https://www.sciencedirect.com/science/article/abs/pii/S1568163726002977

>Aging remodels compartmentalized nicotinamide adenine dinucleotide (NAD⁺) circuits in ways that influence stress responses, senescence, tissue repair and susceptibility to fibrosis. Beyond its classical role as a redox cofactor, NAD⁺ fuels sirtuins, PARPs and CD38, linking cellular metabolism to chromatin remodeling, DNA repair, calcium signaling and cell fate. A central translational question is whether modulating NAD⁺ in a given tissue and time window will favor regeneration, restrain fibrotic remodeling, or support malignant adaptation. In this review, we define NAD⁺ as a compartmentalized, high-turnover metabolic circuit whose topology, timing and cell-type specificity shape tissue trajectories during aging, repair and fibrosis. We first describe how aging reshapes these circuits through CD38 upregulation, PARP-sirtuin competition, extracellular eNAMPT amplification, and altered mitochondrial NAD⁺ transport, which redistributes NAD⁺ between compartments without necessarily changing bulk tissue concentration. We then summarize how de novo, Preiss-Handler Handler (including niacin/GPR109a) and nicotinamide salvage pathways are organized across nuclear, cytosolic, mitochondrial and extracellular compartments, and how key consumers including sirtuins, PARPs, CD38 and SARM1 govern these pools. We then examine how these circuits operate across acute injury, chronic senescence-associated remodeling, and malignant microenvironments in heart, lung, liver, kidney, skin, muscle and brain. Finally, we integrate emerging human data on NAD⁺ precursors and enzyme-directed strategies and propose a framework for NAD⁺-based interventions that prioritizes timing, compartmental targeting and oncologic stratification.

>"...Taken together, these studies suggest a nuanced picture: NR shows the most consistent signal so far for reducing certain lipid peroxidation markers like F2-isoprostanes, especially in populations with elevated cardiovascular risk, while NMN and NAM have not consistently altered oxidative stress biomarkers. Niacin, however, was shown to improve aspects of vascular oxidative stress and HDL function in specific contexts, but its overall antioxidant impact remains mixed...Overall, the current evidence supports a multifaceted approach to healthy oxidative balance, including regular physical activity, adequate sleep, and nutrient-dense dietary patterns. NAD+ precursors represent promising—but still evolving—areas of mechanistic and clinical research that may complement these core behaviors rather than replace them."

This study does not say that giving NR to your apple trees makes them healthy, but it did notice that healthier plants had higher NR levels, suggesting that NAD precursor metabolism as one of the pathways distinguishing vigorous from weaker plants.  

These researchers are solving an adjacent problem to NAD replenishment. Instead of adding NAD through biosynthetic pathways, they are inserting an artificial recycling pathway into cellular metabolism that switches NADH back to NAD+. That necessarily intersects with the Krebs cycle and mitochondrial redox metabolism.

I don’t know how big a problem NADH overload actually is, and I’m not sure it’s fair to compare a persistent catalyst with a single NR treatment when people who take an oral NAD precursor generally take it every day.

But what I do take from the study is agreement on the underlying biology: raising available NAD+ protects against or rescues UV-induced skin damage—at least in their models.

"...The study demonstrated that mice treated with NMN exhibited tumor burden control equivalent to mice treated with an immune checkpoint blockade PD1 inhibitor..."

>"Highlights
• PS-NPs exposure impairs placental nicotinamide metabolism and mitochondrial energetics.
• PS-NPs triggers NMNAT3 downregulation, NAD+ depletion, and ferritinophagy-driven ferroptosis.
• NMNAT3 overexpression rescued PS-NPs-induced defects by inhibiting ferritinophagy-mediated ferroptosis.
• NAM supplementation restores iron homeostasis, suppresses ferroptosis, and rescues adverse pregnancy outcomes." [emphasis added]

>"...Collectively, our study demonstrates that NR enhanced chondrogenic differentiation of hADSCs by regulating SIRT1-mediated deacetylation of SMAD7 and activation of TGF-β/SMAD2/3 pathway. NR may therefore possess prospects as a promising supplement for MSC-based cartilage regeneration and repair therapies."

“NAD+ levels in the body are constantly in flux—cells are always synthesizing and consuming it, and its levels can decline with age, lifestyle, metabolic stress, and disease.

Two major mechanisms drive NAD+ depletion: declining production and increased consumption via enzymes activated during DNA repair, inflammation, and immune responses.

Everyday stressors—including alcohol consumption, overnutrition, UV exposure, viral infections, and a sedentary lifestyle can cause NAD+ depletion.

Lifestyle strategies and supplementation can help maintain NAD+ levels and support cellular resilience.”

>"...Nicotinamide riboside (NR) effectively maintains NAD + levels, improves mitochondrial function, protects spindle and chromosome morphology, reduces ROS accumulation and DNA damage, thereby enhancing oocyte quality and embryonic developmental potential, and holds promise for improving assisted reproductive outcomes. Furthermore, NR upregulates the ovarian expression of key genes involved in mitochondrial dynamics, such as Opa1, Mfn1/2, Drp1, and Fis1. This upregulation promotes the accumulation of energy metabolism intermediates, enhances ATP production, and concurrently activates essential mitochondrial autophagy-related pathways, notably those involving PINK1 and LC 3. These actions collectively reverse ovarian aging phenotypes and improve oocyte quality..."

