?
01:21:21 Resveratrol and pterostilbene—beneficial pairing or pointless stack?
01:22:57 NAD precursor supplements—why sourcing matters
01:25:09 Do NAD precursors increase cancer risk?
01:30:55 Is NR worth supplementing for healthy individuals?
01:33:43 From enzyme nerd to NAD pioneer (Brenner’s origin story)
01:38:13 Simplifying NAD’s role in energy and repair
01:45:00 Why DNA repair depends heavily on NAD
01:46:50 The PARP/NAD‑consumption mechanism
01:49:29 NAD’s role in gene regulation
01:51:49 Why NAD shortages hit the brain hardest
NAD: The Central Coenzyme in Cellular Energy, Biosynthesis, and Repair
NAD (nicotinamide adenine dinucleotide) acts like the "wiring" in a battery-powered system, distributing high-energy electrons from food to power life's essential processes. Think of it as the copper wires in an electric vehicle like a Ford F-150 Lightning: the battery stores electrons, and NAD shuttles them to drivetrains (muscles), wipers (maintenance), and AC (repair).
NAD exists in oxidized (NAD⁺) and reduced (NADH) forms for catabolism—converting fuel (proteins, fats, carbs) to ATP (cellular energy currency) via the electron transport chain. High-energy electrons flow "downhill" from NADH to lower-energy carriers, pumping protons to drive ATP synthesis—unlike burning food, which wastes electrons as smoke.
Complementing this, NADP⁺ and NADPH handle anabolism: NADPH redirects electrons to build lipids, proteins, RNA, DNA, and detoxify reactive oxygen species (ROS) from metabolism or oxygen exposure. These roles cluster into three buckets: fuel-to-ATP conversion, building/repairing cellular components, and maintenance against damage.
Key Insight: Unlike direct fuel burning, NAD couples electron transfers precisely to cellular work—enabling muscle contraction, memory, and heartbeats without energy loss.
NAD Consumption in DNA Repair and Gene Regulation
Beyond redox, NAD fuels "consumer" enzymes that prioritize repair and signaling when resources are limited. PARP1 (poly-ADP-ribose polymerase 1), a major NAD consumer, detects DNA damage (e.g., double-strand breaks from ROS or radiation) and polymerizes ADP-ribose from NAD into signals recruiting repair enzymes. Excessive damage triggers cell death to prevent cancer.
The PARP superfamily (16+ members) modifies proteins with mono- or poly-ADP-ribose for signaling; sirtuins (NAD-dependent deacetylases) remove acetyl groups from histones/lysines, regulating genes (often silencing) and enzyme activity. CD38 (ADP-ribosyl cyclase) cleaves NAD to release calcium for signaling.
Why this matters: Limiting NAD starves repair/gene regulation, amplifying damage in inflammation or aging—cells triage catabolism first. Tissues like liver synthesize NAD robustly from precursors (tryptophan, nicotinic acid, nicotinamide, NR), exporting to needy organs like brain (lacking de novo synthesis).
Does NAD Decline with Age? Blood vs. Tissue Realities
NAD levels do not universally decline in human blood with age—normal adults maintain ~20 μM NAD⁺ volumetrically, unlike mitochondrial disease patients (low) or supplementers (2x higher). However, tissue NAD pools incontrovertibly decline or disturb in aging-related conditions. Animal studies confirm drops in muscle, liver, brain; human parallels likely via inflammation/microbiome.
Blood NAD reflects diet/supplements (e.g., liver/spinach rich in precursors breaking to NR/nicotinamide) but poorly mirrors tissues—you can't biopsy brain/liver casually.
Warning/Common Misconception: "NAD crashes with age" oversimplifies; blood stays stable in healthy elderly, but diseases (obesity, diabetes) disrupt tissue NAD via inflammation, not just chronological age.
Major Drivers of NAD Depletion: Inflammation Takes Center Stage
Inflammation activates PARPs (e.g., 5 upregulated in COVID via dsRNA detection), consuming NAD for innate immune response—common to viruses, ROS, endotoxins. Chronic cases (obesity, Alzheimer's, heart disease) sustain this, taxing NADPH for ROS detoxification.
