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CD47 inhibiting antibody alleviates brain injury after intraventricular hemorrhage in aged rats.
Exp Neurol
Fenghui Ye, Jianru Li, Yingfeng Wan +4 more
Intraventricular hemorrhage (IVH) is a major contributor to acute brain injury and post-hemorrhagic hydrocephalus, especially in older adults. CD47 on erythrocytes delivers a "don't-eat-me" signal that inhibits macrophage/microglia (M/MΦ) mediated phagocytosis, slowing hematoma resolution. While CD47 blockade enhances hematoma clearance after IVH in young animals and in intracerebral hemorrhage models, its therapeutic potential in aged IVH has not been examined.
The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.
Cell Death Dis
Victoria Pozzi-Ruiz, Aida Giner de Gracia, Liliane Glauser +10 more
There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.
Immune checkpoint blockade as an accelerator of adrenal aging: a testable model linking low-grade cortical inflammation to proteostasis failure, LDLR/SULT2A1 suppression, and reduced DHEA output.
J Immunother Cancer
Guanxiong Ding, Yangyang Xu, Ting Guo +1 more
Immune checkpoint blockade (ICB) unleashes antitumor immunity but frequently provokes enduring endocrine toxicities. We hypothesize that ICB accelerates adrenal aging by establishing chronic low-level inflammation within the adrenal cortex, with targeting vulnerability of the zona reticularis. Integrating a recently published human multiorgan aging proteome atlas and primate adrenal aging study with survivorship data after ICB therapy, we propose a testable signaling cascade: ICB-amplified interferon gamma (IFNγ)/ tumor necrosis factor (TNF)/ interleukin-1 signaling activates nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 1 (STAT1), suppressing sterol regulatory element-binding protein 2 (SREBP2)-low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake; concurrent mitochondrial/endoplasmic reticulum stress drives proteome-transcriptome decoupling, loss of cytochrome b5 type A (CYB5A), and impaired cytochrome P450 family 17 subfamily A member 1 (CYP17A1) 17,20-lyase activity; inflammatory transcriptional repression of sulfotransferase family 2A member 1 (SULT2A1) with proteostasis decay reduces dehydroepiandrosterone (DHEA) sulfation. The net result is a persistent fall in DHEA/DHEA sulfate (DHEAS) with comparatively preserved cortisol-mirroring natural adrenal aging. We advocate prospective measurement of DHEAS, DHEA, adrenocorticotropic hormone (ACTH), and cortisol at baseline, during therapy, end of therapy, and 6-24 months post-therapy; if early DHEAS decline is confirmed, targeted interventions including DHEA replacement or glucocorticoid receptor antagonism warrant evaluation. This framework reframes certain endocrine immune-related adverse events as "accelerated organ aging," with implications for risk stratification, toxicity prevention, and survivorship care.
The Laccase-like Property of GHK-Cu and Its Applications in Colorimetric Sensing of Phenolic Compounds.
Biosensors (Basel)
Jiang-Shan Chen, Huan Zhu, Tong-Qing Chai +1 more
Laccase plays an important role in the detection and degradation of phenolic compounds, but it is limited by its cost and stability. In this study, the laccase-like property of copper peptide (GHK-Cu) has been revealed. In terms of enzymatic reaction kinetics, GHK-Cu has a Vmax of 1.735 × 10-4 mM·s-1 and a Km of 0.061 mM, demonstrating good substrate affinity and excellent catalytic efficiency. Then, a colorimetry was developed for rapid detection of epinephrine (EP) and 2-aminophenol (2-AP). The linear response range of EP is 20-240 μM, with a limit of detection (LOD) of 9.5 μM. The linear response ranges of 2-AP are 14-100 μM (in ultrapure water) and 2-120 μM (in seawater), with LODs of 2.56 μM and 1.65 μM. In addition, combined with a smartphone platform, a cotton-based sensor has been developed for the detection of 2-AP in seawater. The linear response ranges are 0-0.2 mM and 0.2-1 mM, with LOD of 0.033 mM. The structure of GHK-Cu provides a reference for the development of novel laccase mimetic enzymes. The constructed colorimetry offers an option for the rapid detection of phenolic compounds, and the developed cotton-based sensor enabled rapid and portable detection of 2-AP.
