NAD+
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Essential coenzyme (not a peptide) that powers sirtuin-mediated longevity pathways, PARP DNA repair, and mitochondrial energy metabolism — with the strongest human clinical trial data of any "supplement-category" compound in this vault.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | NAD, Nicotinamide Adenine Dinucleotide, Coenzyme I, beta-NAD; Precursors: NMN (nicotinamide mononucleotide), NR (nicotinamide riboside) |
| Category | Anti-Aging / Mitochondrial / Metabolic |
| Sequence | Not a peptide — NAD+ is a dinucleotide coenzyme. Included in this vault due to its central role in peptide therapy protocols and longevity medicine. |
| Molecular Weight | 663.43 Da |
| Molecular Formula | C21H27N7O14P2 |
| PubChem CID | 5893 |
| Administration | IV / SubQ / Oral (as NMN or NR precursor supplements) |
| Typical Dose Range | IV: 250-750 mg infusion; Oral NMN: 250-900 mg/day; Oral NR: 500-2000 mg/day |
| Half-Life | IV NAD+: rapid clearance (minutes to hours); NMN/NR oral: variable based on formulation |
| Storage | IV formulation: 2-8 C, protect from light, single use. Lyophilized SubQ: -20 C standard. Oral NMN/NR: cool, dry, dark. |
| FDA Status | Research-only (IV NAD+); NMN and NR sold as dietary supplements. Not FDA-approved as a drug for any indication. |
| WADA Status | Not prohibited (classified as dietary supplement) |
Mechanism of Action
NAD+ (nicotinamide adenine dinucleotide) is a coenzyme present in every living cell, serving as the essential electron carrier in glycolysis, the TCA cycle, and oxidative phosphorylation — the core pathways of ATP production. Beyond energy metabolism, NAD+ is the obligate substrate for three critical enzyme families: the sirtuins (SIRT1-7), the PARPs (poly-ADP-ribose polymerases), and CD38/CD157 ectoenzymes (PMID-24786309, PMID-26785480).
The "NAD World" concept, articulated by Imai and Guarente, describes a systemic regulatory network in which the rate-limiting NAD+ biosynthetic enzyme NAMPT produces NMN, which is converted to NAD+, which in turn activates sirtuins — particularly SIRT1 (nuclear, deacetylates PGC-1alpha for mitochondrial biogenesis) and SIRT3 (mitochondrial, regulates oxidative phosphorylation complexes). This NAMPT-NMN-NAD+-sirtuin axis declines with age: NAD+ levels fall approximately 50% between ages 40 and 60, contributing to mitochondrial dysfunction, impaired DNA repair, and metabolic deterioration (PMID-28721271, PMID-29514064).
PARP enzymes consume NAD+ to repair DNA single-strand and double-strand breaks. As DNA damage accumulates with age, PARP activity increases, creating a "NAD+ sink" that further depletes the cellular pool. Simultaneously, CD38 expression increases with age-related inflammation (inflammaging), and CD38 is now recognized as the dominant NAD+-consuming enzyme in mammalian tissues. These two sinks — PARP and CD38 — are the primary drivers of age-related NAD+ decline.
Supplementation strategies aim to restore NAD+ pools via precursors: NMN (nicotinamide mononucleotide) enters the salvage pathway directly, while NR (nicotinamide riboside) is converted to NMN by NR kinases. IV NAD+ bypasses oral bioavailability limitations entirely. Human RCTs have demonstrated that NMN supplementation increases blood NAD+ levels and improves insulin sensitivity in prediabetic women (PMID-33888596), and NR supplementation raises NAD+ levels in healthy older adults (PMID-29599478).
Key Research Areas
- NMN and insulin sensitivity — Landmark 2021 Science paper demonstrated NMN (250 mg/day, 10 weeks) improved muscle insulin sensitivity in prediabetic postmenopausal women, with increased insulin-stimulated glucose disposal (PMID-33888596).
- NR in healthy aging — Martens et al. (2018, Nature Communications) showed NR (1000 mg/day, 6 weeks) safely elevated NAD+ metabolites in healthy older adults and showed trends toward reduced arterial stiffness and blood pressure (PMID-29599478).
