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What is NAD+ and how does it function in human cells?
Executive Summary
NAD+ is a ubiquitous cellular coenzyme that shuttles electrons in redox reactions and also serves as a substrate for enzymes that control DNA repair, gene expression, and cell signaling; its levels and turnover are central to metabolism and implicated in aging and disease. Multiple recent reviews and studies show NAD+ decline with age in models and humans, implicate NAD+-consuming enzymes such as sirtuins and CD38, and report that boosting NAD+ can reverse some dysfunctions in preclinical models while human translational results and long-term risks remain incompletely characterized [1] [2] [3].
1. What advocates and textbooks say about NAD+: the foundational claims that matter
The core claim across reviews and primary studies is that NAD+ is both an electron carrier and a regulatory metabolite, existing as oxidized NAD+ and reduced NADH and mediating redox balance in glycolysis, the TCA cycle, and oxidative phosphorylation. Sources present NAD+ as indispensable for energy metabolism and also as the essential co-substrate for NAD+-consuming enzymes—sirtuins, PARPs, and CD38—that regulate DNA repair, chromatin state, and signaling [1] [2]. Reviews emphasize a dual identity for NAD+: a metabolic hub that transfers electrons and a signaling molecule whose consumption controls downstream pathways. This dual role underpins claims linking NAD+ homeostasis to broad physiological states, and it frames the proposition that altering NAD+ levels could influence aging and disease processes [1] [2].
2. How NAD+ is produced and spent: the wiring diagram researchers emphasize
Analyses converge on three biosynthetic routes—de novo synthesis, the Preiss–Handler pathway, and the salvage pathway—plus explicit mention that salvage pathways dominate in mammalian tissues, recycling nicotinamide back into NAD+. NAD+-consuming enzymes create a high turnover demand: sirtuins require NAD+ for deacetylation, PARPs use it for ADP-ribosylation during DNA repair, and CD38 degrades NAD+ as part of signaling, all contributing to net NAD+ depletion when hyperactivated [1] [4] [5]. Reviews stress regulation of these pathways and enzymes as the mechanistic link between metabolic state, DNA damage responses, and intracellular NAD+ pools. The literature presented emphasizes that modulating biosynthesis or consumption is the mechanistic lever proposed for restoring NAD+ in aging or disease contexts [1] [4].
3. Evidence tying NAD+ to aging and disease: convergences and limits
Multiple reviews and experimental papers report age-associated declines in tissue NAD+ across rodents and observations in humans, associating low NAD+ with metabolic dysfunction, neurodegeneration, cancer risk, and frailty; restoring NAD+ in models often improves markers of function and longevity-related endpoints [2]. A 2025 mouse study links NAD+ boosting and SIRT2 activity to suppressed age-related inflammation and improved tissue function, showing mechanistic promise but remaining preclinical [3]. The literature also contains nuance: NAD+ depletion can both promote and sometimes restrain specific senescent phenotypes, and the complexity of cell-type-specific effects means causal inferences for humans are still provisional, with translational gaps between animal benefits and long-term outcomes in people [6] [7].
4. Therapeutic enthusiasm versus measured skepticism: where the debate stands
Reviews highlight NAD+ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) as attractive interventions that raise NAD+ in animals and in some short-term human studies, producing metabolic and cellular benefits in preclinical settings [4]. However, authors caution about unknowns: long-term safety, potential to promote certain cancers or maladaptive cell proliferation, optimal dosing, tissue-specific delivery, and interactions with NAD+-consuming enzymes are incompletely resolved [5] [6]. The literature frames NAD+ repletion as a promising translational avenue that requires controlled human trials and mechanistic biomarkers to balance benefits against risks, rather than a clinical panacea already proven for aging or chronic disease in humans [2] [6].
5. What recent (including 2025) work adds and where evidence is thin
The 2025 Aging Cell study shows that boosting NAD+ in mice, with a focus on SIRT2, reduces age-associated inflammation and preserves tissue function, lending timely mechanistic support for anti-inflammatory effects of NAD+ restoration [3]. This complements 2023–2024 reviews that integrate NAD+ with senescence biology and propose combined senolytic and NAD+-boosting strategies, highlighting emerging synergies but also complex bidirectional effects on senescence phenotypes [6] [7]. The gaps are pragmatic: human randomized, long-term trials demonstrating functional healthspan extension and safety are limited, and the field needs standardized biomarkers for NAD+ status and functional outcomes to move from promising animal biology to reliable clinical practice [2].
6. Bottom line for researchers, clinicians, and the public: what to take away
Across the evidence summarized, NAD+ is a central metabolic and signaling metabolite with robust mechanistic rationale linking it to cellular energy, DNA repair, and aging pathways. Preclinical studies and short-term human data justify continued investigation of NAD+ precursors and interventions targeting NAD+-consuming enzymes, but definitive clinical evidence of long-term benefit and safety in humans is not yet established. The literature calls for carefully designed translational trials, mechanistic biomarkers, and attention to tissue- and enzyme-specific effects before broad clinical adoption of NAD+-boosting therapies [1] [5] [3].