“…Median whole-blood NAD⁺ concentration was lower among participants with frailty than among those without frailty (24.00 vs. 25.00 µmol/L; P = 0.007). After adjustment for age, sex, and fasting time, higher whole-blood NAD⁺ concentration was associated with lower odds of frailty…”
"...Restoring NAD levels through supplementation with its precursors or pharmacological inhibition of CD38 activity effectively alleviated the pathological symptoms of colitis...These findings identify macrophage CD38 as a critical regulator of intestinal inflammation and highlight the CD38/NAD axis as a potential therapeutic target for IBD."
“…Clients receiving IV NAD+ reported moderate to severe gastrointestinal symptoms, elevated heart rate, & chest pressure during infusion, while those receiving IV NR reported mild tingling or cramping. Symptoms ceased upon completing infusions. The moderate to severe symptoms from IV NAD+ resulted longer infusion times (97mins) compared to IV NR (37mins). Renal & hepatic biomarkers showed no adverse changes; ALP decreased significantly in NAD+ group but remained within normal ranges. Metabolic markers suggested improved glucose metabolism 30 days post NR & mixed lipid changes post NAD+. QoL measures showed NR group had 30 minutes more total sleep, lower resting heart rate & breath rate, while NAD+ group had higher RMSSD. Minor yet non-significant QoL improvements occurred in both groups….”
Dr. Charles Brenner (University of Helsinki), Dr. Mary McDermott (Northwestern University), and Dr. Andrew Shao (Niagen Bioscience, moderator)
>...Treatment with NR or resveratrol significantly improved metabolic parameters and partially restored BAT structural and molecular alterations. Combined treatment with NR and resveratrol produced the most pronounced effects, nearly normalizing BAT stereological parameters, vascular organization, and thermogenic and mitochondrial-related gene expression, while markedly improving glucose and lipid profiles. NR and resveratrol exert protective and restorative effects on Type 1 Diabetes Mellitus -induced BAT atrophy, likely through activation of NAD⁺/Sirt1-mediated mitochondrial and thermogenic pathways. Combined therapy demonstrated synergistic benefits, suggesting a promising strategy for preserving BAT structure and function under diabetic conditions.
>Conclusion: NR and metformin were associated with beneficial effects on obesity-related hippocampal alterations, accompanied by favourable changes in apoptosis-related, metabolic, and neurotrophic gene expression as well as improved stereological indices of hippocampal integrity. The combined treatment generally produced greater improvements than either monotherapy. These findings support further investigation of NR and metformin as potential interventions for obesity-associated hippocampal dysfunction and cognitive impairment.
>As delayed childbearing becomes increasingly common, elucidating the mechanisms of age-related placental senescence is critical for the development of effective therapeutic strategies. Here, we integrate metabolomics, single-cell RNA sequencing, and spatial transcriptomics to uncover conserved features of aged placentas in humans, mice, and pigs, namely, increased macrophage CD38 expression and NAD⁺ deficiency. Through pharmacological and genetic approaches, we demonstrate that macrophage CD38 depletes NAD⁺ in decidual stromal cells, thereby promoting placental senescence. Mechanistically, early-onset inflammation and senescence-associated secretory phenotype activity drive CD38 expression in macrophages via the IRF5 pathway. Importantly, treatment with NAD⁺ precursors or CD38 inhibitors attenuates age-related placental senescence, rescues intrauterine growth restriction, and improves long-term metabolic outcomes in offspring. These findings reveal a critical role for macrophage-driven metabolic dysregulation in reproductive aging and establish CD38 as a potential therapeutic target for age-associated pregnancy complications.
>Abstract
>Introduction: Nicotinamide adenine dinucleotide (NAD+), an essential cofactor for multiple cellular processes, is critical for cellular health. NAD+ declines with age due to reduced biosynthesis and increased consumption. This causes cellular dysfunction, which exacerbates and contributes to the pathology of age-related CNS diseases including Parkinson’s disease (PD). CD38 is an NAD+-consuming enzyme (NADase) that increases in expression with ageing and disease, likely contributing to the age-related decline in NAD+. Genetic links between CD38 and PD provide a rationale for exploring its function in disease.