>...In this article, we’ll explore the current state of the science on NAD+ and autoimmune disease, including how NAD+ biology intersects with immune function, and what existing research suggests across seven specific autoimmune conditions. It’s important to note that much of the available evidence comes from preclinical models, alongside a limited number of early-stage human studies. While these findings are promising, the research is still evolving, and larger, well-controlled clinical trials are needed before definitive conclusions or clinical recommendations can be made...

>"...we’re also running trials on several of these interventions at my lab in Copenhagen. The results are starting to show what works – and what doesn’t – to improve our health as we get older, and I’m incorporating the successes into my own routine..."

>...Evidence indicates that exercise enhances the activity of key enzymes, such as nicotinamide phosphoribosyltransferase (NAMPT) and sirtuins, thereby improving mitochondrial efficiency, oxidative metabolism, and cellular homeostasis. Additionally, exercise has also been shown to mitigate the age-related decline in NAD+ levels, offering a potential strategy for addressing metabolic dysfunctions and age-associated diseases. 

>*...Here, we observed NAD depletion to be a general feature of innate immune activation and cell death across several triggers. However, restoration of NAD levels prevented cell death only in PANoptosis, and not pyroptosis, necroptosis, or ferroptosis. Mechanistically, the restoration of NAD levels blocked the priming, or signal 1, needed to induce the expression of critical regulators or sensors for PANoptosis. These findings position NAD as a conserved metabolic regulator of PANoptosis across multiple innate immune sensors, linking cellular metabolism directly to inflammatory cell death and identifying the modulation of NAD as a potential therapeutic strategy to limit pathological inflammation driven by PANoptosis...*The ability to restrain PANoptosis through NAD restoration represents a potential immunometabolic strategy to limit pathological inflammation in PANoptosis-associated disease while preserving other essential immune responses.

Abstract

>Microvascular disease (MVD) contributes substantially to morbidity and mortality in diabetes, hypertension, and heart failure. Despite its broad impact, current treatments fail to target common molecular mechanisms driving endothelial dysfunction in MVD, which is characterized by impaired blood flow, endothelial barrier dysfunction, microthrombosis, and capillary rarefaction...Together, these studies highlight the therapeutic potential of NAD+ modulation to mitigate MVD by preventing endothelial barrier dysfunction, inflammation, and capillary rarefaction. The findings are expected to advance understanding of mitochondrial dysfunction in MVD and provide critical preclinical evidence supporting NAD+/SIRT3 targeting for prevention and treatment of microvascular complications.

The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging

>ABSTRACT

>Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD+, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4–6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.

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>ABSTRACT
This study examines the biological and clinical relevance of NAD⁺ supplementation using a combined review and mathematical modelling approach. NAD⁺ plays a central role in cellular energy metabolism, redox balance, and signaling pathways linked to aging, neurodegeneration, and metabolic health. Current evidence shows that oral NAD⁺ precursors such as nicotinamide riboside and nicotinamide mononucleotide can increase circulating NAD⁺ levels, although their clinical benefits remain variable and context-dependent. Intravenous NAD⁺ administration is less well characterized and lacks robust clinical validation. The modelling framework presented here highlights that NAD⁺ responses are nonlinear and influenced by factors such as dose, age, metabolic state, and route of administration. Rather than following a simple dose–response relationship, NAD⁺ supplementation appears to operate within a complex regulatory system involving feedback mechanisms and biological saturation. Overall, these findings emphasize the need for cautious interpretation of current data and for well-designed clinical studies to define effective and safe therapeutic strategies.

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>"...Pang and colleagues report that nicotinamide riboside (NR), an NAD precursor, improves adoptive T cell therapy in hepatocellular carcinoma models by promoting central memory differentiation and mitochondrial fitness. Oral NR enhanced the in vivo therapeutic efficacy of anti-GPC3 CAR-T cells, whereas ex vivo exposure improved the viability, recall responses, and therapeutic performance of OT-I CD8 T cells. Findings in both CAR-driven and TCR-driven systems suggest that NR influences fundamental features of therapeutic CD8 T cell biology rather than a particular receptor design. The study identifies NAD metabolism as a potentially tractable determinant of T cell product quality while emphasizing the need for validation in patient-derived CAR-T and TCR-T products."

>"...While well-known NAD+ precursors like nicotinamide (NAM), also known as niacinamide, have demonstrated anti-aging skin benefits such as improving the look of fine lines and skin hyperpigmentation, the role of dihydronicotinamide riboside (NRH) has been relatively unexplored as a recently described, potent precursor for boosting NAD+ in the skin.

This study investigated the mechanism and efficacy of NRH in enhancing NAD+ levels within key structural skin cells. We demonstrated that the administration of NRH significantly and robustly elevates NAD+ concentrations in both primary human fibroblasts and keratinocytes. NRH increases intracellular NAD+ to levels that are significantly higher than those achieved by NAM. NRH is reported to utilize an alternative salvage pathway that is independent of the enzymes nicotinamide riboside kinase (NRK) and nicotinamide phosphoribosyltransferase (NAMPT).

This powerful NAD+ boosting effect was further confirmed in a human skin explant model. The NRH-induced increase in NAD+ led to measurable changes in primary human fibroblasts, indicating the modulation of key functional pathways associated with skin homeostasis, and anti-aging mechanisms.

Overall, our findings establish NRH as a promising agent for enhancing NAD+ levels in skin cells, supporting its relevance in skin longevity research and potential incorporation into skincare formulations aimed at enhancing skin longevity, improving visible signs of aging, and supporting youthful skin."