- Negative result: NR in obese men — Dollerup et al. (2018, AJCN) found NR (2000 mg/day, 12 weeks) did NOT improve insulin sensitivity, beta-cell function, or metabolic markers in obese, insulin-resistant men. This is an important null finding that tempers enthusiasm (PMID-29992272).
- NMN dose-ranging and safety — Yi et al. (2023, GeroScience) established safety and tolerability of NMN across multiple dose levels in human subjects (PMID-36482258).
- NAD+/sirtuin biology reviews — Foundational reviews by Imai & Guarente and Sinclair articulate the "NAD World" hypothesis and therapeutic rationale (PMID-28721271, PMID-29514064).
- Blood-brain barrier repair — NAD+ rescues aging-induced BBB damage via the CX43-PARP1 axis, relevant to neurodegeneration (PMID-37683629).
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 4 | Yoshino NMN/insulin (Science 2021), Martens NR/aging (Nat Comms 2018), Dollerup NR/obesity (AJCN 2018 — negative), Yi NMN dose-ranging (GeroScience 2023) |
| Human observational | 0 | — |
| Animal in vivo | 1 | BBB repair via CX43-PARP1 axis |
| In vitro | 1 | Neuroinflammation/senescence in AD model |
| Systematic reviews | 0 | — |
| Narrative reviews | 5 | Imai/Guarente NAD World, Sinclair NAD+ review, Verdin aging/metabolism, NAD+ supplementation overview, dietary supplementation directions |
Evidence quality note: NAD+/NMN/NR have the strongest human clinical evidence of any supplement-category compound in this vault, with 4 Level II human RCTs. However, results are mixed — the Dollerup NR trial was negative for metabolic endpoints in obese men, underscoring that NAD+ boosting is not universally beneficial across all populations and endpoints.
Clinical Applications
- Anti-Aging — Core longevity compound; sirtuin activation, DNA repair support, mitochondrial biogenesis
- Cognitive Enhancement — NAD+ supports neuronal energy metabolism, neurotransmitter synthesis
- Neuroprotection — BBB repair, neuroinflammation reduction, PARP-mediated DNA repair in neurons
- Type 2 Diabetes — NMN improved insulin sensitivity in prediabetic women (PMID-33888596)
- Metabolic Syndrome — Metabolic regulation via SIRT1/PGC-1alpha/AMPK axis
Protocols Using This Peptide
Ageless Peps Products
- AP-NAD-Vial — NAD+ Vial, $65, for SubQ/IV administration
- AP-NAD-Gummies — NAD Anti-Aging Gummies, NAD 3000mg + Resveratrol + Ginseng + TMG, $49
- AP-Cognitive-Gummies — Cognitive Support Gummies, contains NAD + brain-supporting nutrients, $39
Dosing Reference
Research Dosing Ranges (from literature)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| IV | 250-750 mg infusion | Daily (loading) to weekly (maintenance) | 4-10 days loading; ongoing maintenance | Clinical integrative practice |
| IV (addiction recovery) | 500-1500 mg over 4-8 hours | Daily | 4-10 days | Addiction recovery protocols |
| SubQ | 50-100 mg | 2-3x per week | Ongoing with breaks | Maintenance protocol |
| Oral (NMN) | 250-900 mg/day | Daily | Ongoing | PMID-33888596, PMID-36482258 |
| Oral (NR) | 500-2000 mg/day | Daily | Ongoing | PMID-29599478, PMID-29992272 |
Cycling
IV loading protocols typically run 4-10 days of daily infusions followed by weekly or biweekly maintenance. SubQ protocols are administered 2-3x per week on an ongoing basis with periodic breaks. Oral NMN/NR supplementation is generally taken daily on an ongoing basis. MTHFR mutation carriers should co-administer TMG (trimethylglycine) 500-1000 mg daily to support methylation balance and prevent homocysteine accumulation.
Contraindications & Safety
- Contraindications: Active malignancy (theoretical concern — NAD+ fuels all rapidly dividing cells, including cancer cells; may support tumor metabolism). This remains theoretical but warrants caution.
- Common side effects: IV: "NAD+ flush" (warmth, chest tightness, nausea — managed by slowing infusion rate), hypotension with rapid IV administration. Oral: GI upset, flushing (niacin pathway activation). SubQ: injection site reactions.