ARID1A deficiency unleashes centromeric RNA transcription to drive chromosomal instability and boosts PKMYT1 inhibitor efficacy via RNA sensing.
bioRxiv
Chengguo Li, Xueqian Cheng, Weizhen Liu +15 more
Cancer gene-associated mutations and molecular hallmarks of chromosomal instability (CIN) are unexpectedly common in histologically normal cells and tissues. These emerging findings challenge the binary distinction between "normal" and "cancerous" cells and suggest that early tumorigenesis may commence against a background of widespread yet largely tolerated genomic instability. However, it remains largely unexplored how a cancer gene-associated mutation can initiate the development of CIN-like states in non-malignant cells and drive tumor evolution. ARID1A , a chromatin remodeling factor, was identified as the most frequently mutated gene in both gastric normal epithelium and tumors. This distinctive molecular convergence presents an opportunity to elucidate the mechanisms by which a cancer-associated gene facilitates the initiation of early CIN phenotypes and develop effective antitumor strategies. In the present study, using primary human gastric organoids, we employed optical genome mapping (OGM) and live-imaging technologies to demonstrate that ARID1A depletion induced a wide spectrum of structural variants (SVs), copy number variants (CNVs), and chromosomal segregation errors, characteristic features of CIN at a very early stage of gastric tumorigenesis. Mechanistically, ARID1A bound centromere repetitive satellite DNA (satDNA) sequences. Its SWI/SNF-associated chromatin remodeling activity was required for suppressing satDNA transcription and the production of α-SatRNA, through restricting RNAPII elongation. Consequently, ARID1A depletion led to overexpression of α-SatRNA, and a higher incidence of sister chromatid exchange (SCE), a sensitive indicator of CIN. Importantly, the elevated α-SatRNA expression in ARID1A -deficient cells further established a dual therapeutic vulnerability for G2/M checkpoint blockade, such as PKMYT1 inhibitor (PKMYTi), by concurrently aggregating CIN-induced cell death and activating self-dsRNA sensing-mediated innate immune response. Notably, PKMYTi markedly promoted α-SatRNA expression, aberrant release of these self-derived dsRNAs into the cytosol and a robust activation of the RIG/MDA5-MAVS-depenent type-I interferon response in ARID1A -depleted cells. As expected, PKMYTi potentiated the efficacy of immunotherapy in ARID1A -deficient gastric tumors. Together, our findings reveal that ARID1A deficiency unleashes centromeric α-SatRNA transcription, which sets the molecular stage for tumor evolution and targeted therapy by coordinately inducing CIN and self-dsRNA-induced innate immune responses.
The Muscle Tissue Environment Limits Muscle Stem Cells in Aged Mice.
bioRxiv
Alicia A Cutler, Tenaya K Vallery, Thomas O Vogler +11 more
Frailty arising from loss of muscle function and mass is a significant health concern impacting quality of life and dramatically increasing health care costs as our population ages. Ameliorating frailty derived from reduced muscle function is thus a critical research priority to improve health span. Cell intrinsic defects in muscle stem cells (MuSC), or satellite cells, occur as skeletal muscle ages, reducing the capacity of MuSCs to maintain and repair skeletal muscle and are accompanied by cell nonautonomous changes. Although rejuvenating stem cells in aged tissues or organs has potential to improve muscle aging phenotypes, we found that the extracellular environment in aged mice abrogates rejuvenated muscle stem cell potential. MuSCs from young mice were unable to grow on extracellular matrix derived from aged mice that contains elevated collagen protein levels, establishing a critical role for the environment in contributing to muscle phenotypes in aging. Combining an inducible FGF receptor 1 (FGFR1) to rescue MuSC intrinsic aging defects with a drug to reduce fibrosis partially rescued muscle mass loss in aged mice. We conclude that aging affects tissues, and particularly skeletal muscle tissue, via complex multifactorial processes requiring multifaceted interventions to improve aging phenotypes.
L-Carnosine Enhances the Proliferation and Myogenic Differentiation of Yanbian Cattle Skeletal Muscle Satellite Cells for Cultured Meat Production via Activating the Akt/mTOR/P70S6K Signaling Pathway.
