Search Results (190)

Background/Objectives: Nicotinamide (NAM), a form of vitamin B3 and precursor of nicotinamide adenine dinucleotide (NAD), has emerged as a potential metabolic and neuroprotective strategy in glaucoma. This systematic review aimed to evaluate the available human evidence on NAM-containing and NAD-targeted strategies in glaucoma, integrating interventional, observational, and mechanistic evidence with particular attention to clinical outcomes, methodological quality, and safety. Methods: A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL), with the search updated through 22 August 2026. Eligible studies included randomized and non-randomized interventional studies evaluating NAM-containing or NAD-targeted supplementation strategies, as well as observational human studies investigating NAM/NAD-related biomarkers or mitochondrial metabolic alterations in relation to glaucoma. Risk of bias was assessed according to study design using RoB 2 for randomized trials, ROBINS-I for non-randomized interventional studies, and a domain-based assessment for observational exposure and biomarker studies. Owing to substantial clinical and methodological heterogeneity, findings were synthesized narratively without quantitative pooling. Results: Thirteen eligible reports representing eight unique human studies were included. Randomized trials provided preliminary evidence that NAM-containing interventions may produce short-term functional and electrophysiological effects. NAM supplementation was associated with improvement in inner retinal electrophysiological function in randomized crossover studies, whereas effects on visual field outcomes were inconsistent. A trial combining NAM with pyruvate reported favorable short-term visual field changes, although the specific contribution of NAM could not be isolated. Non-randomized studies provided complementary evidence on vascular, metabolic, structural, electrophysiological, and patient-reported outcomes but were limited by potential confounding and uncontrolled study designs. Observational studies reported associations between glaucoma and altered circulating NAM concentrations and systemic mitochondrial dysfunction. Available studies were generally small and of limited duration, and the evidence was insufficient to establish sustained neuroprotection or modification of glaucoma progression. Conclusions: Human evidence supports the biological plausibility of targeting NAM/NAD metabolism in glaucoma and provides preliminary signals of short-term biological and functional effects. However, current evidence remains insufficient to support routine high-dose NAM supplementation in clinical practice. Larger, adequately powered, long-term randomized controlled trials are required to establish sustained efficacy, optimal dosing, patient selection, and long-term safety. Full article

Age-related skeletal muscle wasting, clinically expressed as sarcopenia and frailty, significantly limits the efficacy of physical rehabilitation due to an underlying cellular bioenergetic decline, mitochondrial dysfunction, and chronic inflammaging. This narrative review synthesizes current physiological and clinical evidence evaluating mitochondria- targeted nutraceuticals as targeted metabolic adjuvants to physical exercise in older adults. Comprehensive literature searches were executed across PubMed, Web of Science, and Scopus following SANRA guidelines and the SPIDER framework to evaluate functional and bioenergetic outcomes in geriatric cohorts. The findings demonstrate that target-specific biofactors directly impact mitochondrial restrictions: ubiquinol and NAD⁺ precursors restore electron transport chain efficiency and biogenesis; urolithin A upregulates mitophagy to prevent the cytosolic extrusion of pro-inflammatory mitochondrial DNA, while creatine monohydrate and omega-3 polyunsaturated fatty acids selectively restore downstream myofibrillar anabolic pathways. When translated to specialized clinical settings, including post-fracture orthopedic immobilization, chronic pain syndromes managed, and post-ICU-acquired weakness, these bioenergetic substrates safely mitigate tissue proteolysis and enhance recovery kinetics. In conclusion, structurally integrating biomarker-driven nutritional rehabilitation pathways with tailored exercise protocols provides the precise pro-anabolic microenvironment necessary to overcome anabolic resistance, ultimately shortening recovery timelines and maximizing functional independence in the aging population. Full article

