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Role of Exercise in Cardiovascular Disease and Alzheimer's Disease Comorbidity: A Blood Biomarker Perspective.
Cells
Yu Lu, Chunyan Xu, Pengyu Fu +1 more
With the growing of the global population aging, the comorbidity of cardiovascular disease (CVD) and Alzheimer's disease (AD) has gradually become a major contributor to global disease burden, with the two diseases exhibiting interacting pathological characteristics. This review summarizes the mechanisms underlying CVD-AD comorbidity, including cerebral hypoperfusion and protein aggregation, oxidative stress and inflammation, as well as metabolic disorders and genetic factors. We also assess the value of blood biomarkers in this comorbidity, such as p-tau217, NT-proBNP, NfL, GFAP, and miRNAs. We then review the role of exercise in ameliorating this comorbidity, integrating its potential mechanisms into five aspects: repairing cerebral hypoperfusion and endothelial injury, accelerating Aβ clearance and inhibiting Tau protein hyperphosphorylation, reducing inflammation, protecting neuronal structure and the blood-brain barrier, and improving metabolic disorder. We also analyze in detail the relationship between exercise targets and blood biomarkers. Finally, we discussed the impact and application of different exercise modalities in this comorbidity, concluding with suitable exercise prescriptions and relevant safety considerations for each modality, further organized the mainstream pharmacological and nutritional intervention strategies for CVD-AD comorbidity, and objectively explored their potential interactions when combined with exercise interventions. Future research should integrate multi-omics technologies and gradually refine clinical data on comorbidity, with the aim of developing more targeted, personalized exercise prescriptions for patients with comorbidities, thereby providing scientific theoretical guidance for early risk prevention and disease management in patients with co-occurring CVD and AD.
Gamma Oscillations, Sensory Stimulation, and Glymphatic Function: Toward User-Friendly Auditory Interventions for Brain Health in Aging and Neurodegeneration.
Med Sci (Basel)
Peter Wostyn, Piet Goddaer
The glymphatic system is a brain-wide clearance pathway that facilitates the removal of interstitial solutes, including amyloid-β, and plays a critical role in maintaining brain homeostasis. Impairments in glymphatic transport have been implicated in aging and neurodegenerative diseases, including Alzheimer's disease. While glymphatic activity is most pronounced during sleep, emerging evidence suggests that specific patterns of neural activity, including gamma-frequency oscillations entrained by sensory stimulation, can modulate glymphatic transport even during wakefulness. Preclinical studies further indicate that 40 Hz sensory stimulation, delivered via light, sound, or multisensory paradigms, can induce gamma oscillations, reduce pathological protein accumulation, and enhance cognitive performance in animal models of Alzheimer's disease. Early clinical investigations similarly suggest that gamma-frequency sensory stimulation may improve blood-based biomarkers, neuroimaging measures, and cognitive outcomes in patients with Alzheimer's disease. To translate gamma-frequency stimulation into broadly applicable preventive or therapeutic strategies, approaches must be both effective and tolerable for long-term use. Conventional auditory gamma stimulation can be perceived as acoustically rough or monotonous, reducing listener comfort and limiting acceptability for prolonged use in broader populations. User-friendly auditory formats, such as "gamma music" and the more recently introduced "immersive gamma music", have been proposed as potentially useful approaches for delivering gamma-frequency stimulation while improving listening comfort and facilitating sustained use. Collectively, gamma-frequency sensory stimulation represents a promising approach to support healthy brain aging and mitigate neurodegenerative processes, particularly when implemented via user-friendly auditory formats that facilitate repeated and long-term use. While these findings are encouraging, further research is needed to validate these approaches and determine their clinical relevance.
Impact of Economic, Social, and Cultural Capital on Self-Rated Health of Older Adults in an Indian City.
