Nad Plus: Mechanism of Action
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Mechanism of Action
1. Sirtuin Activation (SIRT1–7)
Sirtuins are NAD+-dependent protein deacylases (class III histone deacetylases). They bind NAD+ and an 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 → mitochondrial biogenesis; FOXO → stress resistance; also deacetylates LKB1 → activates AMPK → positive feedback loop increasing NAD+ and fatty acid oxidation[6]
- SIRT3 Pathway: Mitochondrial localization; deacetylates MnSOD → enhanced antioxidant defense; activates 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 than sirtuins, can outcompete for NAD+ during DNA damage. Excessive activation → NAD+/ATP depletion → parthanatos (cell death).[6][7]
3. CD38/CD157 Hydrolysis
CD38 is the 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 increases with aging, directly driving NAD+ decline.[1][8]
4. SARM1 Axonal NADase
SARM1 contains a TIR domain with intrinsic NADase activity. Activated by nerve injury → rapid 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 modulation.[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 bioavailability; GRAS status |
| NMN | Dephosphorylated → NR by CD73 extracellularly | Slc12a8 transporter in small intestine |
| NAM | Passive diffusion | Feedback-inhibits sirtuins/PARPs at high doses |
References
- Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology. 2021;22(2):119-141.
- 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, metabolism, and neurodegeneration. Science. 2015;350(6265):1208-1213.
- Christen S, Redeuil K, Goulet L, et al. The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans. Nature Metabolism. 2025 Jan 15 [Epub].
- Trammell SAJ, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely 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 that promotes pathological axonal degeneration. Neuron. 2017;93(6):1334-1343.e5.
- Tarragó MG, Chini CCS, Kanamori KS, et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell Metabolism. 2018;27(5):1081-1095.e10.
- Zhang H, Ryu D, Wu Y, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-1443.
- Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229.
- Cantó C, Houtkooper RH, Pirinen E, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metabolism. 2012;15(6):838-847.
- Brakedal B, Dölle C, Riber F, et al. The NADPARK study: a randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease. Cell Metabolism. 2022;34(3):396-407.e6.
- Wu J, et al. Nicotinamide riboside reduces pTau217 in older adults with mild cognitive impairment. Alzheimer's & Dementia: TRCI. 2025.
- Das A, Huang GX, Bonkowski MS, et al. Impairment of an endothelial NAD+-H₂S signaling network is a reversible cause of vascular aging. Cell. 2018;173(1):74-89.e20.
- 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 of the American Society of Nephrology. 2017;28(8):2337-2352.
- Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners. Journal of the International Society of Sports Nutrition. 2021;18(1):54.
- Mills KF, Yoshida S, Stein LR, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism. 2016;24(6):795-806.
- 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, increases circulating NMN and NAD+ in a randomized clinical trial. Journal of Clinical Endocrinology & Metabolism. 2023;108(4):862-871.
- Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications. 2018;9(1):1286.
- Wang DD, et al. Nicotinamide riboside in heart failure with reduced 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 randomized, double-blind, placebo-controlled human pilot study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2019;20(1-2):115-122.
- Grant R, Berg J, Mestayer R, et al. A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 hour intravenous infusion of NAD+. Frontiers in Aging Neuroscience. 2019;11:257.
- Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metabolism. 2011;14(4):528-536.
- Poljsak B, Kovač V, Špalj S, Milisav I. The central role of the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases. International Journal of Molecular Sciences. 2023;24(3):2959.
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