Food Sci Nutr
Bin Sun, Huaina Jin, Xuanying Xin +4 more
The composition of muscle fiber types and the development of skeletal muscle are critical determinants of cultured meat quality. L-carnosine, a dipeptide abundant in ruminant muscle, is known to influence meat quality, yet its regulatory mechanisms in bovine skeletal muscle satellite cells (BSCs) for cultured meat production remain unclear. This study aimed to elucidate the effects of L-carnosine on the proliferation, differentiation, and muscle fiber type transformation of Yanbian cattle BSCs. We identified 10 mM as the optimal concentration for enhancing cell proliferation (p < 0.05), a key finding established by screening L-carnosine treatments from 0 to 40 mm. This enhancement was mediated by the upregulation of cell cycle genes (Pax7, Ki67, CDK1, CDK2, PCNA) and the suppression of inhibitors (p21, p53, p16). Furthermore, L-carnosine robustly promoted myotube formation and specifically upregulated fast-twitch muscle fiber markers (MyHC2a, MyHC2b, MyHC2x) while downregulating the slow-twitch marker MyHC1 (p < 0.05). Transcriptomic analysis identified 449 differentially expressed genes, which were significantly enriched in the PI3K-Akt signaling pathway. Western blotting confirmed that L-carnosine activates the Akt/mTOR/P70S6K signaling pathway to drive myogenesis. Additionally, L-carnosine demonstrated significant antioxidant capacity by reducing reactive oxygen species (ROS) and lipid peroxidation (MDA) while enhancing antioxidant enzyme activities (SOD and GSH-Px). In conclusion, this study provides the first evidence that L-carnosine promotes BSC proliferation and fast-twitch fiber differentiation via the Akt/mTOR/P70S6K pathway, suggesting its potential as a highly effective, natural additive for cultured meat production.
Establish a cultured meat model with adjustable muscle-to-fat ratios based on muscle satellite cells and fibroadipogenic progenitor cells in an optimized gelatin-mTG scaffold.
Food Chem
Liu Shuqin, Tao Shaoying, Bo Chunjie +10 more
Cell-cultured meat offers a sustainable alternative to conventional meat; however, existing monocellular models fall short in replicating its texture and sensory qualities. This study developed an economical gelatin/microbial transglutaminase scaffold to construct a multicellular beef analogue. Muscle satellite cells (MuSCs) and Fibroadipogenic progenitor cells (FAPs) were isolated by flow cytometry. Under 2D culture, MuSCs exhibited enhanced myogenesis (MYH3, MyoD, MyoG upregulated 1.5-2.4-fold), while FAPs showed adipogenic potential (ADIPOQ, FABP4 elevated). Scaffold variants were optimized: GOS (Gelatin-Oriented Scaffold) (muscle-supportive) and GAS (Gelatin-Sodium Alginate Scaffold) (fat-supportive), both supporting high proliferation. Transition to 3D culture further promoted differentiation, increasing myogenic/adipogenic gene expression (2-2.3-fold, p < 0.01) and extracellular matrix secretion (∼2-fold). After 14 days, constructs displayed uniform pink coloration. Post-frying, color parameters (a* [redness], L* [lightness]) were comparable to conventional beef (p > 0.05). This scalable approach creates structured, sensory-comparable cultured meat.
LL-37 Inhibits EV71 Infection by Upregulating STAC via the EGFR-ERK Signaling Pathway.
Viruses
Jiaqi Zhang, Hanlin Zhang, Yi Chen +8 more
LL-37, a 37-amino acid human-derived antimicrobial peptide, was shown in our earlier clinical study to shorten the negative conversion time of the Omicron BA.5.1.3 variant of SARS-CoV-2. In this work, we investigated the broad mechanism of LL-37 by examining its inhibitory effect on non-enveloped virus Enterovirus 71 (EV71). LL-37 treatment dose-dependently reduced EV71 viral RNA abundance, suppressed virus-encoded protein expression, and decreased infectious titers, acting predominantly at a post-entry stage of the viral life cycle. Transcriptomic analysis revealed that the SH3 and cysteine-rich domain protein (Stac) was uniquely upregulated by LL-37 irrespective of EV71 infection. Short hairpin RNA (shRNA)-mediated Stac silencing significantly enhanced EV71 infection, while Stac overexpression markedly reduced it. Furthermore, we found that LL-37 activates the EGFR-ERK signaling pathway, leading to time-dependent upregulation of Stac expression. These findings uncover a novel host-directed mechanism by which LL-37 combats EV71 infection and suggests a potential therapeutic use of LL-37 against non-enveloped viral disease.
