Noelia Geribaldi-Doldán

Background/Objectives: Although creatine supplementation has a theoretical rationale for neuroprotection, public interest has outpaced available scientific evidence. Alzheimer’s disease (AD), a major and growing global health concern, is among the neurodegenerative diseases proposed to benefit from creatine supplementation. This scoping review systematically maps the existing literature on creatine supplementation for AD to identify gaps that limit translational progress. Methods: Following JBI methodology and PRISMA-ScR guidelines, a search in five electronic databases was conducted for preclinical and clinical studies evaluating creatine interventions in AD. The methodological quality of the studies was appraised using the SYRCLE and NIH tools, respectively. Results: Nine unique studies were included. The preclinical models investigated neuron apoptosis, oxidative stress, neuroinflammation, mitochondrial function, cognitive outcomes, and pathophysiological clearance. Conversely, clinical studies were limited to a pilot trial that suggested preliminary tolerability but could not establish causality. This review identifies six limitations within the current evidence: (1) a reliance on acute or non-transgenic animal models that lack construct validity; (2) a need to address sexual dimorphism; (3) a lack of studies exploring administration routes to bypass the blood–brain barrier; (4) a complete lack of independent randomized controlled trials (RCTs), with all clinical evidence originating from a single research group; (5) an absence of research assessing creatine as a preventive strategy; and (6) a shortage of assessment regarding physical syndromes, such as frailty. Conclusions: The scientific evidence for creatine in AD remains preliminary. Future research should prioritize progressive transgenic models, evaluate noninvasive administration routes, investigate effects on frailty, assess long-term preventive efficacy, account for sex as a variable, and transition to rigorous RCTs.

How does the complex, adaptive, and autonomous organization of life emerge from the laws of physics and information? This review argues that the answer lies in a convergent set of universal organizational principles that constitute a physical and informational grammar of the living. Living systems are dissipative structures that achieve organizational closure—materially and energetically open, yet causally closed—thereby attaining genuine autonomy and agency. Their architecture exhibits fractal and modular scaling laws that maximize energy flow, robustness, and evolvability under universal physical constraints. Critically, organisms operate at critical transitions—zones of controlled instability where fluctuations amplify information processing, transforming noise into adaptive signal. This self-organized criticality enables functional degeneracy, relational redundancy, and evolutionary antifragility. Cognition emerges as a distributed process of active inference, operating through a predictive–corrective cycle that integrates perception, action, and learning under the Free Energy Principle. From molecular networks to ecosystems, the same physico-informational grammars unfold recursively, revealing a deep organizational holography: the principles of organization are replicated across scales. Evolution under the Law of Increasing Functional Information is not random drift, but a directional expansion of functional complexity—a thermodynamic gradient towards greater agency. This synthesis challenges biological exceptionalism: the trajectory from thermodynamics to cognition is continuous, physically constrained, and potentially inevitable. Life does not violate physical laws—it fulfills them in regimes of high informational complexity, instantiating fundamental principles in self-organized architectures capable of prediction, memory, and purpose. The objective of this work is to articulate how the synthesis of these principles not only unifies physics and biology, but also illuminates the profound continuity between thermodynamics, chemistry, informational constraints, organization, and the mind.

Adult neurogenesis is well established in canonical niches—the dentate gyrus and the subventricular zone, where aerobic exercise reliably enhances progenitor proliferation, survival, and synaptic integration via increased cerebral blood flow, neurotrophins (e.g., BDNF, IGF-1), neurotransmitter regulation, and reduced neuroinflammation. Nutraceuticals (e.g., polyphenols, omega-3, creatine, vitamins) further support neuroplasticity and neuronal survival through convergent trophic, anti-inflammatory, and metabolic pathways. By contrast, the hypothalamus, a metabolically pivotal, non-canonical niche, remains comparatively understudied. Here, we synthesize anatomical and functional features of hypothalamic neural stem cells, primarily tanycytes (α1, α2, β1, β2), which line the third ventricle and differentially contribute to neuronal activity regulation, metabolic signaling, and cerebrospinal fluid–portal vasculature coupling, thereby linking neurogenesis to endocrine control. Notably, tanycytes can form neurospheres in vitro, enabling mechanistic interrogation. Although evidence for adult hypothalamic neurogenesis in humans is debated due to methodological constraints, animal data suggest potential relevance to disorders characterized by neuronal loss, metabolic dysregulation, and impaired neuroendocrine function. We propose that an integrative framework is timely: exercise and diet likely interact in the hypothalamic niche through shared mediators (BDNF, IGF-1, CNTF, GPR40) and exercise-derived signals (e.g., lactate, IL-6) that may be complemented by defined nutraceuticals. Yet critical uncertainties persist, including the extent of bona fide hypothalamic neurogenesis, nucleus-specific responses (arcuate nucleus, paraventricular nucleus, ventromedial hypothalamic nucleus), and the mechanistic integration of lifestyle signals in this region. To address these gaps, we outline actionable priorities: (i) single-cell and lineage-tracing studies of tanycyte subtypes under distinct training modalities (aerobic, high-intensity interval training, resistance); (ii) combinatorial interventions pairing structured exercise with nutraceuticals to test synergy on progenitor dynamics and inflammation; and (iii) multi-omics and translational studies to identify biomarkers and establish clinical relevance. Clarifying these interactions will determine whether lifestyle and supplementation strategies can synergistically modulate hypothalamic neurogenesis and inform therapies for neurological, neuropsychiatric, and metabolic disorders.

How does the complex, adaptive, and autonomous organization of life emerge from the laws of physics and information? This review argues that the answer lies in a convergent set of universal organizational principles that constitute a physical and informational grammar of the living. Living sys-tems are dissipative structures that achieve organizational clo-sure—materially and energetically open, yet causally closed—thereby at-taining genuine autonomy and agency. Their architecture exhibits fractal and modular scaling laws that maximize energy flow, robustness, and evolv- ability under universal physical constraints. Critically, organisms operate at critical transitions—zones of controlled instability where fluctuations amplify information processing, transforming noise into adaptive signal. This self-organized criticality enables functional degeneracy, relational redun-dancy, and evolutionary antifragility. Cognition emerges as distributed ac-tive inference—a predictive-corrective cycle that integrates perception, ac-tion, and learning in accordance with the Free Energy Prin- ciple. From molecular networks to ecosystems, the same physico-informational gram- mars unfold recursively, revealing a deep organizational holography: the principles of organization are replicated across scales. Evolution under the Law of Increasing Functional Information is not random drift, but a direc-tional expansion of functional complexity—a thermodynamic gradient to-wards greater agency. This synthesis chal- lenges biological exceptionalism: the trajectory from thermodynamics to cognition is continuous, physically constrained, and potentially inevitable. Life does not violate physical laws—it fulfills them in regimes of high informational complexity, instan- tiating fundamental principles in self-organized architectures capable of prediction, memory, and purpose.

Background: Exercise has shown beneficial effects on neuronal neuroplasticity; therefore, we want to analyze the influence of high-intensity interval training (HIIT) on neuroplasticity markers in post-stroke patients. Methods: A systematic review of RCTs including studies with stroke participants was conducted using the following databases (PubMed, LILACS, ProQuest, PEDro, Web of Science). Searches lasted till (20/11/2023). Studies that used a HIIT protocol as the main treatment or as a coadjutant treatment whose outcomes were neural plasticity markers were used and compared with other exercise protocols, controls or other kinds of treatment. Studies that included other neurological illnesses, comorbidities that interfere with stroke or patients unable to complete a HIIT protocol were excluded. HIIT protocol, methods to assess intensity, neuroplasticity markers (plasmatic and neurophysiological) and other types of assessments such as cognitive scales were extracted to make a narrative synthesis. Jadad and PEDro scales were used to assess bias. Results: Eight articles were included, one included lacunar stroke (less than 3 weeks) and the rest had chronic stroke. The results found here indicate that HIIT facilitates neuronal recovery in response to an ischemic injury. This type of training increases the plasma concentrations of lactate, BDNF and VEGF, which are neurotrophic and growth factors involved in neuroplasticity. HIIT also positively regulates other neurophysiological measurements that are directly associated with a better outcome in motor learning tasks. Conclusions: We conclude that HIIT improves post-stroke recovery by increasing neuroplasticity markers. However, a limited number of studies have been found indicating that future studies are needed that assess this effect and include the analysis of the number of intervals and their duration in order to maximize this effect.

Neurogenesis is the process of forming new neurons from neural stem cells (NSCs). In adults, this process takes place in specific areas of the brain, known as neurogenic niches. These regions have unique anatomical features that have been studied in animal models and in the human brain; however, there are differences between these models that need to be addressed. The most studied areas are the subventricular zone, the lateral and latero-dorsal walls of the lateral ventricles, and the dentate gyrus of the hippocampus (Hp), which are known as the canonical areas. Other, less-studied niches, such as the hypothalamus, the cerebellum, and the amygdala, are known as non-canonical areas. Anatomy occupies a relevant place in adult neurogenesis, in which the tissue architecture and cellular location are necessities for the interaction and release of diverse molecules that allow this phenomenon. The cell arrangement within the niche and the location of the niche itself are of particular relevance to the state in which the NSCs are found. Consequently, the majority of previous discoveries have been related to pathology. While many studies are based on animal models, discoveries related to neurogenesis in humans have also been made; however, in this case, opinions vary, leading to extensive controversy in recent years. In this review, we address the anatomical characteristics of the different brain regions to better understand their relationships within neurogenesis.

Neuropathological aging is associated with memory impairment and cognitive decline, affecting several brain areas including the neurogenic niche of the dentate gyrus of the hippocampus (DG). In the healthy brain, homeostatic mechanisms regulate neurogenesis within the DG to facilitate the continuous generation of neurons from neural stem cells (NSC). Nevertheless, aging reduces the number of activated neural stem cells and diminishes the number of newly generated neurons. Strategies that promote neurogenesis in the DG may improve cognitive performance in the elderly resulting in the development of treatments to prevent the progression of neurological disorders in the aged population. Our work is aimed at discovering targeting molecules to be used in the design of pharmacological agents that prevent the neurological effects of brain aging. We study the effect of age on hippocampal neurogenesis using the SAMP8 mouse as a model of neuropathological aging. We show that in 6‐month‐old SAMP8 mice, episodic and spatial memory are impaired; concomitantly, the generation of neuroblasts and neurons is reduced and the generation of astrocytes is increased in this model. The novelty of our work resides in the fact that treatment of SAMP8 mice with a transforming growth factor‐alpha (TGFα) targeting molecule prevents the observed defects, positively regulating neurogenesis and improving cognitive performance. This compound facilitates the release of TGFα in vitro and in vivo and activates signaling pathways initiated by this growth factor. We conclude that compounds of this kind that stimulate neurogenesis may be useful to counteract the neurological effects of pathological aging.

Harmonic mechanisms orchestrate neurogenesis in the healthy brain within specific neurogenic niches, which generate neurons from neural stem cells as a homeostatic mechanism. These newly generated neurons integrate into existing neuronal circuits to participate in different brain tasks. Despite the mechanisms that protect the mammalian brain, this organ is susceptible to many different types of damage that result in the loss of neuronal tissue and therefore in alterations in the functionality of the affected regions. Nevertheless, the mammalian brain has developed mechanisms to respond to these injuries, potentiating its capacity to generate new neurons from neural stem cells and altering the homeostatic processes that occur in neurogenic niches. These alterations may lead to the generation of new neurons within the damaged brain regions. Notwithstanding, the activation of these repair mechanisms, regeneration of neuronal tissue within brain injuries does not naturally occur. In this review, we discuss how the different neurogenic niches respond to different types of brain injuries, focusing on the capacity of the progenitors generated in these niches to migrate to the injured regions and activate repair mechanisms. We conclude that the search for pharmacological drugs that stimulate the migration of newly generated neurons to brain injuries may result in the development of therapies to repair the damaged brain tissue.

Al impartir por primera vez Anatomía en el grado en Ciencias de la Actividad Física y Deporte, nos enfrentamos al descontento del alumnado, pues consideraban la Anatomía como una asignatura compleja y sin interés para ellos. Por eso, nos planteamos desarrollar un modelo motivacional y diseñamos prácticas específicas donde estudiar un grupo muscular determinado a través de un deporte seleccionado (futbol, baloncesto, golf, tenis o running). Además, implantamos otra serie de dinámicas que aumentaron el interés por la Anatomía, como la gamificación y la utilización de programas de simulación en 3D. Realizamos cuestionarios de conocimientos antes y después de la experiencia y una encuesta de satisfacción final. Tras el análisis de los resultados, observamos la efectividad de nuestra herramienta y demostramos que, gracias a las prácticas específicas, disminuyó el grado de errores en los cuestionarios realizados. Tanto esta modalidad de docencia, como la gamificación, fueron ampliamente aceptadas por el alumnado.

Glioblastoma (GB) is the most prevalent primary brain cancer and the most aggressive form of glioma because of its poor prognosis and high recurrence. To confirm the importance of epigenetics in glioma, we explored The Cancer Gene Atlas (TCGA) database and we found that several histone/DNA modifications and chromatin remodeling factors were affected at transcriptional and genetic levels in GB compared to lower-grade gliomas. We associated these alterations in our own cohort of study with a significant reduction in the bulk levels of acetylated lysines 9 and 14 of histone H3 in high-grade compared to low-grade tumors. Within GB, we performed an RNA-seq analysis between samples exhibiting the lowest and highest levels of acetylated H3 in the cohort; these results are in general concordance with the transcriptional changes obtained after histone deacetylase (HDAC) inhibition of GB-derived cultures that affected relevant genes in glioma biology and treatment (e.g., A2ML1, CD83, SLC17A7, TNFSF18). Overall, we identified a transcriptional signature linked to histone acetylation that was potentially associated with good prognosis, i.e., high overall survival and low rate of somatic mutations in epigenetically related genes in GB. Our study identifies lysine acetylation as a key defective histone modification in adult high-grade glioma, and offers novel insights regarding the use of HDAC inhibitors in therapy.