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Physiological brain clearance architecture revealed by neuronal protein tracing.
Cell
Yuichi Chayama, Nalini R Rao, Daniela Perla +17 more
The brain must efficiently clear protein waste to maintain homeostasis, yet physiological drainage pathways remain poorly defined. Standard tracer injection approaches may not reflect endogenous efflux. Here, we develop a non-invasive genetic system to trace neuron-derived protein clearance from the brain to cerebrospinal fluid (CSF) and border tissues. We identify distinct drainage routes and border hotspots missed by tracer injection, confirmed by bioorthogonal labeling of endogenous neuronal proteins. Pulse-chase kinetics reveal slow skull outflow versus rapid dural and nasal clearance. Transcriptomic analyses uncover border cells sampling neuronal antigens, including tolerogenic skull-resident B cells. Region-restricted reporter expression demonstrates compartmentalized clearance following a "nearest exit" principle, where anatomical origin dictates drainage pathway. Disease disrupts clearance through distinct mechanisms: inflammation drives vascular leakage into blood, while amyloid pathology causes parenchymal retention and border exit obstruction. These findings define brain clearance as a compartmentalized system of organized pathways and immune niches whose dysfunction may underlie regional vulnerability in neurological disease.
Aging in orbit: the twelve hallmarks as a bidirectional bridge between spaceflight-induced senescence and terrestrial geroscience.
Ageing Res Rev
Piercarlo Minoretti, Simone Lista, Susana López-Ortiz +4 more
Human spaceflight exposes crew members to a combination of environmental stressors - including microgravity, galactic cosmic radiation, circadian disruption, and prolonged confinement - that together induce multisystem physiological changes resembling terrestrial aging. In this narrative review, we examine how short- and medium-term spaceflight affects all twelve recognized hallmarks of aging. Integrated multi-omics analyses in astronauts and rodent models identified mitochondrial dysfunction as a central node of spaceflight biology, with oxidative damage propagating genomic instability, cellular senescence, and chronic inflammation. At the chromosomal level, telomere dynamics were characterized by a paradoxical elongation-shortening cycle that may compress years of terrestrial attrition into months. In parallel, epigenetic clock analyses showed a ~1.9-year biological age acceleration in astronauts after a 9-day orbital mission, with hierarchical post-flight recovery (reversible transcriptomic and epigenomic shifts versus persistent chromosomal inversions and clonal hematopoiesis mutations). This partial reversibility distinguishes the spaceflight paradigm from the largely unidirectional trajectory of chronological aging. We conclude that the relationship between spaceflight biology and terrestrial geroscience is bidirectional. Aging research on Earth provides the interpretive framework that renders astronaut molecular data biologically meaningful, and spaceflight offers geroscience a compressed, partially reversible aging-like phenotype in healthy young subjects that has no direct terrestrial counterpart. The observation that space radiation induces qualitatively distinct senescent phenotypes amenable to senolytic clearance supports a translational framework in which geroprotective strategies may simultaneously serve astronaut health and promote healthy longevity in the broader aging population.
TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.
Free Radic Biol Med
Zhiqiang Li, Yuxiang Tang, Dongyuan Zhang +6 more
Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to autophagy dysfunction remain unclear. Here we identify transglutaminase 2 (TGM2) as a critical regulator linking these processes. We show that TGM2 is selectively upregulated in senescent microglia, where it assembles a previously unrecognized signaling complex with 14-3-3γ (YWHAG) and PI3K (p85α). This complex sustains AKT phosphorylation, constitutively activates mTORC1, and thereby inhibits autophagic flux. Pharmacological inhibition of TGM2 with cystamine dihydrochloride (CD) reduces this complex, restores autophagy, attenuates senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS) level, and significantly reverses cognitive and motor deficits in aged mice. These findings support a model in which TGM2-related signaling is linked to microglial autophagy dysfunction and senescence, suggesting that targeting TGM2 may offer a novel therapeutic approach for age-related neurodegenerative disorders.
Convergence of neuroinflammation across major neurotropic viral exposomes in AD and ADRD.
J Neuroinflammation
Jamile Harmouch, Ryan Green, Karthick Mayilsamy +3 more
Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are multifactorial neurodegenerative disorders driven by complex interactions among genetic susceptibility, aging, and environmental exposures. Growing epidemiological and mechanistic evidence implicates neurotropic viral exposomes, defined as cumulative lifetime viral infections, as significant contributors to AD risk. Viral encephalitis and common viral infections, including herpes simplex virus type 1 (HSV-1), human immunodeficiency virus (HIV), cytomegalovirus (CMV), SARS-CoV-2, and influenza, have been associated with an increased incidence of AD/ADRD; however, the molecular mechanisms underlying these associations remain incompletely understood.
