Research Brief
Nad Plus: Mechanism of Action
26 Citacoes PubMedRevisado por EspecialistasCertificado GMPUltima Revisao: julho de 2026
Mecanismo de Acao
1. Sirtuin Activation (SIRT1–7)
Sirtuins are NAD+-dependent protein deacylases (class III histone deacetylases). They bind NAD+ e um(a) acetylated target protein, cleaving the glycosidic bond to release nicotinamide (NAM) and generate O-acetyl-ADP-ribose. Km range: 94–888 µM.[6]
- SIRT1 Pathway: Deacetylates PGC-1α → biogenese mitocondrial; FOXO → stress resistance; also deacetylates LKB1 → ativa AMPK → positivo(a) feedback loop increasing NAD+ and fatty acid oxidation[6]
- SIRT3 Pathway: Mitochondrial localization; deacetylates MnSOD → aprimorou antioxidante defense; ativa OXPHOS enzymes[6]
2. PARP1/2 DNA Repair
PARP1 detects DNA strand breaks → consumes NAD+ to build poly(ADP-ribose) chains → recruits repair enzymes (XRCC1). Km 20–97 µM — higher affinity do que sirtuins, can outcompete for NAD+ during DNA damage. Excessive ativacao → NAD+/ATP depletion → parthanatos (cell death).[6][7]
3. CD38/CD157 Hydrolysis
CD38 e o(a) major regulator of tissue NAD+ levels (Km ~15–25 µM). It hydrolyzes NAD+ into NAM and ADP-ribose, and cyclizes NAD+ into cADPR → Ca²⁺ mobilization from intracellular stores. CD38 expression aumenta with aging, directly driving NAD+ decline.[1][8]
4. SARM1 Axonal NADase
SARM1 contem a TIR domain with intrinsic NADase activity. Activated by nerve injury → rapido(a) axonal NAD+ depletion → local metabolic collapse and calcium influx → Wallerian degeneration.[7]
5. Extracellular Signaling
Extracellular NAD+ acts at P2X7 purinergic receptors on T-regulatory cells → ART2-P2X7 pathway → immune modulacao.[6]
Precursor Entry Mechanisms
| Precursor | Cellular Entry | Notes |
|---|---|---|
| NAD+ (direct) | Cannot passively cross plasma membrane | Exception: Connexin 43 in heart muscle |
| NR | Equilibrative nucleoside transporters (ENTs) | Best oral biodisponibilidade; GRAS status |
| NMN | Dephosphorylated → NR by CD73 extracellularly | Slc12a8 transporter in pequeno(a) intestine |
| NAM | Passive diffusion | Feedback-inibe sirtuins/PARPs at alto(a) doses |
Referencias
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- Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metabolism. 2018;27(3):529-547.
- Verdin E. NAD+ in aging, metabolismo, and neurodegeneration. Science. 2015;350(6265):1208-1213.
- Christen S, Redeuil K, Goulet L, et al. The differential impact of three diferente NAD+ boosters on circulatory NAD and microbial metabolismo in humans. Nature Metabolism. 2025 Jan 15 [Epub].
- Trammell SAJ, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is unicamente and orally bioavailable in mice and humans. Nature Communications. 2016;7(1):12948.
- Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends in Cell Biology. 2014;24(8):464-471.
- Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/interleukin-1 receptor domain possesses intrinsic NAD+ cleavage activity que promove pathological axonal degeneration. Neuron. 2017;93(6):1334-1343.e5.
- Tarragó MG, Chini CCS, Kanamori KS, et al. A potente and specific CD38 inhibitor melhora age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell Metabolism. 2018;27(5):1081-1095.e10.
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- Brakedal B, Dölle C, Riber F, et al. The NADPARK study: a randomizado phase I trial of nicotinamide riboside supplementation in Parkinson's disease. Cell Metabolism. 2022;34(3):396-407.e6.
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- Guan Y, Wang SR, Huang XZ, et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a sirtuin 1-dependent manner. Journal do(a) American Society of Nephrology. 2017;28(8):2337-2352.
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- Igarashi M, Nakagawa-Nagahama Y, Miura M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj Aging. 2022;8(1):5.
- Yi L, Maier AB, Tao R, et al. The efficacy and safety of β-nicotinamide mononucleotide supplementation in healthy middle-aged adults. GeroScience. 2023;45(1):29-43.
- Pencina KM, Lavu S, Dos Santos M, et al. MIB-626, an oral formulation of a microcrystalline unique polymorph of β-nicotinamide mononucleotide, aumenta circulating NMN and NAD+ in a randomizado ensaio clinico. Journal of Clinical Endocrinology & Metabolism. 2023;108(4):862-871.
- Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is bem tolerado(a) and elevates NAD+ in healthy middle-aged and older adults. Nature Communications. 2018;9(1):1286.
- Wang DD, et al. Nicotinamide riboside in insuficiencia cardiaca with reduziu ejection fraction. JACC: Basic to Translational Science. 2022.
- de la Rubia JE, Drehmer E, Platero JL, et al. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomizado, duplo-cego, controlado por placebo human pilot study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2019;20(1-2):115-122.
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- Poljsak B, Kovač V, Špalj S, Milisav I. The central role do(a) NAD+ molecule in o desenvolvimento of aging e o(a) prevention of cronico(a) age-related diseases. International Journal of Molecular Sciences. 2023;24(3):2959.
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