José Manuel Martínez-Martos

Physiological brain aging is driven by progressive neuro-glial-vascular remodeling, in which neurotransmitter systems serve as the core functional network integrating central resilience and peripheral systemic signaling. This narrative review provides a comprehensive synthesis of the molecular, cellular, and circuit-level mechanisms underlying healthy brain aging. Centered on classical and modulatory neurotransmitter systems, we examine how neurochemical trajectories interact with key regulators of cellular resilience, including the SIRT1/Klotho/mTORC1 signaling network, epigenetic modifications such as the N(6)-methyldeoxyadenosine (N6medA) clock, extracellular matrix dynamics, and multi-organ (muscle–gut–liver–brain) axes. We also discuss how socioeconomic and environmental exposures, such as childhood poverty and air pollution, contribute to individual aging trajectories throughout life. Recent advances in multimodal neuroimaging, spatial transcriptomics (IRISeq), and AI-based brain-age estimation (e.g., ResNet-CrossViT) are highlighted as promising approaches for identifying biomarkers capable of distinguishing physiological aging from the earliest stages of neurodegeneration. Collectively, healthy brain aging represents a dynamic process of biological adaptation in which neurotransmitter remodeling, cellular resilience, metabolic homeostasis, and systemic interactions jointly determine cognitive outcomes. Understanding these interconnected mechanisms provides a framework for developing preventive strategies aimed at preserving cognitive function and extending brain health span.

Glioma progression is accompanied by alterations in redox homeostasis, yet the coordinated expression of antioxidant enzyme isoforms during tumor development remains incompletely understood. In particular, whether the expression of superoxide dismutase (SOD) isoforms is differentially regulated according to biological sex has received little attention. In this study, we characterized the transcriptional (RT-qPCR) and translational (ELISA) profiles of the three SOD isoforms (SOD1-SOD3) in an N-ethyl-N-nitrosourea (ENU)-induced rat glioma model and evaluated potential sex-associated differences. SOD1 expression remained unchanged at both the mRNA and protein levels in glioma tissue compared with healthy brain, indicating preservation of cytosolic enzyme abundance during tumor development. In contrast, SOD2 was significantly upregulated at both transcriptional and protein levels, with a more pronounced increase in male than in female animals. Conversely, SOD3 showed a significant reduction in both mRNA and protein abundance, although this decrease was less marked in females. These findings demonstrate a compartment-specific pattern of antioxidant remodeling characterized by stable SOD1 expression, increased mitochondrial SOD2, and reduced extracellular SOD3. Because the present study quantified transcript and protein abundance rather than direct reactive oxygen species generation, enzymatic activities, or downstream signaling pathways, the functional implications of these expression changes remain to be established. Nevertheless, the observed sex-associated differences suggest that biological sex influences antioxidant responses during experimental gliomagenesis and support its consideration as an important variable in future mechanistic and translational studies.

Neuroinflammation within the tumor microenvironment (TME) of central nervous system (CNS) neoplasms, particularly glioblastoma (GBM), is no longer viewed merely as a reactive phenomenon but rather as a major driver of gliomagenesis and malignant transformation. This process involves a shift from acute immune activation to a chronic, sterile state that reshapes the CNS borders and immune niches to favor tumor evasion. This narrative review provides a comprehensive mechanistically focused analysis of the mechanisms governing the inflammatory stroma in primary and metastatic brain neoplasms. It critically examines the ontogeny and transcriptomic profile of myeloid and glial populations, dismantling the binary M1/M2 polarization model in favor of a continuum of functional states determined by metabolic and oxygenation gradients. It also analyzes intracellular signaling cascades, the subversion of innate immunity sensors such as the cGAS-STING pathway, the epigenetic reprogramming of stromal cells, and the role of extracellular vesicles. The electrochemical integration of tumor cells into neuronal circuits via glutamatergic synapses and connexin 43 gap junction coupling is addressed in detail, defining the mitogenic impact of neuronal activity on the tumor. The inflammatory profiles of IDH-wildtype and IDH-mutant gliomas and of secondary brain metastases are contrasted. Finally, the correlates of functional neuroimaging, liquid biopsies, and resistance mechanisms to conventional therapies are analyzed, including the GIANT and SENIPERA clinical trials, CARv3-TEAM-E bivalent cellular immunotherapy preconditioned with the LDC + R regimen, and the accelerated approval of dordaviprone (Modeyso) in H3 K27M-mutant diffuse midline gliomas.