Methods: NETSseq datasets from human post-mortem brain tissue were used to assess CD38 cell-type specific expression. The pharmacological properties of CVN14, a brain-penetrant selective inhibitor previously described by our group, were characterised using in vitro CD38 enzyme assays, selectivity profiling, pharmacokinetic and brain penetration studies, and brain NAD⁺ measurements in rats and mice. The effects of CD38 inhibition were evaluated in α-synuclein-challenged rat mesencephalic cultures and in a rat AAV1/2-hA53T α-synuclein model of PD.
Results: CD38 was highly enriched in astrocytes in human brain. CVN14 potently inhibited recombinant human, rat, and mouse CD38, with IC₅₀ values of 19.0, 5.1, and 2.4 nM, respectively. This compound was selective, having no activity at its closest homologue, CD157 or at other NADases. CVN14 increased brain NAD+ in rats and mice with no effect in the CD38 knockout mouse, further demonstrating its selectivity against other NADases. In a rat mesencephalic culture, CVN14 showed evidence of increasing dopaminergic neuronal survival following α-synuclein-induced toxicity and reducing the number of neurons positive for pSer129 α-synuclein, supporting further investigation into a potential role for inhibition of CD38 in clearance of pathological protein. In a rat AAV1/2-hA53T α-synuclein model of PD, CVN14 improved motor function in the cylinder test.
Conclusion: Our findings support further investigation of CD38 inhibition as a therapeutic approach for PD. CVN14 elevated brain NAD⁺ in rats and mice, reduced motor deficits in a rat α-synuclein model of PD, and was associated with increased neuronal survival and reduced pathological α-synuclein in vitro, highlighting the therapeutic potential of CD38 inhibition in PD and other α-synucleinopathies.
>Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accumulation of α-synuclein (α-syn), mitochondrial dysfunction, and neuroinflammation. Nicotinamide adenine dinucleotide (NAD⁺), a crucial coenzyme involved in cellular energy metabolism, DNA repair, and epigenetic regulation, declines with aging and is markedly reduced in the brains of patients with PD. Emerging evidence suggests that supplementation with NAD⁺ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), exerts neuroprotective effects through multiple mechanisms, such as activation of the mitochondrial unfolded protein response (UPR^mt), enhancement of autophagy, and suppression of excessive poly(ADP-ribose) polymerase 1 (PARP1) activation. This review summarizes the central role of NAD⁺ dysregulation in the pathogenesis of PD, with particular emphasis on the interplay between NAD⁺ depletion, mitochondrial quality control, proteostasis, and neuroinflammation. Furthermore, we discuss recent advances in NAD⁺-boosting strategies in PD models and clinical studies, highlighting their potential therapeutic implications for PD intervention.
>Background: Mitochondrial disorders are a common cause of inherited neurometabolic disease affecting around 1 in 8000 people. There are currently no treatments for heteroplasmic mitochondrial DNA (mtDNA) disorders which target the underlying disease mechanisms...
Methods: We performed an experimental medicine study in eight participants affected with mtDNA disorders...They were treated with 4-weeks of NR (1250-2000 mg/day)...
Conclusions: We conclude that NR has potential to be the first small-molecule precision treatment for heteroplasmic mtDNA disorders guided by the specific genetic diagnosis.