[Evaluation of Serum LL-37 Levels in Patients with Brucellosis and Their Relationship with Clinical Course].
Mikrobiyol Bul
Kübra Gögebakan, Zülal Özkurt, Nurinnisa Öztürk
This study aimed to determine the serum levels of the LL-37 molecule, associated with the pathophysiology of Brucellosis, in patients diagnosed with Brucellosis and to investigate the relationship between these levels and the clinical course of the disease. The study included 45 acute, 30 subacute, 26 chronic and 19 relapsed patients diagnosed according to clinical, bacteriological and serologic results as Brucellosis, as well as 60 healthy volunteers. Serum LL-37 levels were measured using the enzyme-linked immunosorbent assay method and the results were compared with the clinical data of the patients. Serum LL-37 levels were significantly higher in Brucellosis patients compared to the control group, with variations observed among clinical subgroups. A weak positive correlation was found between serum LL-37 levels and alanine transaminase, C-reactive protein and erythrocyte sedimentation rate values in patients with Brucellosis. Serum LL-37 levels were higher in patients with Brucella spp. growth in blood cultures compared to those without growth. Additionally, patients with complicated Brucellosis involving osteoarticular involvement had significantly higher serum LL-37 levels than those without such complications. Serum LL-37 levels with a cut-off value of 18.26 ng/mL demonstrated a sensitivity of 92% and a specificity of 88% in distinguishing Brucellosis cases from healthy individuals, with a positive predictive value of 82% and a negative predictive value of 91% (area under curve= 0.956, p< 0.001, 95% confidence interval= 0.93-0.98, negative likelihood ratio= 0.09, positive likelihood ratio= 7.66). No previous studies on serum LL-37 levels in Brucellosis were found in the literature. LL-37 appears to have potential as a biomarker for the diagnosis and prognosis of Brucellosis.
Dietary Strategies and Nutritional Management in Patients Receiving GLP-1 and Dual GIP/GLP-1 Receptor Agonists as Adjuncts to Lifestyle Interventions: A Systematic Review of Randomised Clinical Trials.
Diabetes Obes Metab
Rayanne Santos de Paulo, Dandara Baia Bonifácio, Matheus Henrique Lana de Carvalho +1 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 RAs are widely used to manage obesity, prediabetes and type 2 diabetes, typically in combination with lifestyle interventions. Their nutritional implications, however, remain unclear. This systematic review summarised evidence from randomised clinical trials investigating dietary strategies and nutritional management in individuals treated with these medications.
Glucagon-Like Peptide-1 Receptor Agonists for Bile Acid Diarrhea: Emerging Evidence and Clinical Implications.
