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Nicotinamide Riboside Chloride

Nicotinamide riboside chloride (NR) is the chloride salt of nicotinamide riboside, a pyridinium (vitamin B₃) analog comprising nicotinamide bound to a ribose moiety. Upon oral intake, NRCl is absorbed and hydrolyzed to nicotinamide, thereby contributing to the body’s nicotinamide pool and serving as a precursor for NAD⁺ biosynthesis. NAD⁺ is an essential coenzyme for redox metabolism and a substrate for NAD⁺ - dependent enzymes like sirtuins (regulate metabolism, stress response, and longevity) , PARPs (PolyADP-ribose polymerases - consume NAD⁺ to fix damaged genetic material), and CD38 (an immune enzyme that degrades NAD⁺ and drives its age-related depletion) that regulate DNA repair, chromatin structure, and cellular homeostasis (Covarrubias et al., 2020). Notably, aging is accompanied by a progressive decline in tissue and cellular NAD⁺ levels, which is causally linked to multiple age-related pathologies (neurodegeneration, sarcopenia, metabolic disease, frailty)(Fang et al., 2017). Thus, boosting NAD⁺ via NRCl supplementation has attracted attention as a strategy to mitigate cellular aging and promote healthy lifespan.

NR in NAD⁺ Biosynthesis and Cellular Aging

NRCl enters cells and is phosphorylated by nicotinamide riboside kinases (NRK1/2) to nicotinamide mononucleotide (NMN), which is then converted by NMN adenylyltransferases (NMNATs) to NAD⁺. In this way, NRCl bypasses the rate-limiting nicotinamide phosphoribosyltransferase (NAMPT) step of the salvage pathway (Covarrubias et al., 2020). The EFSA (European Food Safety Authority) panel has confirmed that ingested NRCl readily yields nicotinamide and ultimately NAD⁺ in humans. By contrast, aging and inflammation upregulate NAD⁺ consumers (e.g. CD38) and downregulate NAD⁺ synthesis, depleting NAD⁺ pools in multiple tissues (Covarrubias et al., 2020 ; Fang et al., 2017). The resulting NAD⁺ insufficiency impairs mitochondrial oxidative metabolism and the activity of NAD⁺-dependent enzymes (sirtuins, PARPs) that support genomic maintenance and proteostasis (Covarrubias et al., 2020 ; Fang et al., 2017). In summary, NRCl serves to replenish NAD⁺ levels and counteracts age-associated NAD⁺ decline.

Mechanisms: Sirtuins, Mitochondria and DNA Repair

Restoring NAD⁺ through NRCl supplementation has key mechanistic impacts on aging pathways. Increased NAD⁺ activates sirtuins (class III histone deacetylases) and PARP DNA-repair enzymes, linking metabolic status to gene regulation and genomic stability (Covarrubias et al., 2020 ; Cantó, Carles et al., 2012). For example, Canto showed that NR supplementation in cells and mice raises intracellular NAD⁺, activating sirtuins like SIRT1 and SIRT3, which enhances mitochondrial oxidative phosphorylation and biogenesis, protecting against metabolic stress (Cantó, Carles et al., 2012). SIRT1 activation deacetylates PGC-1α, promoting mitochondrial gene transcription and fuel oxidation, while SIRT3 in mitochondria deacetylates enzymes for efficient electron transport. In addition, sufficient NAD⁺ enables PARP1/2 activity to support DNA single-strand break repair, thereby maintaining genomic stability (Covarrubias et al., 2020). Conversely, NAD⁺ depletion impairs these repair systems and promotes accumulation of DNA damage, a hallmark of aging (Covarrubias et al., 2020 ; Fang et al., 2017). Thus, NRCl drives NAD⁺-dependent signaling that underpins healthy mitochondrial function and DNA repair.

NRCl also influences inflammatory and proteostasis pathways. Sirtuin activation can suppress inflammatory gene expression and induce mitophagy and unfolded protein responses that clear damaged proteins. For instance, in aged human trials NRCl reduced circulating pro-inflammatory cytokines (IL-6, TNF-α) without causing adverse effects (Conze et al., 2019). The anti-inflammatory signature observed with NRCl is consistent with reduced “senescence-associated secretory phenotype” and improved tissue homeostasis. In animal models, NR boosts autophagy and the mitochondrial unfolded protein response (mtUPR - A protective mitochondrial stress response that restores protein quality and function), addressing loss of proteostasis (Fang et al., 2017). Collectively, NRCl-induced NAD⁺ repletion engages sirtuin/PARP pathways to improve mitochondrial bioenergetics, chromatin maintenance and protein quality control - key mechanisms counteracting multiple aging processes (Cantó, Carles et al., 2012 ; Covarrubias et al., 2020).