Hormonal, metabolic and metabolomic biomarkers in long COVID.
Adv Clin Chem
Dimitra Petropoulou, Irene Karampela, Gerasimos Socrates Christodoulatos +3 more
Long COVID (LC), a complex syndrome affecting approximately 6-12 % of individuals post infection, is characterized by persistent, fluctuating, or progressive symptoms lasting at least three months. Its pathogenic mechanisms involve viral persistence, chronic inflammation, immune dysregulation, endothelial dysfunction, and endocrine/metabolic abnormalities. Currently, no specific diagnostic tests exist for LC, highlighting the need for reliable biomarkers. This review synthesizes current evidence on hormonal, metabolic, and metabolite biomarkers in LC. While vitamin D deficiency is prevalent in LC, being associated with neurocognitive symptoms, delayed recovery and poor physical performance, particularly in older adults, its lack of specificity reduces diagnostic utility. Insulin resistance markers consistently correlate with fatigue, mood disturbances, and myalgia, suggesting a distinct metabolic LC phenotype. Lower cortisol frequently correlates with fatigue, sensory disturbances, and neurocognitive symptoms. Alterations in cortisol/adrenocorticotropic hormone, growth hormone, prolactin, and gonadotropins suggest a potential hypothalamic-pituitary axis involvement; however, these abnormalities are often transient, dynamic or nonsignificant. While some patients may exhibit low free triiodothyronine associated with fatigue, no significant incidence of thyroid dysfunction and autoimmunity was associated with LC. Despite the absence of a distinct and consistent metabolomic signature, LC is characterized by the activation of the kynurenine pathway, including increased kynurenine and quinolinic acid, being associated with fatigue, neurocognitive and depressive symptoms. Emerging metabolites of mitochondrial dysfunction and lipid metabolism alterations require further validation. Despite promising findings, evidence remains scattered, hindered by small sample sizes and methodological limitations. Future research should prioritize standardization of biomarker assessment, validation in diverse populations, and exploration of targeted therapeutic interventions.
Temporal Profiles of Natriuretic Peptides and Echocardiographic Indices During Decongestion: Insights from a Cardio-Renal Hemodialysis Model.
Am J Cardiol
Hisao Yoshikawa, Masaki Iwasaki, Katsushi Amemiya +2 more
The temporal behavior of natriuretic peptides and echocardiographic indices during hemodialysis (HD) remains incompletely characterized. We aimed to delineate their dynamic profiles and rank the timing of changes within a single HD session.
Cardiovascular Risk Reduction With Tirzepatide, a Dual GIP/GLP-1 Agonist, in Patients With Type 2 Diabetes Mellitus.
J Lipid Atheroscler
Sakiko Terui, Taichi Minami, Keita Nakamura +1 more
Tirzepatide is the first dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GLP-1) receptor agonist to be approved for the treatment of diabetes mellitus. The SURPASS trials investigated the efficacy and safety of tirzepatide, both as monotherapy and as add-on therapy, in comparison with placebo, basal insulin, semaglutide, or dulaglutide in patients with type 2 diabetes. Tirzepatide at doses of 5 mg, 10 mg, or 15 mg produced significant reductions in hemoglobin A1c levels (-1.87% to -2.58%) and body weight (-6.2 to -12.9 kg) in patients with type 2 diabetes, without increasing the risk of serious hypoglycemia. Tirzepatide also improved lipid parameters and lowered blood pressure. Most of the observed adverse events were mild gastrointestinal symptoms, and the occurrence rate of these events was comparable to that associated with GLP-1 receptor agonists such as semaglutide (1 mg) or dulaglutide (0.75 mg). In this review, we summarize the pharmacodynamics and pharmacokinetics of tirzepatide, review the findings from the phase III SURPASS clinical trials, and discuss the anticipated beneficial effects of tirzepatide on the prevention and management of atherosclerosis and dyslipidemia in patients with type 2 diabetes mellitus.
Comparative Efficacy and Safety of Tirzepatide versus Semaglutide: A Systematic Review and Meta-Analysis with Cardiometabolic Implications.