These connect to prior roles: inflammation ramps PARP/sirtuin demand, depleting redox pools—explaining "inflammaging."
Boosting NAD: Why Precursors Like NR, Not Direct NAD or NMN?
Cells can't uptake phosphorylated NAD/NMN (phosphates block transport)—oral NAD IVs degrade painfully to NR/nicotinamide, invoking innate immunity without entry. NR (nicotinamide riboside), the largest cell-penetrable NAD piece, enters via nucleoside transporters; NRK (NR kinase) adds phosphate, then amidated to NMN/NAD.
NR superiority:
Important: Direct NAD supplements waste money—degrade to precursors; IV NR emerging but oral has more data.
Clinical Evidence: NR's Proven and Emerging Benefits
NR shines in inflammation/exercise, building on depletion drivers.
Lifestyle Strategies: Prioritize Inflammation Reduction and Exercise
Address root drivers first—NR augments, doesn't replace.
Connection: Exercise counters depletion by upregulating synthesis, linking to energy/recovery roles.
Dosing, Safety, Testing, and When to Use NR
Dose: 500-1000mg/day (clinical standard; safe to 3g in some); morning with food (mimics nutrient/coenzyme rebuild). No need beyond—individual variability exists.
Safety:
Dr. Brenner's lab (brenerlab.net) pioneered NR via NAD synthetase discovery (glutamine-fueled pathway).
Many symptoms attributed to aging are also consistent with chronic inflammatory stress and impaired NAD metabolism. Dr. Charles Brenner explains the mechanisms, the human data, and what interventions actually move the needle. He also cuts through the crowded world of NAD boosters, including oral NAD pills, NMN, NR, and NAD IV drips, clarifying what actually raises NAD in humans and what emerging research suggests about NR for lowering inflammation and improving recovery.
CHAPTERS:
00:00:00 Introduction
00:01:58 Why disease states disrupt NAD levels
00:06:42 How coronavirus infection impacts NAD levels
00:09:55 Can diet and supplements artificially inflate NAD levels?
00:11:49 Why blood NAD might not show the full picture
00:13:20 How obesity and insulin resistance drain NAD resources
00:16:01 Does poor sleep disrupt NAD levels?
00:16:53 The anti-inflammatory effects of nicotinamide riboside (NR)
00:21:38 Can a single lifestyle change restore NAD?
00:24:22 Cognitive benefits of NAD precursors
00:27:58 Should you measure your NAD levels?
00:30:59 Does exercise boost NAD—and if so, which type?
00:33:01 Can NAD precursors speed exercise recovery?
00:35:35 Is acute sleep loss enough to lower NAD?
00:37:07 Does NR supplementation during pregnancy benefit offspring?
00:41:42 Safety of nicotinamide riboside during pregnancy
00:43:48 Could NR supplementation support fertility?
00:44:58 Shift work and jet lag—can NAD precursors help?
00:47:41 Morning or night—when should you take NR?
00:50:41 NAD supplements vs. precursors—what actually boosts NAD?
00:54:28 NAD IV drips—real benefits or just hype?
00:55:36 Oral vs. IV nicotinamide riboside—what’s more effective?
00:57:06 Do oral NAD supplements genuinely raise NAD levels?
00:58:58 NMN vs. NR—does being ‘one step closer’ really matter?
01:02:06 Does the gut microbiome influence NAD production?
01:04:44 Could NR supplementation enhance immune function?
01:08:02 Can NR supplementation improve peripheral artery disease?
01:12:26 Can NR realistically reduce liver fat?
01:17:33 Does NR supplementation give athletes a recovery edge?
01:19:18 What’s a safe dosage for nicotinamide riboside?
01:21:21 Resveratrol and pterostilbene—beneficial pairing or pointless stack?
01:22:57 NAD precursor supplements—why sourcing matters
01:25:09 Do NAD precursors increase cancer risk?
01:30:55 Is NR worth supplementing for healthy individuals?
