NAD⁺

Overview

Nicotinamide adenine dinucleotide (NAD⁺) is a ubiquitous redox coenzyme investigated for its roles in cellular metabolism and signaling. NAD⁺/NADH redox cycling mediates electron transfer across glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation in preclinical systems. Beyond redox, NAD⁺ serves as a substrate for sirtuins, PARPs, and CD38/CD157, linking energy status to DNA repair, gene regulation, calcium signaling, and mitochondrial programs. Age- and stress-related NAD⁺ decline has been associated with disrupted bioenergetics and repair pathways in preclinical literature; strategies to raise intracellular NAD⁺ using precursors (NR, NMN) are studied to probe these mechanisms.

Mechanistic Insights

• Redox Mediation: NAD⁺/NADH couples drive electron transfer to the respiratory chain, facilitating ATP synthesis in mitochondria and animal tissues.
• Sirtuin-Dependent Signaling: NAD⁺ activates class III deacetylases (SIRT1–SIRT7) that modulate FOXO and PGC-1α programs related to stress resistance and mitochondrial efficiency in cell/rodent models.
• DNA Damage Response (PARP Pathway): PARPs consume NAD⁺ to synthesize PAR chains recruiting repair factors; NAD⁺ limitation impairs these processes in preclinical assays.
• CD38/CD157 and Calcium/Immune Signaling:CD38/CD157 metabolize NAD⁺ to cADPR/NAADP, regulating calcium signaling and immune-cell activation in animal and cellular systems.
• Mitonuclear Crosstalk: NAD⁺ availability coordinates transcriptional programs and mitochondrial biogenesis, supporting proteostasis and unfolded-protein responses in preclinical models.

Key Research Findings / Observations

• Cellular Energy & Mitochondrial Function:Elevating NAD⁺ in mice associated with increased PGC-1α signaling and mitochondrial biogenesis; reversal of pseudohypoxic signatures and improved respiration (preclinical).
• DNA Repair & Genomic Stability: NAD⁺ required for PARP-dependent repair; depletion accelerates senescence markers and DNA damage in cell models; augmentation supports genome-maintenance signaling.
• Neuroprotection & Brain Aging: Increased NAD⁺ associated with enhanced neuronal respiration and reduced neuroinflammation via SIRT1/3 in preclinical systems.
• Metabolic Regulation & Insulin Signaling:NAD⁺/sirtuin–AMPK networks observed to improve hepatic glucose handling and lipid oxidation in rodent models receiving NAD⁺ precursors.
• Longevity & Cellular Homeostasis: Up-regulated stress-response and autophagy genes; mouse studies report improvements in healthspan/lifespan metrics (preclinical).
• Cardiovascular and Vascular Indices: Improved endothelial NO signaling and attenuated ischemia–reperfusion injury with higher NAD⁺ availability in animal work.
• Immunometabolism & Inflammation Control:Sirtuin–NF-κB interactions suppress pro-inflammatory signaling; CD38-driven NAD⁺ catabolism associated with inflammaging phenotypes in animal/cell studies.
• Circadian, Sleep, and Stress Pathways: NAD⁺ oscillates with CLOCK/BMAL1 networks; SIRT1-mediated deacetylation of PER2/BMAL1 modulates circadian amplitude in preclinical systems.

Research References

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