Nepal J Epidemiol
Azhar Hafiz Baba, Rameez Akhtar, Anurag Rawat +8 more
Obesity and type 2 diabetes are significant global health problems. Tirzepatide, a dual GIP/GLP-1 receptor agonist, and semaglutide, a selective GLP-1 receptor agonist, are the top incretin therapy options, but their relative effectiveness and safety based on direct head- to -head studies have not been pooled. This meta-analysis aims to compare the efficacy and safety of tirzepatide versus semaglutide.
DNA-based delivery of incretin receptor agonists using MYO Technology leads to durable weight loss in a diet-induced obesity model.
Mol Ther Nucleic Acids
Linda Sasset, Andrew D Cameron, Carleigh Sussman +8 more
Incretin receptor agonists (IRAs) have recently come to prominence as powerful weight and glucose control drugs and are approved for the treatment of type 2 diabetes (T2D) and obesity. Semaglutide and tirzepatide, currently the most widely prescribed within this class, are both potent molecules but have a short half-life, requiring weekly dosing. This requirement can negatively affect quality of life and the adherence to therapy, as well as create a significant financial burden for patients who may have a life-long need for treatment. The MYO Technology platform was developed to overcome these barriers. It consists of therapeutic-encoding plasmid DNA, and a proprietary medical device for intramuscular injection and in vivo electroporation of muscle cells. This leads to the uptake of injected DNA, expression of the therapeutic, and its secretion into peripheral circulation. Here, we demonstrate that MYO Technology-delivered IRAs are efficacious in promoting long-lasting weight and glucose control in mouse models of diet-induced obesity. Moreover, engineering the IRAs to facilitate blood-brain barrier penetration further enhances treatment efficacy, with benefits persisting beyond 1 year following a single administration. Together, these findings highlight MYO Technology's potential to transform standard of care by enabling long-lasting therapeutic effects with minimal dosing.
GLPs Significantly Decrease the Risk of Postoperative Surgical Complications: A TriNetX Retrospective Cohort Study.
Dermatol Surg
Marie Vu, Madelyn Schmidt, Smiti Gandhi +1 more
Glucagon-like peptide-1 (GLP) receptor agonists have demonstrated anti-inflammatory and wound-healing properties, but their impact on outcomes after dermatologic surgery has not been evaluated.
Cutaneous Variations in Stem-Cell Population in Those on GLP1-Receptor Agonists: A Comparative Controlled Study.
Dermatol Surg
Maya Firsowicz, Payvand Kamrani, Raheel Zubair +3 more
Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with cutaneous changes including accelerated skin aging and volume loss. The biological mechanisms underlying these effects remain poorly understood, with limited in vivo human data.
A cross-talk between p16High senescence and cellular reprogramming.
Clin Sci (Lond)
Alexander Emelyanov, Dmitry V Bulavin
Cellular senescence and OSKM (Oct4, Sox2, Klf4, and Myc)-mediated reprogramming represent interconnected biological programs that both play important roles in regulating cellular plasticity. Recent studies have highlighted the role of p16-driven senescence in establishing a stable barrier to reprogramming by limiting epigenetic flexibility. Mechanistically, p16High senescent fibroblasts enforce this barrier through stress-induced and AP-1-driven epigenetic remodeling and NNMT-mediated metabolic SAM depletion, which restricts methylation-dependent chromatin remodeling in both p16High and neighboring p16Low cells via a paracrine mechanism. Conversely, clearance of p16High cells restores SAM levels and enhances cellular plasticity in neighboring cells, enabling the acquisition of totipotent-like states during reprogramming. Within p16High cells themselves, reprogramming can reverse some features of senescence, restoring more youthful cellular states under controlled conditions. Importantly, p16High cells remain highly resistant to full reprogramming, minimizing the risk of teratoma and tumor formation in vivo and making them promising target for rejuvenation strategies based on partial reprogramming. In this review, we examine the molecular interplay between p16High senescence and reprogramming, highlighting their dual roles as both barriers to and facilitators of cell fate transitions.
Sex-Biased Pharmacotherapeutic Disparities in Hypertension.