J Cross Cult Gerontol
Anamika Singh, Esha Chatterjee
A rapid increase in ageing population across the globe has made it necessary for countries to focus on the health and well-being of older adults. City-level data on ageing is limited in the context of developing countries. The present study examines the associations between Bourdieu's core forms of capital (economic, cultural, and social) and self-rated health of older adults aged 60 and above, in Lucknow city, India. The study employs a multistage cluster sampling design. Face-to-face interviews were conducted with 410 respondents aged 60 years and older, between May 2023 to August 2023. Ordered logistic regression is used to assess the associations between all three forms of capital and self-rated health of older adults after controlling for their gender, caste and religious group, age group, overall fitness, and recreational participation. In the full model, high levels of social support from informal ties, and higher levels of cultural capital (higher education and cultural engagement) are associated with better self-rated health, while economic capital is not significant once social and cultural capital are accounted for. This study highlights the role of neighbourhood social capital and cultural engagement as possible intervention mechanisms for improving the health of older adults, which is key to policy and practice for achieving the goal of active ageing.
Cardiorenal Effects of Switching from Eplerenone to Esaxerenone in Patients with Chronic Heart Failure and Hypertension: A Prospective Clinical Study.
J Pers Med
Akira Sezai, Masanori Abe, Takashi Maruyama +3 more
Background/Objectives: Esaxerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA) with potent cardiorenal protective effects. However, the clinical effects of switching from eplerenone to esaxerenone in patients with chronic heart failure complicated by hypertension remain unclear. This study investigated the effects of switching from eplerenone to esaxerenone on blood pressure, heart failure biomarkers, renal function, and the renin-angiotensin-aldosterone system (RAAS). Methods: A total of 156 patients with chronic heart failure and hypertension who had been receiving eplerenone for more than one year were prospectively enrolled. Eplerenone was switched to esaxerenone, and the patients were followed for 6 months. Blood pressure, heart rate, brain natriuretic peptide (BNP), renal function, urinary albumin-to-creatinine ratio (UACR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary osmolality (U-OSM) were evaluated. Results: Following the switch to esaxerenone, systolic and diastolic blood pressure significantly decreased (both p < 0.001), whereas heart rate remained unchanged. BNP levels significantly decreased at 3 and 6 months (p = 0.008 and p = 0.002, respectively). Serum creatinine decreased (p = 0.017), estimated glomerular filtration rate increased (p = 0.028), and UACR significantly decreased at both time points (both p < 0.001). PRA and PAC significantly increased after switching (both p < 0.05), whereas angiotensin II levels remained unchanged. U-OSM significantly decreased (p = 0.01 and p = 0.002 at 3 and 6 months, respectively). No major cardiovascular events or severe adverse events were observed. Conclusions: In patients with chronic heart failure and hypertension, switching from eplerenone to esaxerenone was associated with reductions in blood pressure, BNP, UACR, and urinary osmolality, together with improvements in renal function. These findings suggest favorable physiological changes following the switch from a steroidal to a non-steroidal mineralocorticoid receptor antagonist, although confirmation in randomized controlled studies with clinical outcome measures is warranted.
Effects of Pulsed Electromagnetic Field Application on Glucose Metabolism in Rats.
Bioelectromagnetics
Harun Gencer, Hakkı Murat Bilgin, Veysi Akpolat +4 more
The present study aimed to evaluate the effects of pulsed electromagnetic field (PEMF) exposure on glucose metabolism-related hormonal and oxidative stress markers. Twenty-three male Wistar albino rats were randomly assigned to three groups: sham-control (n = 7), PEMF (n = 8), and PEMF + vitamin C (n = 8). The PEMF and PEMF + vitamin C groups were exposed to a pulsed magnetic field at 50 Hz and 1.5 mT for 4 h daily over 4 weeks. Vitamin C (250 mg/kg/day) was administered orally to the PEMF + vitamin C group. Serum and tissue levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), sirtuin 1 (SIRT1), total antioxidant capacity (TAC), and total oxidant capacity (TOC) were measured. Histopathological evaluations of brain, liver, and pancreatic tissues were also performed. Serum glucose, insulin, glucagon, GLP-1, SIRT1, TAC, and TOC levels did not differ significantly among the experimental groups. Gastric TAC levels were significantly higher in the PEMF + vitamin C group. In renal tissue, insulin levels were significantly elevated only in the PEMF + vitamin C group. PEMF exposure did not induce systemic biochemical changes in healthy rats but elicited tissue-specific biochemical responses, particularly in gastric tissue. These findings suggest that PEMF may modulate glucose-related endocrine and redox pathways at the gastrointestinal level without causing structural tissue damage. Bioelectromagnetics. 00:00-00, 2026. © 2026 Bioelectromagnetics Society.