Cureus
Eunice K Omeludike, Cherechi O Nwabueze, Nneoma Ubah +7 more
Bile acid diarrhea (BAD) is an underrecognized cause of chronic diarrhea that makes a significant contribution to the symptom burden and impaired quality of life. Despite increasing awareness, BAD is frequently misdiagnosed as diarrhoea-predominant irritable bowel syndrome (IBS-D), leading to delayed diagnosis and incomplete symptom control. Current management relies primarily on bile acid sequestrants, which are effective for many patients but limited by poor tolerability, variable adherence, and incomplete response in a subset, prompting interest in alternative therapeutic approaches targeting bile acid dysregulation. Advances in understanding enterohepatic signaling have highlighted the role of the farnesoid X receptor-fibroblast growth factor 19 (FXR-FGF19) axis in regulating bile acid synthesis, secretion, and motility. In parallel, glucagon-like peptide-1 (GLP-1) receptor agonists, which are commonly used in the treatment of metabolic diseases, affect gastrointestinal motility, secretion, and neurohormonal signaling by mechanisms that overlap with those that are implicated in BAD. Emerging clinical studies, including randomized trials comparing GLP-1-based therapy with established bile acid sequestrants, have begun to explore their potential role in BAD, although the current evidence base remains limited and investigational. This narrative review synthesizes peer-reviewed evidence examining the biological rationale, diagnostic context, and clinical data relevant to GLP-1 receptor agonists in BAD. Literature was identified primarily by PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE) searches supplemented by manual screening of reference lists of key reviews and clinical studies and integrated narratively because of heterogeneity of study design, exposure definitions, and outcome measures. Current evidence suggests that GLP-1 receptor agonists represent a biologically plausible area of investigation for selected patients with persistent symptoms despite standard therapy. This review does not advocate routine clinical use but aims to contextualize emerging BAD-specific and mechanistic data to inform hypothesis generation, patient selection, and future research. Available data are still limited, and GLP-1 receptor agonists have not been established as a treatment for BAD. Further prospective studies with standardized outcomes are needed to clarify their role and inform evidence-based clinical practice.
Familial partial lipodystrophy type 2 associated with a novel LMNA variant (c.604G>C; p.Glu202Gln): a Colombian family case series.
Front Endocrinol (Lausanne)
Carolina Mendoza, Raquel Cano, Luis Burgos +1 more
Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant laminopathy caused by LMNA gene variants. It is characterized by progressive gluteofemoral lipoatrophy and severe metabolic derangements, including insulin resistance and metabolic dysfunction-associated steatotic liver disease.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in dermatology: cutaneous adverse events and emerging efficacy in inflammatory skin diseases.
Expert Rev Clin Immunol
Meng Jie Ho, Choon Fong Liew, Nguan Soon Tan +2 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and next-generation incretin therapies are increasingly used for diabetes and obesity, yet cutaneous adverse events remain incompletely characterized. New-onset dermatological manifestations after GLP-1RA initiation such as rash or alopecia may be misattributed to baseline inflammatory skin disease rather than drug-induced toxicity.
Pink1 at the crossroads of aging, exercise, and diet in Parkinson's disease: a mechanistic review.
Front Aging Neurosci
Ying Lin, Deng-Tai Wen
Pink1 (PTEN-induced kinase 1) is a key guardian of mitochondrial quality via mitophagy; its mutations are tightly linked to early-onset PD. This review synthesizes how aging, exercise, and high-fat diet (HFD) modulate Pink1 activity and thereby PD risk. Aging down-regulates Pink1, impairing clearance of damaged mitochondria and promoting α-synuclein aggregation. Exercise up-regulates Pink1-Parkin signaling, enhances PGC-1α and brain-derived neurotrophic factor (BDNF), and protects dopaminergic neurons in humans and rodents. Conversely, chronic HFD suppresses Pink1, exacerbates oxidative stress, microglial activation and insulin resistance, accelerating Parkinson's disease pathology. Cross-species cautions (mouse vs. primate) are highlighted. Targeting Pink1-mediated mitophagy through lifestyle interventions offers a non-pharmacological strategy to delay PD onset and progression in aging populations.
The senescent niche hypothesis: microglial dysfunction and replacement strategies in drug-resistant epilepsy.