Drugs
Serge Yaacoub, Charles Bardawil, Ryan Yammine +2 more
Hypertension manifests with striking sex-based disparities in prevalence, pathophysiology, and therapeutic outcomes, necessitating the reappraisal of current management paradigms. For example, men exhibit higher blood pressure (BP) in early adulthood, while post-menopausal women suffer from accelerated cardiovascular risk owing to estrogen depletion, endothelial dysfunction, and distinct aging trajectories. Moreover, the renin-angiotensin-aldosterone system (RAAS) operates rather divergently: testosterone upregulates vasoconstrictive angiotensin II type 1 receptors in men, whereas estrogen enhances nitric oxide bioavailability and modulates angiotensin II type 2 receptor in premenopausal women. These hormonal influences extend to cardiovascular aging, as women develop greater arterial stiffness post-menopause, predisposing them to heart failure with preserved ejection fraction. Conversely, men demonstrate higher endothelial dysfunction and cardiomyocyte apoptosis. Furthermore, sex-specific pharmacokinetic profiles (e.g., renal clearance, hepatic metabolism) and pharmacodynamic responses to antihypertensives underscore the inadequacy of uniform treatment strategies. This is demonstrated in women by the observed reduced efficacy of angiotensin-converting enzymes inhibitors, but superior blood pressure control using diuretics. Men, however, respond more robustly to beta blockers. Emerging evidence highlights epigenetic modifiers, including X-chromosome-linked microRNAs (miRNAs) and sex-hormone-driven transcriptional regulators, as pivotal mediators of vascular tone and drug metabolism disparities. Despite these insights, clinical guidelines remain relatively inadequately stratified by sex, perpetuating suboptimal outcomes. This review synthesizes molecular, physiologic, and pharmacotherapeutic axes of sexual dimorphism in hypertension. It also advocates for precision medicine approaches that integrate hormonal status, aging-related vascular remodeling, and genetic polymorphisms. Addressing these physiological paradigms promises to bridge the translational gap between bench and bedside, ultimately mitigating the global burden of hypertensive disease, while mitigating shortcomings in sex-based antihypertensive management.
Associations of PYY, GLP-1 and LEAP2 with changes in feeding-related cognition, body weight and glucose homeostasis after bariatric surgery in non-diabetic women.
J Neuroendocrinol
María F Andreoli, Pablo N De Francesco, Wei Zhou +6 more
Roux-en-Y gastric bypass (RYGB) is an effective surgical intervention for severe obesity, but the role of gastrointestinal hormones in its benefits remains unclear. We examined longitudinal pre-to-post-meal gastrointestinal hormone changes and their relationships with glucose homeostasis and feeding-related cognitive responses in women undergoing RYGB. Seventeen non-diabetic women were evaluated pre-RYGB (Visit 1, V1), 1-month post-RYGB (Visit 2, V2), and 1-year post-RYGB (Visit 3, V3). Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), ghrelin, and liver-expressed antimicrobial peptide 2 (LEAP2) were measured before and after a breakfast in all visits. Appetite ratings and feeding-related cognitive performance were evaluated using visual analog scales, Ideal Portion Size, and Food Stroop tasks. At V3, RYGB induced weight loss (30.8%) and improved glucose homeostasis (p = .020), accompanied by reduced hunger (p = .042), smaller self-reported ideal portion size (p < .001), and improved cognitive control toward food-cues (p = .002). Fasting GLP-1 and PYY levels remained stable across visits but showed enhanced post-meal responses at V2 and V3 (GLP-1: p < .001; PYY: p = .013). Ghrelin levels increased post-RYGB (p = .010) without post-meal variation. LEAP2 concentrations remained stable. Fasting LEAP2 correlated positively with BMI at V1 (p < .001). Fasting PYY correlated inversely with BMI at V3 (p = .005), and its post-meal rise inversely correlated with ideal portion size at V1 (p = .022). GLP-1 increments negatively correlated with ideal portion size (p = .007) at all visits and glycemia (p = .017) at V1. In non-diabetic women, RYGB improves feeding-related cognitive processes. BMI is associated with LEAP2 only pre-surgery, and with PYY 1-year post-RYGB. Restoration of GLP-1 and PYY post-meal increments contributes to metabolic and behavioral improvements. Clinical Trial Registry: This study was registered at clinicaltrials.gov as NCT01815216. https://clinicaltrials.gov/study/NCT01815216.
Targeting Inflammation and Fibrosis in Lipedema: The Potential Role of Glucagon-like Peptide-1 Receptor Agonist Therapies.
Dermatol Surg
Yasmine Mohseni, Aria Vazirnia, Ardalan Minokadeh +2 more
Lipedema is a chronic disorder characterized by disproportionate accumulation of subcutaneous fat, most commonly affecting the extremities, and is associated with pain, inflammation, and fibrosis. Effective medical therapies are lacking, and liposuction remains the primary treatment. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate metabolic and anti-inflammatory effects, but their role in lipedema remains unclear.
Baseline serum cortisol as a prognostic biomarker for immune checkpoint inhibitor therapy in advanced gastric cancer.
Front Oncol
Yufei Zhao, Zhanjun Guo, Jingjing Zhang +1 more
Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced gastric cancer (AGC), but only a subset of patients benefit. Validated prognostic biomarkers for ICI efficacy in AGC remain limited, and the role of endogenous cortisol-an immunosuppressive steroid hormone-in modulating ICI response is unclear.
Sex-specific molecular and cellular phenotypes during resolution of neuropathic pain in dorsal root ganglia.
Cell Rep
Felicitas Schlott, Beate Hartmannsberger, Thorsten Bischler +5 more
The dorsal root ganglion (DRG) is examined for sex-dependent phenotypes in sensory neurons, satellite glial cells (SGCs), and local macrophages following traumatic nerve injury and during natural pain resolution. Systematic analysis of 7,495 DRG immunofluorescence images and 62 transcriptomes reveals pronounced sex-specific, multicellular DRG phenotypes, particularly during pain resolution. Tissue size and neuron density also show sex-dependent differences. Neuropathic pain is resolved without tissue or sensory neuron loss. After injury, macrophages localize to the space between sensory neurons and SGCs; this effect is partially reversed during pain resolution, particularly in males. In females, immune-related gene expression and macrophage phenotypes persist longer, while SGC activation and contact with sensory neurons are more persistent in males. During resolution, synaptic and excitability-related processes are marked in both sexes. In summary, injury responses were largely shared between sexes, whereas the resolution phase exhibited distinctly sex-specific molecular and cellular signatures.
Visualizing a lung neutrophil-platelet immunothrombosis cascade during sepsis in mice.
Science
Luke Brown, Jared Schlechte, Mahum Rashid +8 more
Sepsis is an immune paradox in which host defense is necessary for survival but also contributes to organ damage and death. We defined an immunothrombosis cascade of neutrophil and platelets in the lung microcirculation of Escherichia coli-septic mice. Cathelicidin, an antimicrobial peptide, localized neutrophils to E. coli and initiated immunothrombi through formyl-peptide receptors. Immunothrombi captured bacteria, and cathelicidin enabled antimicrobial activities in platelets. Blocking cathelicidin prevented immunothrombosis and attenuated early sepsis death but resulted in delayed death with uncontrolled infection. Leukotriene B4, an important neutrophil-to-neutrophil communication molecule, amplified immunothrombi, and inhibiting it improved vascular compromise while preserving host defense, thus representing a discrete inflection point of sepsis disease progression. Therefore, targeting the immunothrombi cascade can mitigate immunopathology without suppressing host defense during sepsis.
Comparative Effectiveness of CagriSegma, Semaglutide, Cagrilintide and Tirzepatide in the Management of Overweight and Obesity: A Network Meta-Analysis of Randomized Clinical Trials.
Endocrinol Diabetes Metab
Sultan Hamarsheh, Abdel Rahman Jaber, Omar Abu-Khazneh +4 more
Obesity is a chronic, progressive disease affecting over 1 billion adults worldwide, linked to serious comorbidities, including diabetes, hypertension, and cardiovascular disease and associated with increased mortality. Achieving clinically meaningful weight loss is critical to reducing cardiometabolic risk. Tirzepatide, semaglutide, cagrilintide and their combination (CagriSema) have demonstrated efficacy in clinical trials; however, no direct head-to-head studies have compared all advanced anti-obesity medications. This network meta-analysis examines their comparative efficacy and safety.
Safety, tolerability and efficacy of GLP-1 receptor agonists (GLP-1 RA) in the management of post-liver transplant weight gain: A multicenter, observational study.
Liver Transpl
Mohammad Qasim Khan, Chiara Becchetti, Mahmoud Riyam Jouid +13 more
Post-liver transplant (LT) weight gain and metabolic dysfunction predispose to cardiovascular (CV) morbidity, allograft steatosis, and reduced long-term survival. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) promote weight loss and improve cardiometabolic health, yet evidence in liver transplant recipients (LTR) is limited. We aimed to evaluate the safety, tolerability, and efficacy of GLP-1 RAs in post-LT weight management.