Saxagliptin Combined with Liraglutide vs. Saxagliptin Alone on Microinflammation and Adipokines in Obese T2DM Patients with Poor Metformin Response.
J Vis Exp
Lihui Zhang, Wanwen Wu, Hao Lu
Metformin is the first-line therapy for obese patients with type 2 diabetes mellitus (T2DM); however, a substantial proportion of patients exhibit inadequate glycemic control despite optimal dosing. This protocol describes a retrospective cohort approach to evaluate the effects of saxagliptin combined with liraglutide on microinflammation and adipokine profiles in obese T2DM patients with poor response to metformin. A total of 116 eligible patients were identified from electronic medical records and assigned to receive either saxagliptin monotherapy or saxagliptin combined with liraglutide based on predefined clinical criteria. The protocol includes standardized procedures for patient selection, group allocation, metabolic assessment, and laboratory measurement of inflammatory markers, adipokines, and metabolic parameters. Representative outcomes demonstrate that both treatment regimens are associated with improvements in glycemic control, lipid metabolism, and insulin resistance. The combination regimen shows greater reductions in inflammatory markers and more favorable modulation of adipokine profiles compared to monotherapy, while maintaining a comparable safety profile. These findings illustrate the application of this protocol for evaluating multi-target metabolic interventions in real-world clinical settings. This method provides a reproducible framework for assessing combined pharmacological strategies in obese T2DM patients with suboptimal response to first-line therapy and may support further clinical and translational investigations. Key words: Saxagliptin; Liraglutide; Obesity-related type 2 diabetes; inflammatory response; Microinflammatory response.
A challenging diagnosis of pediatric (cyclic) Cushing disease: the decisive role of hair cortisol.
JCEM Case Rep
Lizanne Berkenbosch, Saartje Straetemans
Cushing disease is a rare and often difficult diagnosis. Therefore, a significant delay between the onset of symptoms and the final diagnosis frequently occurs. We present a previously healthy 12-year-old boy in whom hypercortisolism was suspected based on clinical symptoms: abrupt excessive weight gain despite adequate exercise and dietary interventions in combination with growth arrest. The results of conventional biochemical diagnostics for Cushing disease were contradicting and could not confirm the diagnosis. Because of a persistent clinical suspicion after a wait-and-see period, cortisol levels in the boy's 11 cm long hair were analyzed. The very high hair cortisol levels supported the clinically suspected Cushing disease. Magnetic resonance imaging of the pituitary showed evidence of an adenoma, which was confirmed postoperatively as an adrenocorticotropic hormone producing adenoma. This confirmed the diagnosis of Cushing disease, with most likely a cyclical course, 1.5 years after the initial presentation. This case adds to the scarce literature on pediatric cyclic Cushing disease and emphasizes the added value of hair cortisol.
Probable Primary Adrenal Insufficiency Associated With Granulomatous Adrenal Calcifications, Non-tuberculous Mycobacterial Ileitis, and Crohn's Disease: A Case Report.
Cureus
Gilberto M Lozano Dubernard, Perla J Ruíz López, Francisco I Aguiar Hernández +1 more
Granulomatous adrenal involvement is an uncommon cause of primary adrenal dysfunction, while intestinal non-tuberculous mycobacterial (NTM) infection and Crohn's disease share substantial clinical, endoscopic, radiological, and histopathological overlap. The coexistence of these entities represents an exceptional diagnostic challenge, and epidemiological data regarding their association are currently lacking. We report the case of a 61-year-old man who presented with progressive cutaneous hyperpigmentation. Computed tomography demonstrated bilateral adrenal calcifications, calcified lymph nodes suggestive of granulomatous disease, and a calcified hepatic granuloma. Biochemical evaluation revealed markedly elevated adrenocorticotropic hormone (ACTH) levels, while morning cortisol and aldosterone.
Suspected adrenal insufficiency in hemodialysis patients with recurrent intradialytic hypotension.
Int Urol Nephrol
Noha Mohamed Elkholy, Mohammad Elraggal, Merna AbouKhatwa +1 more
Intradialytic hypotension (IDH) is a frequent complication of maintenance hemodialysis and is associated with increased morbidity. The role of adrenal insufficiency (AI) as a potential contributor to recurrent IDH remains insufficiently characterized.