Preclinical Evidence: Animal and Cellular Studies

Numerous animal and cell studies have demonstrated that NR supplementation can ameliorate aging-related dysfunction. In mice, dietary NR elevates tissue NAD⁺, activates SIRT1/3, and increases mitochondrial function. Canto found that NR-treated mice on a high-fat diet exhibited improved oxidative metabolism, higher energy expenditure, and were protected against obesity and metabolic derangements (Cantó, Carles et al., 2012). Similarly, Zhang reported that feeding aged mice NR or NMN improved muscle mitochondrial function and slowed age-related neuromuscular decline (increased lifespan and running endurance)  (Zhang et al., 2016). NR has also shown benefit in disease models: Trammell demonstrated that NR ameliorates insulin resistance and neuropathy in diabetic mice (Trammell et al., 2016), and Diguet found that NR preserves cardiac function in a mouse cardiomyopathy model (Diguet et al., 2018). In these studies, NR restored NAD⁺ and SIRT3-dependent deacetylation of mitochondrial proteins, improving metabolic resilience.

In cultured cells, NR raises NAD⁺ and modulates stress responses. For example, NR delays replicative senescence in human fibroblasts by sustaining mitochondrial respiration and preventing ROS (Reactive Oxygen Species) accumulation. It also enhances neuronal survival under oxidative stress, reflecting improved DNA repair capacity. The extensive preclinical data establish that NR-derived NAD⁺ supports hallmarks of metabolic health – including better redox balance, reduced inflammation and maintained proteostasis (Cantó, Carles et al., 2012; Fang et al., 2017) providing a strong rationale for human trials.

Human Studies: Aging Biomarkers and Metabolic Effects

Clinical trials in humans have begun to test NRCl’s effects on NAD⁺ levels, metabolism and aging indicators. In healthy adults (aged ~40 - 60), NRCl supplementation dose-dependently increases blood NAD⁺ and metabolites (Conze et al., 2019). Conze conducted an 8-week trial in overweight adults given 100 - 1000 mg/day NRCl. Even at the highest dose (1000 mg/day), NRCl safely elevated whole-blood NAD⁺ by ~142% over baseline within two weeks (Conze et al., 2019). Importantly, no flushing or major adverse events were observed; blood lipids and one-carbon metabolism remained unchanged (Conze et al., 2019).

In elderly subjects, short-term NRCl (1 g/day for 3 weeks) similarly boosted muscle NAD⁺ metabolites and reduced inflammation. Elhassan gave 12 men (70-80 years old) 1 g/day NRCl vs. placebo in a crossover design (Elhassan et al., 2019) . Targeted metabolomics showed NR raised muscle NAD⁺-related metabolites (NAAD, MeNAM, etc.), and RNA profiling revealed downregulation of inflammatory and mitochondrial stress pathways. Concurrently, serum IL-6, IL-2 and TNF-α levels fell significantly on NRCl. These results confirm that oral NRCl is bioavailable to aged human tissues and exerts an anti-inflammatory transcriptomic signature.

Some positive signals have emerged: an acute study (single dose NRCl) in healthy older adults showed modest increases in exercise endurance and redox improvements, suggesting enhanced mitochondrial reserve. Another meta-analysis in peripheral artery disease reported better 6-minute walk distance with NAD⁺ precursors. Additionally, NRCl has been tested as an adjunct in chronic conditions (Parkinson’s, kidney disease), generally confirming safety and NAD⁺ elevation, though efficacy data are still preliminary. Overall, human trials consistently show dose-dependent NAD⁺ boosts (Conze et al., 2019) but variable impact on clinical endpoints. Aging biomarkers such as inflammatory cytokines and epigenetic clocks may be more sensitive to NRCl: for example, modest reductions in inflammatory IL-6 and biological “age” (PhenoAge, GrimAge) were noted in NRCl-treated older adults (Orr et al., 2024).

Targeting Hallmarks of Aging

By restoring NAD⁺, NRCl impacts multiple “hallmarks of aging” (Covarrubias et al., 2020 ; Fang et al., 2017). For genomic instability, NRCl-derived NAD⁺ fuels PARP-dependent DNA repair and sirtuin-mediated chromatin maintenance, preserving genome integrity. In preclinical models, NR delays DNA damage accumulation, and cells maintain telomeres and lower mutation rates with NAD⁺ support (Covarrubias et al., 2020 ; Fang et al., 2017). Regarding mitochondrial dysfunction, NRCl activates SIRT1/3 and PGC-1α pathways to enhance mitochondrial biogenesis and respiration, improving ATP production and organelle quality (reducing ROS) (Cantó, Carles et al., 2012 ; Fang et al., 2017). For proteostasis and proteolytic stress, elevated NAD⁺ induces autophagy and the mitochondrial unfolded protein response, helping clear misfolded proteins and damaged organelles (Fang et al., 2017). Loss of proteostasis is also countered via sirtuin-dependent regulation of protein chaperones. NRCl also counters inflammation and cellular senescence. NAD⁺ repletion lowers pro-aging NF-κB signaling and senescence-associated secretions (as seen by reduced IL-6, TNF-α in humans), thus restoring healthier intercellular communication. In sum, NRCl addresses aging’s metabolic and molecular hallmarks by sustaining NAD⁺ dependent maintenance systems (Covarrubias et al., 2020 ; Cantó, Carles et al., 2012).