Front Immunol
Jingheng Wu, Miaomiao Li, Yetong Shi +1 more
Epilepsy is one of the most prevalent neurological disorders, affecting over 70 million individuals worldwide. However, despite the introduction of more than 30 anti-seizure medications over three decades, approximately 30% of patients continue to suffer from drug-resistant epilepsy (DRE). Here, we advance the "Senescent Niche Hypothesis," proposing that the epileptogenic focus in DRE harbors a pathological accumulation of senescent microglia that have lost homeostatic surveillance capacity and acquired a toxic secretory phenotype. We present the "Iron-Senescence Axis" as the mechanistic driver: recurrent seizure-induced blood-brain barrier disruption leads to chronic parenchymal iron deposition; microglia accumulate iron through erythrophagocytosis and sustain sub-lethal ferroptotic stress-characterized by lipid peroxidation, mitochondrial dysfunction, and DNA damage-that drives their irreversible transition to a senescent state rather than acute cell death. Once senescent, these microglia paradoxically acquire resistance to ferroptosis through lysosomal iron sequestration, occupy the niche indefinitely, and perpetuate epileptogenesis via the senescence-associated secretory phenotype (SASP), establishing a positive feedback loop. Converging transcriptomic and experimental evidence from both human surgical specimens and rodent models substantiates this framework, demonstrating that senolytic clearance of senescent cells significantly reduces seizure burden and can prevent epilepsy development. Building on these findings, we evaluate two complementary therapeutic strategies: senolytic therapy using dasatinib plus quercetin (D+Q) for selective elimination of senescent cells, and the Microglial Intervention Strategy for Therapy and Enhancement by Replacement (MISTER) for comprehensive niche reconstitution through CSF1R inhibitor-mediated microglial depletion followed by donor cell engraftment. We critically assess donor cell sources, advances in non-genotoxic conditioning, and CSF1R-inhibitor resistant donor cells that may enable clinical translation. This synthesis argues that targeting the senescent microglial niche may represent a disease-modifying approach that shifts the therapeutic focus from seizure suppression to neuroimmune niche restoration.
Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.
Cells
Gianmarco Bertoni, Sara Ristori, Daniela Monti
Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.
Retinal Pigment Epithelium Ageing: Cellular and Molecular Mechanisms of Long-Term Homeostasis and Age-Related Dysfunction.
Cells
Yijing Yang, Pei Liu, Jiangwei Li +4 more
The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood-retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues.
Autoimmune Features of Post-COVID-19 Vaccination Syndrome and Their Impacts on the Renin-Angiotensin System.
Vaccines (Basel)
Paolo Bellavite, Giuseppe Di Fede, Mauro Mantovani +1 more
One of the most critical aspects of post-acute COVID-19 syndrome (PACS) and post-acute COVID-19 vaccination syndrome (PACVS) is the presence of autoantibodies. These autoantibodies are directed against various receptors in the autonomic and cardiovascular systems, including those targeting proteins of the renin-angiotensin system (RAS). The RAS plays a central role in regulating vascular homeostasis, inflammation, and endothelial function. During SARS-CoV-2 infection, the interaction of the spike (S) protein with angiotensin-converting enzyme 2 (ACE2) can alter the balance of the RAS, favoring an imbalance towards the ACE/Angiotensin II/AT1R axis, known for its pro-inflammatory, pro-thrombotic, and vasoconstrictive properties. Similar pathological mechanisms also come into play in response to vaccinations that use the S protein as an antigen. Studies conducted by other groups and us on patients with PACS and PACVS have revealed the presence of autoantibodies directed against these RAS components and the mechanisms by which these antibodies can worsen the clinical situation. In particular, anti-ACE2, presumably formed by the anti-idiotype network or molecular mimicry, is correlated with PACVS symptoms in many patients. Furthermore, the presence of anti-MAS1 antibodies can reduce the efficiency of the ACE2/Angiotensin-(1-7)/MAS1 axis, which normally acts as a counter-regulator. Considering this evidence, an analysis of RAS molecules and the autoantibodies implicated in reactions to them may be useful for evaluating a state of persistent dysregulation associated with post-vaccination symptoms such as asthenia, headache, skin edema and bruising, cardiovascular alterations, and neurovegetative manifestations. Finally, we offer insights into diagnosing these multifaceted syndromes and working hypotheses to guide research into possible therapeutic approaches.
Sushi, von Willebrand Factor Type A, EGF and Pentraxin Domain-Containing Protein 1: A Novel Fibroblast-Derived Circulating Biomarker Reflecting Cardiac Fibrosis.
J Am Heart Assoc
Naoya Kuwahara, Manabu Nagao, Yu Izawa +9 more
Cardiac fibrosis is a hallmark of heart failure and can be quantified by the extracellular volume fraction (ECV) derived from diagnostic imaging. However, noninvasive assessment is limited by the lack of specific circulating biomarkers. Recent large plasma proteome analyses have identified SVEP1 (Sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1) as candidate molecules reflecting cardiac fibrosis. This study aimed to evaluate SVEP1 as a biomarker for cardiac fibrosis.