Possible Attenuation of Early Weight Loss During Tirzepatide Therapy in a Patient Treated With Levosulpiride: A Case Report and Mechanistic Hypothesis.
Cureus
Augusto Carducci, Pierfrancesco Di Matteo, Claudio Ferri +1 more
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, induces significant weight loss and glycemic improvement. Dopaminergic pathways are critically involved in appetite regulation and reward processing, and the pharmacological modulation of dopamine signaling may influence metabolic responses to incretin-based therapies. We report the case of a 54-year-old woman with obesity and newly diagnosed type 2 diabetes mellitus (T2DM) who initiated tirzepatide therapy while receiving levosulpiride for functional dyspepsia. During the co-administration of tirzepatide 5 mg weekly and levosulpiride, only modest weight reduction was observed, followed by a plateau. After the discontinuation of levosulpiride and the titration of tirzepatide to 7.5 and 10 mg weekly, a marked and progressive reduction in body weight occurred, with an overall loss of 11 kg from baseline. Glycemic control improved substantially (glycated hemoglobin {HbA1c}: 5.0%), and no episode of pancreatitis occurred despite asymptomatic lipase elevation. This case raises the hypothesis of a potential pharmacodynamic interaction between dopaminergic antagonism and incretin receptor agonism, possibly mediated by opposing effects on gastric motility and central reward pathways. Although causality cannot be established, clinicians should consider concomitant neuroactive medications in cases of suboptimal early weight response to dual incretin therapy.
Left Ventricular Dimension as an Independent Factor Associated with Amino-Terminal pro-Brain Natriuretic Peptide Values in Heart Failure.
Am J Med
Julio Núñez, Josep Lupón, Freya Sophie Jenkins +11 more
The specific contribution of left ventricular chamber dimensions to amino-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations in heart failure remains underexplored. We evaluated the association between left ventricular end-diastolic diameter (LVEDD) and circulating NT-proBNP levels across the spectrum of acute and chronic heart failure.
Metabolic-Hormonal Interplay and the Case for a Reproductive-Metabolic Framework in the Glucagon-Like Peptide-1 (GLP-1) Era.
Cureus
Alisha Lakhani, Sahil Lakhani
Polycystic ovary syndrome (PCOS), proposed by some investigators to be more accurately termed polycystic-morphology ovary syndrome (PMOS), reflecting its heterogeneous and not universally cystic pathophysiology, remains the most prevalent endocrine disorder among reproductive-age women worldwide. Despite this, its clinical management continues to be fragmented along specialty lines, with gynecologists addressing menstrual irregularity and contraception, endocrinologists managing insulin resistance and metabolic risk, and dermatologists treating hyperandrogenic manifestations. This editorial proposes the Reproductive-Metabolic Axis (RMA) as a unifying conceptual framework for understanding PCOS/PMOS beyond its phenotypic surface. We argue that contraceptive decision-making in women with PCOS/PMOS cannot be separated from metabolic status, insulin resistance, androgen excess, and cardiovascular risk profiling. In the glucagon-like peptide-1 (GLP-1) receptor agonist era, which has transformed the management of obesity and insulin resistance, new clinical questions arise regarding the interaction between incretin-based therapies, hormonal contraception, and ovarian function restoration. The present editorial does not propose a validated therapeutic protocol, but rather a hypothesis-generating framework that invites further clinical investigation into whether integrated reproductive-metabolic management improves outcomes for women with PCOS/PMOS.
Charge-dependent insertion of the antimicrobial peptide magainin 2 into lipid monolayers probed by neutron reflectivity.