>Early-life exposure to dietary excess of lipids increases lifelong vulnerability to metabolic dysfunction, but the determinants of this susceptibility remain unclear. Here, we combine paired-tissue transcriptomics (whole head and fat body), metabolomics, and gut microbiota profiling in Drosophila melanogaster to define how transient developmental exposure to a high-fat diet (HFD) remodels adult metabolism. Larval HFD exposure was associated with extensive transcriptional remodeling in the adult fat body, including coordinated repression of tricarboxylic acid (TCA) cycle and oxidative phosphorylation genes, accompanied by increased ROS accumulation and reduced mitochondrial bioenergetic function. In contrast, the whole-head transcriptome showed a weaker response to HFD than the fat body. Integrated host-microbiome profiling revealed persistent remodeling of the gut microbial community, with altered bacterial diversity and structure. Targeted adult interventions with the NAD precursor nicotinamide riboside, the TCA intermediate α-ketoglutarate, or commensal bacteria (Acetobacter and Lactobacillus spp.) restored mitochondrial redox balance, improved respiratory capacity, and extended lifespan. Together, these findings identify mitochondrial dysfunction and microbial remodeling as enduring features of developmental dietary lipid stress and suggest that this metabolic state remains partially reversible through mitochondrial and microbiota-directed interventions.
>"...According to the evidence currently available, depletion of intracellular NAD⁺ levels during aging may contribute to mitochondrial dysfunction, impaired metabolic regulation, chronic inflammatory signaling, and neurodegenerative alterations. Although NAD⁺ precursors such as NMN and NR have shown promising biological effects in experimental studies, some limitations are still evident when these findings are translated to humans, including pharmacokinetic instability, tissue-specific bioavailability, and variability in clinical responses. Moreover, chronic inflammation and CD38 overexpression appear strongly associated with progressive intracellular NAD⁺ depletion during aging and menopause. Thus, modulation of NAD⁺ metabolism may represent a promising strategy in longevity medicine and menopausal health. However, despite the important mechanistic advances achieved in recent years, long-term clinical evidence is still insufficient to support a definitive therapeutic conclusion..."
>"...NAD+ and GLP-1s affect metabolism through different mechanisms. NAD+’s role in metabolism and its age-related decline is well documented, but whether raising NAD+ alongside GLP-1 therapy improves outcomes remains untested and unproven. For now, that means this idea is interesting but not established.
>"In the bigger picture, metabolic health is not a single lever to pull or a single drug (or supplement) to take. It reflects the sum of how cells produce energy, how hormones regulate appetite and glucose, and how daily habits like sleep, movement, and nutrition support those processes. Understanding where NAD+ and GLP-1s fit is less about choosing one over the other and more about seeing the larger system they both influence."
>"Nicotinamide adenine dinucleotide (NAD^(+)**) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD*^(+)* restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for “mutator” mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels, and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while beneficial for heart, chronic NAD^(+) boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD^(+) boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases."
>"...Collectively, the interaction among vitamin B3 supplementation, physical activity, and gut microbiota may represent a promising framework for investigating strategies aimed at supporting cognitive health and brain resilience during aging, although definitive therapeutic applications require further validation..."
>"...I investigated the potential of NR to modulate epigenetic aging, an estimate of biological aging, both in vivo and in vitro. NR supplementation was associated with reduced skeletal muscle epigenetic age, which correlated with increased NAD⁺ metabolite levels but decreased mtDNAq. The results were highly clock-specific, suggesting that while NR may modulate epigenetic aging, different epigenetic aging algorithms likely capture distinct molecular signatures following NR use...Collectively, these studies demonstrate a significant link between mitochondrial biogenesis and nuclear DNAm in the context of obesity and aging..."
“…Oral administration of NAD⁺ precursors delayed progression of precancerous lesions in a spontaneous pancreatic cancer model, LSL-KRASG12D/+ pdxCre/+, and protected non-malignant cells from carcinogen-induced stress. In premalignant settings, NAD⁺ precursor supplementation reduced DNA damage and oxidative stress while improving mitochondrial function. Notably, just as NAD⁺ precursors are protective to normal pancreatic ductal cells against stress, the cofactor also exhibited protective effects in pancreatic cancer cells under stress, promoting chemotherapy resistance in both in vitro and in vivo models.”
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.