01:33:43 From enzyme nerd to NAD pioneer (Brenner’s origin story)
01:38:13 Simplifying NAD’s role in energy and repair
01:45:00 Why DNA repair depends heavily on NAD
01:46:50 The PARP/NAD‑consumption mechanism
01:49:29 NAD’s role in gene regulation
01:51:49 Why NAD shortages hit the brain hardest
NAD: The Central Coenzyme in Cellular Energy, Biosynthesis, and Repair
NAD (nicotinamide adenine dinucleotide) acts like the "wiring" in a battery-powered system, distributing high-energy electrons from food to power life's essential processes. Think of it as the copper wires in an electric vehicle like a Ford F-150 Lightning: the battery stores electrons, and NAD shuttles them to drivetrains (muscles), wipers (maintenance), and AC (repair).
NAD exists in oxidized (NAD⁺) and reduced (NADH) forms for catabolism—converting fuel (proteins, fats, carbs) to ATP (cellular energy currency) via the electron transport chain. High-energy electrons flow "downhill" from NADH to lower-energy carriers, pumping protons to drive ATP synthesis—unlike burning food, which wastes electrons as smoke.
Complementing this, NADP⁺ and NADPH handle anabolism: NADPH redirects electrons to build lipids, proteins, RNA, DNA, and detoxify reactive oxygen species (ROS) from metabolism or oxygen exposure. These roles cluster into three buckets: fuel-to-ATP conversion, building/repairing cellular components, and maintenance against damage.
Key Insight: Unlike direct fuel burning, NAD couples electron transfers precisely to cellular work—enabling muscle contraction, memory, and heartbeats without energy loss.
NAD Consumption in DNA Repair and Gene Regulation
Beyond redox, NAD fuels "consumer" enzymes that prioritize repair and signaling when resources are limited. PARP1 (poly-ADP-ribose polymerase 1), a major NAD consumer, detects DNA damage (e.g., double-strand breaks from ROS or radiation) and polymerizes ADP-ribose from NAD into signals recruiting repair enzymes. Excessive damage triggers cell death to prevent cancer.
The PARP superfamily (16+ members) modifies proteins with mono- or poly-ADP-ribose for signaling; sirtuins (NAD-dependent deacetylases) remove acetyl groups from histones/lysines, regulating genes (often silencing) and enzyme activity. CD38 (ADP-ribosyl cyclase) cleaves NAD to release calcium for signaling.
Why this matters: Limiting NAD starves repair/gene regulation, amplifying damage in inflammation or aging—cells triage catabolism first. Tissues like liver synthesize NAD robustly from precursors (tryptophan, nicotinic acid, nicotinamide, NR), exporting to needy organs like brain (lacking de novo synthesis).
Does NAD Decline with Age? Blood vs. Tissue Realities
NAD levels do not universally decline in human blood with age—normal adults maintain ~20 μM NAD⁺ volumetrically, unlike mitochondrial disease patients (low) or supplementers (2x higher). However, tissue NAD pools incontrovertibly decline or disturb in aging-related conditions. Animal studies confirm drops in muscle, liver, brain; human parallels likely via inflammation/microbiome.
Blood NAD reflects diet/supplements (e.g., liver/spinach rich in precursors breaking to NR/nicotinamide) but poorly mirrors tissues—you can't biopsy brain/liver casually.
Warning/Common Misconception: "NAD crashes with age" oversimplifies; blood stays stable in healthy elderly, but diseases (obesity, diabetes) disrupt tissue NAD via inflammation, not just chronological age.
Major Drivers of NAD Depletion: Inflammation Takes Center Stage
Inflammation activates PARPs (e.g., 5 upregulated in COVID via dsRNA detection), consuming NAD for innate immune response—common to viruses, ROS, endotoxins. Chronic cases (obesity, Alzheimer's, heart disease) sustain this, taxing NADPH for ROS detoxification.
- Obesity/metabolic syndrome: High-fat diets induce T2D in mice, disturbing liver NAD (PARP-centered), degrading ROS detox; human fat/liver biopsies promising but pending.
- Sleep/circadian disruption: Mice lose NAD synchrony with age; shift work/jet lag assuredly disturbs via misaligned synthesis cues.