Biochim Biophys Acta Biomembr
Arnaud Marquette, Andrew R J Nelson, Sophie Combet +1 more
Many antimicrobial peptides act by disrupting cellular membranes, with therapeutic selectivity arising from their ability to discriminate between bacterial and mammalian cells, a distinction largely governed by membrane surface charge. Here, we investigate the interfacial organisation and membrane insertion of the cationic antimicrobial peptide magainin 2 using specular neutron reflectometry on lipid monolayers that mimic bacterial and mammalian membranes. Negatively charged dipalmitoylphosphatidylglycerol (DPPG) and zwitterionic dipalmitoylphosphatidylcholine (DPPC) were used as respective representative model systems. Experimental conditions were adjusted to compensate for the markedly different membrane association constants of magainin 2, enabling direct comparison of peptide behavior at the two interfaces. Despite similar peptide coverages, magainin 2 exhibits strikingly different interfacial behavior. At the DPPG interface, the magainin 2 α-helix inserts deeply and adopts an orientation parallel to the membrane surface, with hydrophobic residues facing the lipid chains and cationic residues interacting with the polar headgroups. In contrast, at the DPPC interface, the peptide displays limited interaction with the monolayer and a diffuse intensity distribution across the headgroup and acyl-chain regions, consistent with a largely disordered conformation. These results demonstrate that electrostatic interactions not only promote membrane binding but also dictate peptide insertion depth and interfacial organisation. By directly linking membrane charge to peptide penetration and structural arrangement, this work provides mechanistic insight into the selective antibacterial activity of magainin 2 and establishes a general framework for understanding the membrane-disruptive action of cationic antimicrobial peptides.
Comparative effectiveness of Chinese herbal medicine versus liraglutide for weight loss in adults with obesity: A 12-month real-world target trial emulation study.
Integr Med Res
Yu-Ning Liao, Tsung-Hsien Yang, Yi-Chin Lu +4 more
Chinese herbal medicine (CHM) is commonly used for weight control in Taiwan. This study aimed to compare the effectiveness and mechanisms of a fixed combination of CHM with liraglutide using a target trial emulation real-world study.
Tirzepatide and the gut microbiota-obesity axis: metabolic mechanisms and therapeutic perspectives.
Front Microbiol
Santiago Cadena-Ullauri, Andrés S Cadena Paredes, Lenín Guamán-Herrera +6 more
Obesity is a chronic multifactorial metabolic disorder characterized by adipose tissue dysfunction, insulin resistance, low-grade inflammation, and altered energy homeostasis. Evidence indicates that the gut microbiota contributes to obesity-related metabolic dysfunction through microbial metabolite production, intestinal barrier regulation, immune activation, bile acid signaling, and gut-brain communication. This narrative review, supported by a structured literature search, synthesizes current evidence on the gut microbiota-obesity axis and the potential role of tirzepatide in modulating microbiota-related metabolic pathways. Microbiota-derived metabolites, including short-chain fatty acids, bile acids, tryptophan derivatives, trimethylamine N-oxide, and fatty acid-derived compounds, may exert beneficial, detrimental, or context-dependent effects depending on microbial composition, diet, host metabolic status, and tissue-specific signaling pathways. Lifestyle, dietary patterns, host genetics, and medication exposure can further modulate gut microbiota composition and function, influencing metabolic outcomes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist, improves glycemic control and promotes weight loss. Evidence suggests that tirzepatide may also be associated with changes in gut microbiota composition, microbial metabolites, intestinal barrier integrity, and inflammatory signaling. However, whether these microbial changes represent direct pharmacological effects or secondary consequences of weight loss, reduced caloric intake, delayed gastric emptying, improved glucose control, or dietary modification remains unclear. This review summarizes current evidence on the gut microbiota-obesity axis and the potential relevance of tirzepatide-associated microbiota modulation.
Individualized osilodrostat treatment for patients with ACTH-dependent Cushing's syndrome: real-world evidence.
Front Endocrinol (Lausanne)
Aleksandra Gilis-Januszewska, Aleksandra Gamrat-Żmuda, Mari Minasyan +2 more
Osilodrostat is an 11β-hydroxylase inhibitor that has demonstrated high efficacy in Cushing's syndrome (CS) in clinical trials; however, real-world data remain limited.
Stress-associated transient enlargement of pre-existing adrenal hyperplasia in 21-hydroxylase deficiency: a case report.
Front Endocrinol (Lausanne)
Chengcheng Zheng, Lianling Zhao, Tao Chen
The adrenal gland plays a pivotal role in the stress response via the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenomedullary system (SAMS). Congenital adrenal hyperplasia (CAH) results from pathogenic variants in genes encoding adrenal steroidogenic enzymes. The most common form, 21-hydroxylase deficiency, impairs cortisol biosynthesis, leading to compensatory overproduction of adrenocorticotropic hormone (ACTH) and chronic adrenal hyperplasia.
