NAD+

NAD+ functions as an electron carrier in redox reactions, shuttling electrons between enzymes during metabolic processes like glycolysis, the citric acid cycle, and oxidative phosphorylation. Without adequate NAD+, cells cannot efficiently convert food into usable energy.

Sirtuin Activation: NAD+ is consumed as a substrate by sirtuins (SIRT1-SIRT7), a family of deacetylase enzymes. SIRT1 deacetylates histones and transcription factors like PGC-1alpha and FOXO3, promoting mitochondrial biogenesis, stress resistance, and DNA repair. SIRT3 operates in the mitochondria, regulating oxidative metabolism and protecting against reactive oxygen species. Each sirtuin reaction consumes one molecule of NAD+, producing nicotinamide as a byproduct.

PARP Interaction: Poly(ADP-ribose) polymerases (PARPs) also consume NAD+ during DNA repair. PARP1 is activated in response to DNA strand breaks and uses NAD+ to build poly(ADP-ribose) chains that recruit repair machinery. In conditions of chronic DNA damage (aging, oxidative stress), PARP activity can deplete NAD+ reserves, leaving less available for sirtuins. This competition between PARPs and sirtuins is a key dynamic in aging biology.

CD38 and NAD+ Consumption: The enzyme CD38 is one of the largest consumers of NAD+ in the body. CD38 expression increases with age and inflammation, accelerating NAD+ depletion. Inhibiting CD38 or replenishing NAD+ directly are two strategies researchers are exploring to restore youthful NAD+ levels.

Circadian Regulation: NAD+ levels oscillate on a circadian rhythm, peaking during waking hours. The enzyme NAMPT (nicotinamide phosphoribosyltransferase), which recycles nicotinamide back into NAD+, is clock-controlled. Disrupted circadian rhythms (shift work, poor sleep) impair NAD+ recycling, creating a link between sleep quality and cellular energy status.

Cellular Energy and Mitochondrial Function NAD+ is required for mitochondrial electron transport chain function. Restoring NAD+ levels in aged or stressed cells improves ATP production and mitochondrial membrane potential. In mouse studies, NAD+ repletion reversed age-related mitochondrial dysfunction in muscle tissue within one week. Users of IV NAD+ frequently report a noticeable increase in physical and mental energy, often within hours of infusion.

DNA Repair and Genomic Stability Every day, each cell sustains tens of thousands of DNA lesions from oxidative stress, replication errors, and environmental insults. NAD+ fuels both sirtuin-mediated chromatin maintenance and PARP-mediated strand break repair. Declining NAD+ means slower repair, more accumulated mutations, and higher cancer risk. Supplementation aims to keep the repair machinery running at full capacity.

Cognitive Function The brain is metabolically expensive, consuming roughly 20% of the body's energy at rest. NAD+ depletion in neurons contributes to cognitive decline, neuroinflammation, and neurodegeneration. Animal studies show NAD+ supplementation improves memory, reduces neuroinflammation, and protects against beta-amyloid toxicity. Early human data suggests improved mental clarity and reduced brain fog, though large-scale trials are still needed.

Metabolic Health NAD+ supplementation improves insulin sensitivity, lipid profiles, and glucose metabolism in preclinical models. SIRT1 activation by NAD+ enhances fat oxidation and suppresses inflammatory pathways linked to metabolic syndrome. These effects are especially relevant for the MOTS-c stacking approach, which targets mitochondrial metabolism from a complementary angle.

Exercise Performance and Recovery NAD+ supports the metabolic pathways that fuel exercise. Mouse studies demonstrate improved running endurance, better muscle function, and faster recovery after NAD+ precursor supplementation. The mechanism involves PGC-1alpha activation via SIRT1, driving mitochondrial biogenesis in skeletal muscle.

Anti-Aging and Longevity The convergence of sirtuin activation, DNA repair, mitochondrial optimization, and reduced inflammation positions NAD+ as a broad-spectrum anti-aging intervention. Combined with Epitalon for telomere maintenance, it covers two of the most studied hallmarks of aging.

Common Side Effects (IV infusion): - Flushing, warmth, or tingling during infusion (very common, usually transient) - Nausea or stomach discomfort - Headache during or after infusion - Chest tightness or shortness of breath at high infusion rates (slow the drip to resolve)

Common Side Effects (sublingual/oral): - Mild GI discomfort or nausea - Headache - Fatigue paradox: some users feel tired before feeling energized as cellular repair ramps up

Less Common: - Anxiety or restlessness (especially with high-dose IV) - Insomnia if taken late in the day - Muscle cramping - Vivid dreams

Contraindications and Cautions: - Cancer patients should consult an oncologist before NAD+ therapy. While NAD+ supports DNA repair in healthy cells, there is theoretical concern that it could also support DNA repair in cancer cells, though evidence is mixed. - Individuals on blood thinners or diabetes medications should coordinate with their physician, as NAD+ may affect glucose and clotting pathways. - Pregnant or breastfeeding women should avoid NAD+ supplementation due to insufficient safety data. - IV NAD+ should be administered by trained medical professionals in a clinical setting.