- Alcohol: Liver NAD disturbed.
- Other: Sun (skin), heart failure, neurodegeneration, microbiome variations.
These connect to prior roles: inflammation ramps PARP/sirtuin demand, depleting redox pools—explaining "inflammaging."
Condition | NAD Impact Mechanism | Evidence Level |
Acute Infection (e.g., COVID) | PARP activation on dsRNA | Mouse/human lung data |
Obesity/T2D | ROS overload, PARP↑ | Mouse liver; human pending |
Chronic Inflammation | Sustained consumer enzymes | 8 human RCTs (NR anti-inflammatory) |
Sleep Loss | Circadian desynchrony | Mouse models |
Boosting NAD: Why Precursors Like NR, Not Direct NAD or NMN?
Cells can't uptake phosphorylated NAD/NMN (phosphates block transport)—oral NAD IVs degrade painfully to NR/nicotinamide, invoking innate immunity without entry. NR (nicotinamide riboside), the largest cell-penetrable NAD piece, enters via nucleoside transporters; NRK (NR kinase) adds phosphate, then amidated to NMN/NAD.
NR superiority:
- Upregulated in stress (e.g., heart failure NMRK2 craves NR).
- Safety-tested (Niagen); NMN often impure (17/20 products fail labels), converts back to NR anyway.
- Nicotinic acid flushes at high doses; nicotinamide safe but less potent in stressed tissues.
Important: Direct NAD supplements waste money—degrade to precursors; IV NR emerging but oral has more data.
Clinical Evidence: NR's Proven and Emerging Benefits
NR shines in inflammation/exercise, building on depletion drivers.
- Anti-inflammatory: 8 RCTs (e.g., elderly muscle biopsies: sustained IL-6↓ post-NR; COPD primary endpoint met).
- Exercise recovery/performance: Anecdotal (Patriots/Tom Brady used Niagen); boosts NAD synthesis genes; synergizes with training.
- Peripheral artery disease (PAD): RCT (n~75/arm): NR↑ 6-min walk vs. placebo decline (resveratrol blocked).
- Cognition (MCI/Long COVID): ↑ cerebral blood flow; within-group executive function/sleep↑.
- Liver fat: 21%→11% in T2D elderly (p=0.13, near-significant).
- Infection: Phase 2/3 cocktails shorten COVID recovery.
Outcome | Key Trial | NR Effect |
Inflammation | Elderly grip (secondary); COPD | ↓IL-6/10, sputum markers |
PAD Walking | McDermott 3-arm | ↑6-min test |
Liver Fat | Dahl et al. 2018 | 10% absolute ↓ |
Lifestyle Strategies: Prioritize Inflammation Reduction and Exercise
Address root drivers first—NR augments, doesn't replace.
- Reduce inflammation: Weight loss (GLP-1 + resistance training for obese); quit alcohol/drugs; manage stress.
- Exercise: Any type boosts NAD biosynthetic genes/mitochondrial biogenesis; aerobic/resistance both rational.
- Sleep/circadian: Align eating/light (bright AM sun); shift workers: "breakfast" (coffee+NR) at shift start.
- Diet: Liver/spinach for precursors; no universal fasting.
Connection: Exercise counters depletion by upregulating synthesis, linking to energy/recovery roles.
Dosing, Safety, Testing, and When to Use NR
Dose: 500-1000mg/day (clinical standard; safe to 3g in some); morning with food (mimics nutrient/coenzyme rebuild). No need beyond—individual variability exists.
Safety:
- Sourcing critical: Third-party tested (NSF); Amazon risks contaminants/low actives.
- Cancer: Preventative (Australian nicotinamide RCTs ↓ skin cancer); no population risk, despite contrived mouse tumors.
- No stacks needed: Resveratrol/pterostilbene useless/block NR (↑LDL).
- Testing: Unnecessary for healthy (like aspirin); clinical trials only.
Dr. Brenner's lab (brenerlab.net) pioneered NR via NAD synthetase discovery (glutamine-fueled pathway).
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