Integrating polyphenols and exercise in cancer prevention, treatment, and rehabilitation: cellular and molecular mechanisms linking the injury-recovery-musculoskeletal resilience axis.
Front Oncol
Sen Lin, Mengrui Bi
Cancer progression, therapeutic interventions, and rehabilitation profoundly affect musculoskeletal integrity, impair tissue resilience, and compromise recovery, leading to functional decline and reduced quality of life. Increasing evidence suggests that combining exercise with polyphenol supplementation exerts synergistic effects in preventing tissue injury, mitigating treatment-related damage, and promoting functional recovery. This review integrates current findings on the cellular and molecular mechanisms by which polyphenols such as curcumin, resveratrol, quercetin, and green tea catechins, modulate oxidative stress, inflammation, apoptosis, autophagy, and anabolic signaling in muscle, bone, and cardiac tissues. Exercise induces mechanical loading and metabolic adaptations that activate PI3K/Akt/mTOR, MAPK/ERK, AMPK, and Nrf2 pathways, enhancing protein synthesis, mitochondrial biogenesis, and redox-adaptive capacity. Polyphenols further reinforce these effects by suppressing NF-κB and pro-inflammatory cytokines, modulating BDNF/CREB in the nervous system, and attenuating chemotherapy- or radiotherapy-induced tissue damage. Together, these interventions support musculoskeletal resilience, accelerate recovery, and optimize rey -30habilitation outcomes. By elucidating these mechanistic pathways, this review provides a framework for evidence-based integrative strategies to enhance functional preservation and repair in cancer prevention, treatment, and rehabilitation.
Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism.
Nat Metab
Jo Edward Lewis, Mireia Montaner, Danae Nuzzaci +8 more
The development of dual agonists for the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has been a landmark moment in the treatment of type 2 diabetes and obesity. However, for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss1. Here we show that distinct brain regions mediate the appetite-suppressing effects of GIPR agonists and the synergistic weight loss effects conferred by GIPR antagonists. We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide. GiprAP-KO mice exhibit partial protection against diet-induced obesity, reduced responsiveness to the appetite-suppressing effects of acyl-GIP and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY. Weight loss effects of liraglutide are comparable in GiprAP-KO and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Giprhypo-KO mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Giprhypo-KO also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide-an effect that is not mediated by nucleus tractus solitarius preproglucagon neurons. GIPR antagonism and Giprhypo-KO also sensitise to cagrilintide-induced weight loss. Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists.
Loss-of-function Dnmt3a mutation leads to aberrant neutrophil migration.
Exp Hematol
Frieda Zimmer, Daniel E Kennedy Ii, Spencer L Redding +10 more
Clonal hematopoiesis (CH), an age-related expansion of somatically mutated hematopoietic clones, is associated with increased risk of severe infections including COVID-19, yet the underlying mechanisms remain unclear. Here, we investigated the impact of Dnmt3a deficiency in a murine model of influenza A virus (IAV) pneumonia. Dnmt3a-deficient mice exhibited increased pulmonary viral burden and reduced neutrophil accumulation in IAV-infected lungs despite comparable circulating neutrophil numbers. Functional analyses of neutrophils showed impaired chemotactic migration in vitro, while maturation, antimicrobial enzyme content, and metabolic capacity were unchanged. Transcriptomic profiling revealed downregulation of pathways involved in chemotaxis, cytokine signaling, and cellular activation, including reduced expression of Cxcr1. Supporting the translational relevance of these findings, proteomic analysis of plasma from individuals with germline DNMT3A mutations (Tatton-Brown-Rahman syndrome) revealed alterations in proteins associated with cell migration and cytoskeletal dynamics. Collectively, our findings demonstrate that Dnmt3a loss compromises innate immune defense by impairing neutrophil migration in a cell-intrinsic manner, leading to ineffective pathogen clearance. This work provides mechanistic insight into how CH-associated mutations contribute to age-associated susceptibility to infection and highlights altered leukocyte trafficking as a potential therapeutic target in aging populations with CH.