- Drug interactions: May theoretically affect chemotherapy efficacy (NAD+ supports cellular energy that chemotherapy aims to disrupt). MTHFR variants require TMG co-administration. May potentiate effects of other sirtuin activators (resveratrol, etc.).
- Pregnancy/nursing: Insufficient data; not recommended.
- Special populations: MTHFR mutation carriers must co-administer TMG to manage homocysteine. Geriatric patients are the primary target population. IV administration requires clinical supervision.
Synergistic Combinations
- SS-31 + NAD+ — Comprehensive cellular energy restoration: SS-31 optimizes mitochondrial membrane (cardiolipin), NAD+ fuels sirtuin/PARP pathways
- MOTS-C + NAD+ — AMPK activation (MOTS-C) synergizes with NAD+/sirtuin axis for metabolic optimization
- Epitalon + NAD+ — Multi-pathway longevity: telomere maintenance (Epitalon) + sirtuin activation (NAD+)
- GHK-Cu + NAD+ — Extracellular matrix rejuvenation paired with intracellular metabolic restoration
- TMG (Trimethylglycine) — Essential co-supplement for methylation support, especially in MTHFR variants
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| PMID-24786309 – NAD+ and sirtuins in aging and disease. | NAD+ and sirtuins in aging and disease | 2014 | Narrative review |
| PMID-26785480 – NAD+ in aging, metabolism, and neurodegeneration. | NAD+ in aging, metabolism, and neurodegeneration | 2015 | Narrative review |
| PMID-28721271 – NAD World Imai Guarente sirtuin biology review | NAD+ and sirtuin biology (Imai & Guarente) | 2017 | Narrative review |
| PMID-29514064 – NAD+ therapeutic potential Sinclair review | NAD+ therapeutic potential (Sinclair) | 2018 | Narrative review |
| PMID-29599478 – NR supplementation in healthy older adults Martens | Chronic NR supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults | 2018 | RCT |
| PMID-29992272 – NR in obese insulin-resistant men Dollerup negative | Nicotinamide riboside does not alter insulin sensitivity in obese men — a negative result | 2018 | RCT |
| PMID-33888596 – NMN insulin sensitivity prediabetic women Yoshino Science | NMN increases muscle insulin sensitivity in prediabetic women | 2021 | RCT |
| PMID-34497121 – NAD supplementation reduces neuroinflammation AD model | NAD+ supplementation reduces neuroinflammation and cell senescence in Alzheimer's model | 2021 | Animal in vivo |
| PMID-36482258 – NMN dose-ranging safety study Yi GeroScience | NMN dose-ranging safety and tolerability in humans | 2023 | RCT |
| PMID-37068054 – Dietary Supplementation With NAD+-Boosting Compounds in Huma | Dietary supplementation with NAD+-boosting compounds in humans: current knowledge | 2023 | Narrative review |
| PMID-37683629 – NAD rescues aging-induced BBB damage CX43-PARP1 | NAD+ rescues aging-induced blood-brain barrier damage via CX43-PARP1 axis | 2023 | Animal in vivo |
References
- PMID-24786309 — NAD+/sirtuin review (Imai)
- PMID-26785480 — NAD+ in aging (Verdin)
- PMID-28721271 — NAD World (Imai & Guarente)
- PMID-29514064 — Therapeutic potential (Sinclair)
- PMID-29599478 — NR in older adults (Martens, Nature Comms)
- PMID-29992272 — NR negative result in obesity (Dollerup, AJCN)
- PMID-33888596 — NMN insulin sensitivity (Yoshino, Science)
- PMID-34497121 — NAD+ in AD model
- PMID-36482258 — NMN dose-ranging (Yi, GeroScience)
- PMID-37068054 — NAD+ supplementation review
- PMID-37683629 — BBB repair via NAD+
Research Purposes Only. This vault is for educational and research reference. Nothing constitutes medical advice. Peptide therapies vary in regulatory status by jurisdiction. Always consult a qualified healthcare provider before initiating any peptide protocol. Dosing information reflects ranges reported in peer-reviewed literature and practitioner guides and must be individualized by a clinician.
FDA Disclaimer: The products and claims made about specific products have not been evaluated by the United States Food and Drug Administration and are not approved to diagnose, treat, cure, or prevent disease.
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#peptide #anti-aging #mitochondrial #metabolic #iv #subq #oral