Glucose transport across biological membranes in mammals depends primarily on two transporter families: the facilitative glucose transporters of the SLC2 family and the sodium-dependent cotransporters of the SLC5 family. Together, these proteins mediate tissue-specific glucose uptake, epithelial absorption and reabsorption, nutrient sensing, and adaptive responses to metabolic stress. This review summarizes current knowledge of transporter classification, structural mechanism, tissue distribution, intracellular trafficking, and disease associations, with emphasis on GLUT1, GLUT2, GLUT3, GLUT4, SGLT1, and SGLT2. It also discusses less well-characterized members of the extended GLUT family, the therapeutic implications of SGLT inhibition, and unresolved questions regarding transporter specificity. Furthermore, the review integrates emerging evidence on CAR-T cell engineering, Alport syndrome, lupus nephritis, erythropoietic responses, and the reduction in dementia risk associated with transporter modulation.

Glioblastoma (GB) is the most aggressive primary central nervous system tumor in adults and the most common malignant primary brain tumor, representing approximately 50.9% of all malignant CNS tumors, with a median overall survival of approximately 14.6 months despite standard multimodal treatment, consisting of surgical resection, concurrent radiotherapy, and temozolomide (TMZ), followed by adjuvant TMZ (Stupp protocol). Tumor recurrence is inevitable and attributed to diffuse infiltration of neoplastic cells into the brain parenchyma, marked intratumoral heterogeneity, the presence of glioma stem cells, and the protection conferred by the BBB. Flavonoids are plant-derived polyphenolic compounds with more than 8000 identified. They have attracted growing interest as potential therapeutic agents because of their capacity to modulate multiple oncogenic signaling pathways and their favorable toxicity profile. Here we synthesize the preclinical evidence on the main flavonoids with documented activity in GB models, with emphasis on quercetin, apigenin, luteolin, and EGCG, while distinguishing glioblastoma-specific evidence from indirect findings derived from other experimental systems. We analyze their underlying molecular mechanisms, including induction of apoptosis through the intrinsic and extrinsic pathways, inhibition of cell proliferation and angiogenesis, suppression of migration and invasion, epigenetic modulation, and, particularly, the capacity to target the glioma stem cell population. We also examine the limited oral bioavailability and restricted penetration across the BBB, as these factors remain major barriers to translational development. We conclude with an analysis of emerging nanotechnological strategies, targeted delivery systems, and synergistic combinations with conventional chemotherapeutic agents, together with a cautious assessment of the current clinical evidence, which remains insufficient to support the use of flavonoids outside controlled clinical trials.

Breast cancer (BC) is associated with metabolic factors that may influence circulating lipids and apolipoproteins. We performed a cross-sectional observational study including 198 women with infiltrating ductal breast carcinoma and 78 cancer-free controls. In the analyzed data, the breast cancer cohort included 39 premenopausal and 44 postmenopausal women without neoadjuvant chemotherapy (NACT), and 35 premenopausal and 54 postmenopausal women exposed to NACT; controls included 63 premenopausal and 52 postmenopausal women. Serum ApoA1 and ApoB were measured by ELISA, and HDL and LDL cholesterol were measured by enzymatic methods. Analyses included two-way ANOVA, Tukey post hoc testing, false-discovery-rate correction, and multivariable linear models adjusted for age and BMI, with HC3 robust sensitivity analyses. In cancer patients, HDL was lower in women exposed to NACT (adjusted β = −8.16, 95% CI −12.61 to −3.71), and ApoA1 differed by menopausal status. Subtype-aware analyses in the available subset did not show independent molecular subtype effects after multiplicity correction. These findings support cross-sectional associations between menopausal status, treatment exposure, and lipid/apolipoprotein profiles, but do not establish causality or prognostic value. Prospective longitudinal studies are required.

The calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide belonging to the calcitonin family, discovered as a product of alternative splicing of the calcitonin gene. CGRP has emerged as a pleiotropic signaling molecule with widespread distribution in the central and peripheral nervous systems, particularly within primary sensory neurons. This narrative review synthesizes current knowledge on the CGRP system, integrating recent advances in its molecular structure, gene organization, and post-translational processing with high-resolution structural insights into its heterodimeric receptor complex (CLR-RAMP1) obtained through cryo-electron microscopy. We also include long-term safety data on anti-CGRP monoclonal antibodies, emerging cardiovascular risk signals, and novel therapeutic applications in vestibular migraine and pediatric populations. The intracellular signaling cascades activated by CGRP, including the canonical cAMP-PKA pathway, MAP kinase activation, and context-dependent calcium signaling, are discussed in relation to its diverse physiological functions. These encompass vasodilation, nociception modulation, neurogenic inflammation, gastrointestinal motility, bone metabolism, tissue regeneration, and energy homeostasis. The central role of CGRP in migraine pathophysiology is examined to understand the development of targeted therapies. The current pharmacological landscape is reviewed, including the evolution of small-molecule CGRP receptor antagonists (gepants) through three generations and the four approved monoclonal antibodies targeting CGRP or its receptor, with comparative analysis of their efficacy, safety profiles, and clinical positioning. Beyond migraine, emerging and predominantly preclinical roles of the CGRP system are discussed in chronic pain, osteoarthritis, cardiovascular diseases, sepsis, cancer (particularly bone metastases and tumor microenvironment immunomodulation), and neurodegenerative disorders such as Alzheimer’s disease. In these areas, the available evidence remains heterogeneous and, in most cases, is not yet sufficient to support clinical translation. Finally, future directions are discussed, including the development of stable CGRP analogs, allosteric modulators, and the potential expansion of therapeutic applications into oncology, intensive care medicine, and neuroprotection.

Alzheimer’s disease (AD), the leading cause of global dementia, is a multifactorial process that goes beyond the accumulation of β-amyloid (Aβ) plaques and tau protein tangles, including glia cell-mediated neuroinflammation, vascular dysfunction, metabolic alterations, and synaptic loss. Its complex etiology also involves oxidative stress and mitochondrial dysfunction. Multiple neurotransmitter systems involved in the pathogenesis and the various cognitive and non-cognitive symptoms of AD are thus altered. The cholinergic system, historically the first to be associated with AD, suffers early degeneration and loss of neurons/receptors, correlating with cognitive impairment. The glutamatergic system, the main excitatory system, exhibits excitotoxicity due to increased extracellular glutamate and alterations in NMDA/AMPA receptor distribution, exacerbating neuronal damage. The GABAergic system, the main inhibitor, shows alterations in parvalbumin-positive interneurons, leading to hyperexcitability and dysfunction of neuronal networks. Monoaminergic systems (serotonergic, dopaminergic and noradrenergic) undergo early degeneration in key nuclei such as the raphe and locus coeruleus, contributing to the apathy, depression and sleep disturbances characteristic of AD. Other less explored systems, such as histaminergic and purinergic, are also crucial in cognitive modulation and neuroinflammation. The endocannabinoid system acts as a master modulator with neuroprotective and anti-inflammatory effects. These systems do not operate in isolation; their complex interactions generate pathological circuits that amplify neuronal dysfunction. The limited efficacy of current therapies, which are primarily symptomatic, highlights the need for multimodal approaches that may transform AD treatment toward personalized and more effective interventions.

Neuronal synapses are the functional units of communication in the central nervous system. This review describes the molecular mechanisms regulating synaptic transmission, plasticity, and circuit refinement. At the presynaptic active zone, scaffolding proteins including bassoon, piccolo, RIMs, and munc13 organize vesicle priming and the localization of voltage-gated calcium channels. Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1. Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways. Postsynaptically, the postsynaptic density (PSD) serves as a protein hub where scaffolds such as PSD-95, shank, homer, and gephyrin anchor excitatory (AMPA, NMDA) and inhibitory (GABA-A, Glycine) receptors are observed. Synaptic strength is modified during long-term potentiation (LTP) and depression (LTD) through signaling cascades involving kinases like CaMKII, PKA, and PKC, or phosphatases such as PP1 and calcineurin. These pathways regulate receptor trafficking, Arc-mediated endocytosis, and actin-dependent remodeling of dendritic spines. Additionally, synapse formation and elimination are guided by cell adhesion molecules, including neurexins and neuroligins, and by microglial pruning via the complement cascade (C1q, C3) and “don’t eat me” signals like CD47. Molecular diversity is further expanded by alternative splicing and post-translational modifications. A unified model of synaptic homeostasis is required to understand the basis of neuropsychiatric and neurological disorders.

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients.