דו״ח מאומת

Epidemiological studies indicate a consistent global increase, including in the Russian Federation, in the number of patients with cognitive impairments associated with neurodegenerative diseases and various affective disorders. In this context there is a clear need in the development of more effective therapeutic approaches for their corrections. Good evidence exists that regular physical activity improves cognitive functions and alleviates depression. Working muscles secrete biologically active substances known as myokines, which regulate muscle recovery and functions of internal organs, endocrine glands, the immune system, and the brain. This results in a coordinated response of organs and systems aimed at restoring functional activity of the body after physical exercises and improves memory and learning ability. Patients with cognitive impairments or depression are often unable to engage in regular physical activity due to physical limitations or decreased motivation. Therefore, pharmaceuticals that mimic the effects of muscle activity are a promising therapeutic option. One potential direction in this field could be the development of drugs based on the myokine irisin, which is produced during physical exercise and exerts a range of beneficial effects on cognitive function and mood. This review summarizes existing data on the effects of physical exercise on cognitive function in health and disease; it describes the physiological effects of irisin, and presents the proposed mechanisms of irisin action on cognitive function and symptoms of depression.…

PMID: 41556070

Physical exercise is a potent non-pharmacological strategy for the prevention and management of chronic non-communicable diseases (NCDs), including type 2 diabetes, cardiovascular diseases, obesity, and certain cancers. Growing evidence demonstrates that the benefits of exercise extend beyond its physiological effects and are largely mediated by coordinated molecular and cellular adaptations. This review synthesizes current knowledge on the key mechanisms through which exercise modulates metabolic health, emphasizing intracellular signaling pathways, epigenetic regulation, and myokine-driven inter-organ communication. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, mTOR, MAPKs, and NF-κB, leading to enhanced mitochondrial biogenesis, improved oxidative capacity, refined energy sensing, and reduced inflammation. Additionally, repeated muscle contraction stimulates the release of myokines-including IL-6, irisin, BDNF, FGF21, apelin, and others-that act through endocrine and paracrine routes to regulate glucose and lipid metabolism, insulin secretion, adipose tissue remodeling, neuroplasticity, and systemic inflammatory tone. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term metabolic reprogramming. Collectively, these molecular adaptations establish exercise as a systemic biological stimulus capable of restoring metabolic homeostasis and counteracting the pathophysiological processes underlying NCDs. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in preventive and therapeutic medicine.…

PMID: 41465520

The global challenge of population aging underscores the critical need to delay brain aging and cognitive decline, a pressing public health issue. The brain-gut-muscle axis is a complex regulatory network connecting skeletal muscle, gut microbiota, and the brain. It has received considerable research attention for its crucial role in maintaining brain health and counteracting aging. As a safe and effective non-pharmacological intervention, exercise modulates gut microbiota composition and diversity and promotes the secretion of myokines from skeletal muscle. These actions, in turn, influence neural plasticity, inflammatory responses, and cognitive function. This review summarizes the mechanisms mediated by exercise within the brain-gut-muscle axis. We focus on: (1) how exercise dynamically regulates gut microbiota; (2) the interplay between myokines and gut microbiota; (3) the neuroprotective role of myokines; and (4) the potential mechanisms of the brain-muscle and gut-muscle pathways. Finally, we integrate these findings to present a synthesized view of how exercise delays brain aging through the brain-gut-muscle axis.…

PMID: 41858789

<h4>Background</h4>Physical exercise is widely recognized for promoting cognitive function and psychological resilience; however, the precise systemic mechanisms remain fragmented across isolated disciplines. Existing models often fail to capture the complex, multi-systemic nature of these adaptations.<h4>Methods</h4>We conducted a comprehensive literature search in PubMed, Web of Science, and Scopus databases up to December 2025. Keywords included "exercise," "neuroinflammation," "metabolism," "kynurenine pathway," and "gut-brain axis." We prioritized high-quality preclinical and clinical studies that examined bidirectional cross-talk between at least two physiological systems (neural, immune, or metabolic) to construct a unified theoretical synthesis.<h4>Results</h4>Based on this synthesis, we propose the "Neuro-Immuno-Metabolic (NIM) Axis." Unlike linear bipartite models, this framework positions exercise as a systemic "energy challenge" that triggers a coordinated recalibration. Key mechanisms identified include: (1) Metabolic Signaling: Lactate, ketone bodies, and the PGC-1α-mediated kynurenine detoxification pathway act as systemic signalers; (2) Immune Regulation: Exercise drives a shift from pro-inflammatory surveillance to "repair-oriented inflammation" rather than binary M1/M2 phenotypes; and (3) Gut-Brain Integration: Gut metabolites (e.g., indoles, SCFAs) regulate central immune tolerance via AhR signaling. Furthermore, we delineate the mechanistic specificity of aerobic, resistance, and high-intensity interval training (HIIT).<h4>Conclusion</h4>The NIM axis provides a novel, integrative framework that explains how metabolic stress is transduced into psychological resilience. These insights establish a theoretical foundation for precision exercise medicine and advocate for future multi-omics research to develop individualized interventions.…

PMID: 41878041

Major depressive disorder is increasingly recognized as a metabolic-immune disorder in which chronic inflammation diverts tryptophan (Trp) metabolism toward the kynurenine pathway (KP), reducing serotonin synthesis and producing neurotoxic metabolites such as quinolinic acid (QA). Elevated kynurenine (KYN)/Trp ratios and an altered QA/kynurenic acid (KYNA) balance have been consistently reported in depressed individuals, implicating the KP as a key therapeutic target. Exercise provides a unique, translationally relevant intervention: unlike pharmacological agents acting directly on neurotransmission, contracting skeletal muscle acts as a "kynurenine sink" by inducing kynurenine aminotransferases that convert circulating KYN into neuroprotective KYNA, thereby reducing brain KYN uptake and mitigating excitotoxicity. Clinical studies and meta-analyses confirm that aerobic, resistance, and high-intensity training produce antidepressant effects comparable to pharmacotherapy, while also improving cognition, fatigue tolerance, and cardiometabolic function. Beyond KP remodeling, exercise-induced myokines (irisin, IL-6, BDNF, apelin, FGF21) and adipokines (adiponectin, leptin modulators) coordinate systemic anti-inflammatory and neurotrophic adaptations that enhance resilience and brain plasticity. Furthermore, pharmacological "exercise mimetics" and metabolic modulators, such as PPAR agonists, AMPK activators, NAD⁺ boosters, meldonium, trimetazidine, and adiponectin receptor agonists, may be promising adjuncts for patients with low exercise capacity or metabolic comorbidities. This review provides a novel concept, positioning exercise as a systemic antidepressant that breaks the kynurenine lock of depression. Through proper interpretation of skeletal muscle as an endocrine organ of resilience, we integrate molecular, clinical, and translational findings to show how exercise remodels Trp-KYN metabolism and inflammatory signaling and how pharmacological mimetics may extend these benefits. This perspective consolidates scattered mechanistic and clinical data and outlines a forward-looking therapeutic framework that links exercise and lifestyle, metabolism, and drug discovery. We highlight that re-consideration of our understanding of depression, as a whole-body disorder, should provide new opportunities for precision interventions.…

PMID: 41516008

In the past, the role of physical activity as a life-style modulating factor has been considered as that of a tool to balance energy intake. Although it is important to avoid obesity, physical inactivity should be discussed in a much broader context. There is accumulating epidemiological evidence that a physically active life plays an independent role in the protection against type 2 diabetes, cardiovascular diseases, cancer, dementia and even depression. For most of the last century, researchers sought a link between muscle contraction and humoral changes in the form of an 'exercise factor', which could be released from skeletal muscle during contraction and mediate some of the exercise-induced metabolic changes in other organs such as the liver and the adipose tissue. We have suggested that cytokines or other peptides that are produced, expressed and released by muscle fibres and exert autocrine, paracrine or endocrine effects should be classified as 'myokines'. Given that skeletal muscle is the largest organ in the human body, our discovery that contracting skeletal muscle secretes proteins sets a novel paradigm: skeletal muscle is an endocrine organ producing and releasing myokines, which work in a hormone-like fashion, exerting specific endocrine effects on other organs. Other myokines work via paracrine mechanisms, exerting local effects on signalling pathways involved in muscle metabolism. It has been suggested that myokines may contribute to exercise-induced protection against several chronic diseases.…

PMID: 21177953

Skeletal muscle health and function are important determinants of systemic metabolic homeostasis and organism-wide responses, including disease outcome. While it is well known that exercise protects the central nervous system (CNS) from aging and disease, only recently this has been found to depend on the endocrine capacity of skeletal muscle. Here, we review muscle-secreted growth factors and cytokines (myokines), metabolites (myometabolites), and other unconventional signals (e.g. bioactive lipid species, enzymes, and exosomes) that mediate muscle-brain and muscle-retina communication and neuroprotection in response to exercise and associated processes, such as the muscle unfolded protein response and metabolic stress. In addition to impacting proteostasis, neurogenesis, and cognitive functions, muscle-brain signaling influences complex brain-dependent behaviors, such as depression, sleeping patterns, and biosynthesis of neurotransmitters. Moreover, myokine signaling adapts feeding behavior to meet the energy demands of skeletal muscle. Contrary to protective myokines induced by exercise and associated signaling pathways, inactivity and muscle wasting may derange myokine expression and secretion and in turn compromise CNS function. We propose that tailoring muscle-to-CNS signaling by modulating myokines and myometabolites may combat age-related neurodegeneration and brain diseases that are influenced by systemic signals.…

PMID: 36448045

Accumulating evidence exists that regular exercise offers protection against chronic disorders such as cardiovascular diseases, type 2 diabetes, dementia, and depression. Although acute and chronic exercise has numerous consequences, it is still discussed how contracting skeletal muscles mediate metabolic and physiological effects of benefits on health. For years the search for the stimulus that initiates and maintains the change of excitability or sensibility of the regulating centers in exercise has been progressing. For lack of more precise knowledge, it has been called the 'work stimulus,' 'the work factor' or 'the exercise factor.' In other terms, the big challenge for muscle and exercise physiologists has been to determine how muscles signal to central and peripheral organs. Recently, we identified that muscle fibers produce and release the cytokine IL-6 into the circulation during exercise. We further proposed that IL-6 and other cytokines, which are produced and released by skeletal muscles, exerting their effects in other organs of the body, should be named 'myokines.' In line with that adipokines have been suggested as a term, which is restricted to cover cytokines and other peptides which are produced and secreted by adipocytes, we suggest that the term "myokines" should be used exclusively to describe cytokines or other peptides, which are produced and released by muscle fibers per se. Myokines may represent the link from working muscle to other organs such as the adipose tissue, the liver, and the vascular compartments. Here, we review the literature on muscle- and brain-derived IL-6. We further suggest that myokines may also provide an explanation as to how regular muscle activity influences mood, performance, and cognitive function.…

PMID: 15935612

Major depressive disorder is increasingly recognized as a metabolic-immune disorder in which chronic inflammation diverts tryptophan (Trp) metabolism toward the kynurenine pathway (KP), reducing serotonin synthesis and producing neurotoxic metabolites such as quinolinic acid (QA). Elevated kynurenine (KYN)/Trp ratios and an altered QA/kynurenic acid (KYNA) balance have been consistently reported in depressed individuals, implicating the KP as a key therapeutic target. Exercise provides a unique, translationally relevant intervention: unlike pharmacological agents acting directly on neurotransmission, contracting skeletal muscle acts as a "kynurenine sink" by inducing kynurenine aminotransferases that convert circulating KYN into neuroprotective KYNA, thereby reducing brain KYN uptake and mitigating excitotoxicity. Clinical studies and meta-analyses confirm that aerobic, resistance, and high-intensity training produce antidepressant effects comparable to pharmacotherapy, while also improving cognition, fatigue tolerance, and cardiometabolic function. Beyond KP remodeling, exercise-induced myokines (irisin, IL-6, BDNF, apelin, FGF21) and adipokines (adiponectin, leptin modulators) coordinate systemic anti-inflammatory and neurotrophic adaptations that enhance resilience and brain plasticity. Furthermore, pharmacological "exercise mimetics" and metabolic modulators, such as PPAR agonists, AMPK activators, NAD⁺ boosters, meldonium, trimetazidine, and adiponectin receptor agonists, may be promising adjuncts for patients with low exercise capacity or metabolic comorbidities. This review provides a novel concept, positioning exercise as a systemic antidepressant that breaks the kynurenine lock of depression. Through proper interpretation of skeletal muscle as an endocrine organ of resilience, we integrate molecular, clinical, and translational findings to show how exercise remodels Trp-KYN metabolism and inflammatory signaling and how pharmacological mimetics may extend these benefits. This perspective consolidates scattered mechanistic and clinical data and outlines a forward-looking therapeutic framework that links exercise and lifestyle, metabolism, and drug discovery. We highlight that re-consideration of our understanding of depression, as a whole-body disorder, should provide new opportunities for precision interventions.…

PMID: 41516008

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.…

PMID: 21282661

Neurological and mental illnesses account for a considerable proportion of the global burden of disease. Exercise has many beneficial effects on brain health, contributing to decreased risks of dementia, depression and stress, and it has a role in restoring and maintaining cognitive function and metabolic control. The fact that exercise is sensed by the brain suggests that muscle-induced peripheral factors enable direct crosstalk between muscle and brain function. Muscle secretes myokines that contribute to the regulation of hippocampal function. Evidence is accumulating that the myokine cathepsin B passes through the blood-brain barrier to enhance brain-derived neurotrophic factor production and hence neurogenesis, memory and learning. Exercise increases neuronal gene expression of FNDC5 (which encodes the PGC1α-dependent myokine FNDC5), which can likewise contribute to increased brain-derived neurotrophic factor levels. Serum levels of the prototype myokine, IL-6, increase with exercise and might contribute to the suppression of central mechanisms of feeding. Exercise also increases the PGC1α-dependent muscular expression of kynurenine aminotransferase enzymes, which induces a beneficial shift in the balance between the neurotoxic kynurenine and the neuroprotective kynurenic acid, thereby reducing depression-like symptoms. Myokine signalling, other muscular factors and exercise-induced hepatokines and adipokines are implicated in mediating the exercise-induced beneficial impact on neurogenesis, cognitive function, appetite and metabolism, thus supporting the existence of a muscle-brain endocrine loop.…

PMID: 30837717

Of wide interest for health is the relation existing between depression, a very common psychological illness, accompanied by anxiety and reduced ability to concentrate, and adult neurogenesis. We will focus on two neurogenic stimuli, fluoxetine and physical exercise, both endowed with the ability to activate adult neurogenesis in the dentate gyrus of the hippocampus, known to be required for learning and memory, and both able to counteract depression. Fluoxetine belongs to the class of selective serotonin reuptake inhibitor (SSRI) antidepressants, which represent the most used pharmacological therapy; physical exercise has also been shown to effectively counteract depression symptoms in rodents as well as in humans. While there is evidence that the antidepressant effect of fluoxetine requires its pro-neurogenic action, exerted by promoting proliferation, differentiation and survival of progenitor cells of the hippocampus, on the other hand fluoxetine exerts also neurogenesis-independent antidepressant effects by influencing the plasticity of the new neurons generated. Similarly, the antidepressant action of running also correlates with an increase of hippocampal neurogenesis and plasticity, although the gene pathways involved are only partially coincident with those of fluoxetine, such as those involved in serotonin metabolism and synapse formation. We further discuss how extra-neurogenic actions are also suggested by the fact that, unlike running, fluoxetine is unable to stimulate neurogenesis during aging, but still displays antidepressant effects. Moreover, in specific conditions, fluoxetine or running activate not only progenitor but also stem cells, which normally are not stimulated; this fact reveals how stem cells have a long-term, hidden ability to self-renew and, more generally, that neurogenesis is subject to complex controls that may play a role in depression, such as the type of neurogenic stimulus or the state of the local niche. Finally, we discuss how fluoxetine or running are effective in counteracting depression originated from stress or neurodegenerative diseases.…

PMID: 30236533

Aging and neurodegenerative disorders are distinguished by dysfunction within the hippocampus, resulting in compromised spatial memory and cognitive deterioration. The modulation of neurogenesis and neuroinflammation has surfaced as a promising strategy to restore hippocampal functionality and enhance cognitive capabilities. Natural substances, encompassing polyphenols, flavonoids, and various bioactive compounds, display neuroprotective, antioxidant, and anti-inflammatory effects, whereas physical exercise promotes neurogenesis, synaptic plasticity, and anti-inflammatory pathways. Recent findings indicate that the integration of dietary modifications alongside regular physical activity yields synergistic advantages for preserving cerebral health and alleviating cognitive decline. This review consolidates existing knowledge regarding the molecular mechanisms by which natural substances and physical activity impact hippocampal neurogenesis and neuroinflammation. It emphasizes critical pathways, including the regulation of neurotrophic factors, reduction of oxidative stress, and modulation of inflammatory cytokines, which collectively underpin cognitive functionality. Through the amalgamation of nutritional and lifestyle interventions, this methodology presents prospective preventive and therapeutic advantages for geriatric demographics and individuals afflicted with neurodegenerative conditions. Comprehending the intricate relationship between dietary habits and physical activity in relation to cerebral health may facilitate the formulation of accessible, non-pharmacological strategies aimed at augmenting hippocampal functionality, safeguarding memory retention, and enhancing overall cognitive efficacy.…

PMID: 41809492