β-Nicotinamide mononucleotide (NMN) is an important intermediate in nicotinamide adenine dinucleotide (NAD⁺) metabolism and has attracted increasing interest as a bioactive compound and biomanufacturing product. In this study, Pseudomonas putida KT2440 was engineered for NMN production using a “block–enhance–transport” strategy. Deletion of nicB impaired nicotinic acid degradation and resulted in the accumulation of 66.2 μM nicotinic acid in cell extracts, whereas additional deletion of the putative NMN-consuming genes pncC and ushA did not lead to detectable NMN accumulation. Coexpression of endogenous pncB and engineered Francisella tularensis nadE* enabled low-level NMN formation through a Preiss–Handler pathway-based route. By contrast, overexpression of endogenous nadA, nadB, and nadC strengthened precursor supply through the NAD⁺ de novo biosynthetic pathway and resulted in approximately 0.17 mM NMN in cell extracts. Chromosomal integration of an engineered Salmonella enterica pnuC* transporter cassette was associated with pronounced extracellular NMN accumulation. Additional overexpression of genes involved in downstream NAD⁺ metabolism or phosphoribosyl pyrophosphate supply did not considerably improve production, possibly because of metabolic competition or expression burden. The best-performing strain, LW10, produced 1.28 mM extracellular NMN, corresponding to approximately 0.43 g/L, after 96 h of shake-flask cultivation in basal salt medium containing glucose and L-aspartate. These results suggest the feasibility of NMN biosynthesis in engineered P. putida KT2440 and highlight the importance of balancing precursor supply, competing reactions, and product transport. Thus, P. putida KT2440 represents an alternative chassis for further pathway balancing and process optimization toward fermentative NMN production. Full article

Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. A structured narrative review of the PubMed, Scopus, and Web of Science literature published between January 2010 and May 2026 was conducted, with seminal earlier studies retained where relevant. The review focused on molecular pathways implicated in aging, pharmacological interventions targeting these pathways, and their preclinical and clinical evaluation. Particular emphasis was placed on translational evidence, including human biomarker studies and randomized clinical trials, and on the distinction between biomarker modulation and clinically meaningful outcomes. Repurposed drugs such as metformin and rapamycin have among the most extensive preclinical and translational evidence, although clinical evidence for broadly applicable geroprotection remains limited. Statins, SGLT2 inhibitors, GLP-1 receptor agonists, and menopausal hormone therapy have established disease-specific or cardiometabolic benefits that may have indirect relevance to geroprotection, but direct effects on biological aging and healthspan remain unproven. Other candidates, including senolytics, NAD⁺ precursors, taurine, and epigenetic reprogramming approaches, are at different stages of translational development, with evidence ranging from promising preclinical findings to early human studies. Across interventions, a substantial gap remains between mechanistic plausibility and clinically validated geroprotection. Geroprotective pharmacology represents a promising but incompletely validated approach to extending healthspan. Major uncertainties include the absence of universally accepted biomarkers and clinical endpoints of biological aging, heterogeneity in treatment response, optimal timing and duration of interventions, and long-term safety. Future research should prioritize adequately powered randomized clinical trials integrating standardized measures of biological aging with clinically meaningful outcomes, alongside biomarker-guided patient selection, appropriate treatment timing, and careful assessment of long-term safety. The future of geroprotective medicine will depend not only on identifying additional pharmacological targets, but on demonstrating that their modulation produces durable and clinically meaningful benefits in humans. Full article

Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD⁺) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune–metabolic regulation. This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD⁺ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework. Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation. Full article

Nursery-plant grading relies on morphological traits, but leaf metabolic variation associated with nursery-plant grade remains unclear. In this study, untargeted HPLC-QTOF-MS metabolomics was applied to mature and young leaves of Grade I, II, and III apple nursery plants to explore grade-associated metabolic variation and its relationship with growth performance. After quality filtering, 198 positive-ion features were retained from mature leaves, while 259 positive-ion and 8 negative-ion features were retained from young leaves. Multivariate analysis showed clear grade-associated separation in both leaf types, with stronger discrimination in young leaves. A combination of orthogonal partial least squares (OPLS) modeling and trend analysis identified 20 and 28 differential features in mature and young leaves, respectively. Cross-model prioritization further highlighted key metabolites putatively annotated as methyl nicotinate and 1-palmitoyl-sn-glycero-3-phosphocholine in mature leaves, and methyl nicotinate, nicotinamide riboside, cis-jasmone, and methyl (9Z,14Z)-12,13,16-trihydroxyoctadeca-9,14-dienoate in young leaves. These key metabolites were potentially associated with NAD precursor metabolism, membrane lipid remodeling, and oxylipin-related signaling. Correlation analysis showed that they were associated with both initial grading traits and post-transplant growth performance. These metabolites represent candidate molecular correlates of grade-associated physiological variation and growth performance in apple nursery plants. Full article

Glaucoma is the leading cause of irreversible blindness worldwide and a paradigmatic age-related neurodegenerative disease in which retinal ganglion cells (RGCs) are selectively lost through mechanisms that extend beyond intraocular pressure. Age-dependent NAD⁺ depletion in RGCs, compounded by the progressive impairment of NAD⁺ biosynthesis and by the hyperactivation of NAD⁺-consuming enzymes under oxidative stress, defines a metabolic vulnerability that current pressure-lowering therapy does not address. Pyrroloquinoline quinone (PQQ) is a tricyclic ortho-quinone present in plant-derived foods that acts on the NAD⁺ pool through a mechanism distinct from that of conventional precursors. Rather than expanding the pool by net synthesis, PQQ binds lactate dehydrogenase and oxidizes NADH to NAD⁺ through catalytic redox cycling, raising NAD⁺ availability without altering the total dinucleotide content and independently of the two biosynthetic enzymes selectively impaired in glaucomatous RGCs. The resulting increase in NAD⁺ availability activates sirtuin-dependent programs that drive mitochondrial biogenesis. PQQ additionally engages an NRF2-dependent antioxidant response, addressing molecular deficits directly implicated in glaucomatous RGC degeneration. In retinal cell models, PQQ preserves ATP content and viability under mitochondrial stress. In vivo, it protects RGC density in optic nerve degeneration models and elevates NAD⁺ along the visual pathway. A randomized clinical trial demonstrated functional improvement in glaucoma patients receiving a PQQ-containing combination. The redox biochemistry of PQQ places it at a mechanistic intersection with the NAD⁺ deficit that characterizes glaucomatous neurodegeneration. Its complementarity with conventional NAD⁺ precursors and neuroprotective compounds acting on distinct molecular targets supports the design of combination regimens addressing multiple dimensions of RGC vulnerability. Critical questions regarding bioavailability, molecular target characterization, and clinical validation in dedicated trials remain open. Full article

Background: Cisplatin is a widely used chemotherapeutic agent whose clinical application is often limited by severe hepatorenal toxicity associated with oxidative stress and cellular injury. Nicotinamide riboside (NR), a natural precursor of nicotinamide adenine dinucleotide (NAD+), has emerged as a promising cytoprotective compound with antioxidant and metabolic regulatory properties. This study investigated the protective effects of NR against cisplatin-induced hepatorenal toxicity and explored its potential mechanisms of action. Methods: Thirty-six adult male Wistar rats were randomly assigned to four groups (n = 6): control, cisplatin (7 mg/kg, i.p.), nicotinamide riboside (50 mg/kg/day, orally), and cisplatin plus NR. Renal and hepatic function biomarkers, lipid profile parameters, oxidative stress markers, and antioxidant status were evaluated. Relative mRNA expression of Nrf2 and NQO1 was determined using RT-qPCR. Histopathological examinations of liver and kidney tissues were also performed. Results: Cisplatin administration induced marked hepatorenal injury, evidenced by significant elevations in serum KIM-1 (395.27 vs. 116.04 ng/mL), urea (71.16 vs. 21.33 mg/dL), creatinine (3.49 vs. 0.26 mg/dL), AST (325.83 vs. 95.16 U/L), and ALT (102.83 vs. 45.50 U/L), accompanied by dyslipidemia, oxidative stress, and severe histopathological alterations. NR treatment significantly attenuated these changes, reducing KIM-1, urea, creatinine, AST, and ALT by 55.5%, 47.8%, 48.1%, 55.4%, and 33.5%, respectively, compared with the cisplatin group. NR also improved antioxidant status by increasing GSH and SOD levels while reducing MDA and NO concentrations. Hepatic NAD⁺ levels and the NAD⁺/NADH ratio were significantly decreased by cisplatin and significantly restored by NR treatment. In addition, NR significantly upregulated the relative mRNA expression of Nrf2 and NQO1 and markedly preserved hepatic and renal histological architecture. Pharmacological inhibition of Nrf2 with ML385 significantly attenuated these protective effects of NR across biochemical, lipid, and oxidative stress parameters, confirming that they are, at least in part, Nrf2-dependent. Conclusions: Nicotinamide riboside exerts protective effects against cisplatin-induced hepatorenal toxicity that are mechanistically linked to activation of the Nrf2/NQO1 antioxidant pathway and restoration of hepatic NAD⁺ homeostasis. This finding supports the potential of NR as an adjunctive strategy for mitigating cisplatin-associated hepatorenal injury and warrants further preclinical and clinical investigation. Full article

Drying method is a key factor influencing the nutritional quality and flavor characteristics of Chenpi. In this study, peels of Citrus reticulata ‘Chachi’ (Xiaoqinggan) were subjected to natural air drying (NAD), hot-air drying (HAD), and vacuum drying (VD) to evaluate changes in physicochemical properties, free amino acids, and volatile compounds. VD exhibited superior retention of total flavonoids and soluble sugars, resulting in the best overall physicochemical quality. NAD preserved the highest total free amino acid content and amino acid diversity, whereas HAD was characterized by a predominance of bitter amino acids, contributing to a pronounced bitter taste. In contrast, VD maintained a more balanced amino acid composition with relatively high proportions of sweet amino acids and effective retention of aroma precursors. A total of 75 volatile compounds were identified by GC–MS, with olefins representing the dominant class. NAD exhibited the highest total volatile content, while VD retained the greatest diversity of volatile compounds and a more balanced aroma composition. Odor activity value (OAV) analysis revealed that key aroma-active compounds were effectively preserved in VD-treated samples, with linalool identified as the major contributor to citrus peel aroma. Overall, VD achieved the most favorable balance between nutritional quality, taste characteristics, and aroma preservation. These findings provide scientific guidance for optimizing drying technologies and improving the quality of Chenpi products. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy. In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1–dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP). While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation. We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases. Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets. Full article

The liver ranks among the peripheral organs exhibiting the most robust circadian rhythmicity, with glucose homeostasis, lipid metabolism, and bile acid turnover governed by tightly phased diurnal oscillations. Mitochondria execute these programs, their output coordinated with the hepatocyte circadian state. The mitochondrial network undergoes dynamic remodeling across the 24 h cycle, encompassing oscillatory changes in bioenergetics, fusion–fission balance, and quality control. This interplay is bidirectional: core clock components drive rhythmic remodeling via cyclin-dependent kinase 1/mitogen-activated protein kinase (CDK1/MAPK)-dependent phosphorylation of dynamin-related protein 1 (DRP1) and the NAD⁺–SIRT1/SIRT3 axis, while retrograde signals modulate clock amplitude and entrainment. Circadian disruption is associated with mitochondrial dysfunction implicated in MASLD onset and progression to MASH and HCC, though this evidence remains largely correlative and derives predominantly from rodent models. This review integrates clock–mitochondria coupling with metabolic liver disease. Restoring this coupling has been proposed as a candidate chronotherapeutic strategy, supported by preliminary rhythmicity data in primary human hepatocytes and a hepatocellular carcinoma cell line, though causal validation in healthy human liver is lacking. Time-restricted feeding, NAD⁺ precursors, PPAR agonists, and ACC inhibitors converge on clock-regulated pathways and may benefit from circadian-informed timing, though this remains unverified. Full article

Acute myeloid leukaemia (AML) exhibits profound metabolic plasticity that enables leukaemic cells to survive environmental stress, nutrient limitation, and therapeutic pressure, ultimately driving disease persistence and relapse. While genetic and epigenetic alterations have guided risk stratification and therapeutic development, accumulating evidence indicates that nutrient-dependent metabolic rewiring represents a critical and targetable vulnerability in AML. Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor whose intracellular availability is tightly linked to dietary intake of its precursors, including tryptophan, niacin (vitamin B3), nicotinamide, and nicotinamide riboside. NAD supports redox balance, mitochondrial metabolism, DNA repair, and stress adaptation, processes that are particularly critical for leukaemic stem cell survival under therapeutic stress. Recent studies demonstrate that AML cells, including those resistant to venetoclax- and hypomethylating agent–based regimens, exhibit heightened dependence on the NAD salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological inhibition of this pathway induces profound NAD depletion, mitochondrial dysfunction, and selective leukaemic cell death. In this review, we integrate nutritional biology with emerging translational evidence to examine NAD metabolism as a nutrient-regulated metabolic vulnerability in AML. We discuss dietary sources and systemic regulation of NAD, the role of NAD-dependent pathways in leukaemic persistence, the translational exploitation of NAD salvage dependency, and the emerging controversy surrounding NAD supplementation in cancer. Finally, we highlight key knowledge gaps and future directions at the interface of nutrition, metabolism, and therapy response in AML. Full article

Background/Objectives: Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD⁺), is used as a dietary supplement, but its safety and metabolic effects in adults remain unclear. This review assessed the short-term safety and tolerability of oral NMN or NMN-related supplementation and examined metabolic and vascular outcomes. Methods: PubMed, Embase, Scopus, Web of Science, CNKI, and Wanfang were searched from inception to 13 May 2026. Eligible studies were parallel randomized controlled trials comparing oral NMN or NMN-related preparations with placebo, blank control, lifestyle control, or the same background intervention without NMN. Safety outcomes included adverse events, serious adverse events, withdrawals due to adverse events, system-specific adverse events, alanine aminotransferase, and aspartate aminotransferase. Random-effects models were used, with GRADE for evidence certainty. Results: Fifteen trials were included, with 10 contributing to safety analyses. NMN doses ranged from 250–2000 mg/day, and durations ranged from 14 days to 24 weeks. NMN did not increase overall, serious, withdrawal-related, or system-specific adverse events, nor did it significantly elevate ALT or AST. No significant effects were observed on body weight, BMI, fasting glucose, HbA1c, lipid profiles, or systolic blood pressure. Diastolic blood pressure decreased slightly, while HOMA-IR showed a non-significant downward trend. Conclusions: Short-term oral NMN or NMN-related supplementation showed favorable tolerability, with no clear increase in adverse events or hepatic biochemical abnormalities. Broad metabolic benefits were not evident, but changes in diastolic blood pressure and HOMA-IR suggest preliminary vascular-metabolic signals, especially in older adults or people with early metabolic risk. Larger and longer trials should confirm efficacy and long-term safety. This review was registered in PROSPERO (CRD420261382497). Full article

Nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD⁺), and NAD⁺ are integral to a variety of cellular processes. NAM supplementation has been shown to have benefits for cellular senescence. However, the mechanism by which NAM improves skin photoaging remains unclear. In this study, the multi-omics analysis revealed that insufficient nicotinamide metabolism may be associated with a decrease in NAD⁺ synthesis during skin aging. Importantly, we found that NAM has an ameliorating effect on the skin photoaging in mice. Supplementation with NAM restored the expression of the salvage-pathway enzymes and NAD⁺ consumers. In addition, the supplementation with NAM was shown to restore the expression of skin barrier-related proteins (ZO1 and E-cadherin) and collagen I, while reducing the expression of senescence markers (γ-H2AX, p53, and p21). Furthermore, we found that NAM effectively suppresses the senescence-associated secretory phenotype (SASP) factors’ expression in skin photoaging. Our research reveals the dual role of NAM in attenuating skin photoaging, acting not only to delay cellular senescence but also to suppress the SASP. Full article

Metabolic dysfunction and proteinopathy are hallmarks of neurodegenerative disease, yet their mechanistic interplay remains poorly understood. Here, we show that loss of the neuronal NAD⁺-synthesizing enzyme Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) disrupts amyloid precursor protein (APP) processing in cortical neurons, leading to accumulation of APP C-terminal fragments (APP-CTFs). NMNAT2 deficiency lowers the NAD⁺/NADH redox ratio coincident with APP-CTF buildup. Temporal profiling reveals a biphasic increase in APP-CTFs, with an initial gradual rise followed by rapid accumulation, paralleling the expansion of differentially expressed proteins. Pathway analysis indicates early activation of JNK/MAPK signaling, followed by late-stage suppression of mitochondrial pathways and induction of endoplasmic reticulum stress and unfolded protein response programs. Seahorse analyses reveal early glycolytic impairment followed by deficits in mitochondrial respiration. Knockdown of the NAD⁺ hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) restores mitochondrial function and normalizes APP-CTF levels in NMNAT2 knockout neurons, whereas NAD⁺ supplementation provides only modest rescue. Together, these data demonstrate that neuronal NAD⁺ depletion drives progressive, SARM1-dependent disruption of glucose metabolism and proteostasis, impairing APP processing. The NMNAT2–SARM1 axis thus links metabolic stress to proteinopathy and highlights SARM1 as a central mediator of neurodegenerative dysfunction. Full article