Recent advances on the molecular mechanisms of exercise-induced improvements of cognitive dysfunction

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Feb. 27, 2023

Abstract Physical exercise is of great significance for maintaining human health. Exercise can provide varying degrees benefits to cognitive function at all stages life cycle. Currently, with the aging world’s population and increase expectancy, dysfunction has gradually become a disease high incidence, which accompanied by neurodegenerative diseases in elderly individuals. Patients often exhibit memory loss, aphasia weakening orientation once diagnosed, are unable have normal life. Cognitive largely affects physical mental health, reduces quality life, causes economic burden society. At present, most interventions aimed maintain current level delay deterioration cognition. In contrast, as nonpharmacological therapy advantages its nontoxicity, low cost universal application. The molecular mechanisms underlying effect on cognition complex, studies been extensively centered neural plasticity, direct target brain. addition, mitochondrial stability energy metabolism essential brain status. Meanwhile, organ-brain axis responds induces release cytokines related this review, we summarize latest evidence effects cognition, point out directions future research.

Language: Английский

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Cellular reprogramming as a tool to model human aging in a dish

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 28, 2024

Abstract The design of human model systems is highly relevant to unveil the underlying mechanisms aging and provide insights on potential interventions extend health life span. In this perspective, we explore 2D or 3D culture models comprising induced pluripotent stem cells transdifferentiated obtained from aged age-related disorder-affected donors enhance our understanding catalyze discovery anti-aging interventions.

Language: Английский

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The ubiquitin-conjugating enzyme UBE2D maintains a youthful proteome and ensures protein quality control during aging by sustaining proteasome activity

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(1), P. e3002998 - e3002998

Published: Jan. 29, 2025

Ubiquitin-conjugating enzymes (E2s) are key for protein turnover and quality control via ubiquitination. Some E2s also physically interact with the proteasome, but it remains undetermined which maintain proteostasis during aging. Here, we find that have diverse roles in handling a model aggregation-prone (huntingtin-polyQ) Drosophila retina: while some mediate aggregate assembly, UBE2D/effete (eff) other required huntingtin-polyQ degradation. UBE2D/eff is skeletal muscle: eff levels decline aging, muscle-specific knockdown causes an accelerated buildup insoluble poly-ubiquitinated proteins (which progressively accumulate aging) shortens lifespan. Mechanistically, necessary to optimal proteasome function: reduces proteolytic activity of this rescued by transgenic expression human UBE2D2, homolog. Likewise, UBE2D2 partially rescues lifespan deficits caused RNAi re-establishes physiological -regulated proteins. Interestingly, young age reproduces part proteomic changes normally occur old muscles, suggesting decrease occurs aging contributes reshaping composition muscle proteome. However, concertedly up-regulated regulators (e.g., chaperones Pomp) transcriptionally induced presumably as adaptive stress response loss proteostasis. Altogether, these findings indicate E2 ubiquitin-conjugating enzyme ensures helps youthful proteome

Language: Английский

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Muscle-to-Brain Signaling Via Myokines and Myometabolites

Brain Plasticity, Journal Year: 2022, Volume and Issue: 8(1), P. 43 - 63

Published: Jan. 7, 2022

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

Language: Английский

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The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(15), P. 8283 - 8283

Published: July 27, 2022

The vascular endothelium has several important functions, including hemostasis. homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins fibrinolytic antifibrinolytic ones. Coagulopathies are characterized by mutation-induced alteration the function certain coagulation factors or disturbed mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement nonreplacement treatments administration agents. Rebalancing products reestablish inhibiting natural pathways. These agents include monoclonal antibodies, such as concizumab marstacimab, which target tissue factor pathway inhibitor; interfering RNA therapies, fitusiran, targets antithrombin III; protease inhibitors, serpinPC, active protein C. In cases thrombophilia (deficiency C, S, V Leiden), treatment may direct oral anticoagulants, therapy (plasma recombinant ADAMTS13) congenital deficiency ADAMTS13, immunomodulators (prednisone) if autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) used context severe thrombophilia, regardless cause disorder. disseminated intravascular coagulation, choice consists antifibrinolytics, all-trans-retinoic acid, soluble human thrombomodulin.

Language: Английский

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Contribution of proteases to the hallmarks of aging and to age‐related neurodegeneration

Aging Cell, Journal Year: 2022, Volume and Issue: 21(5)

Published: March 29, 2022

Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement proteostasis is a primary cause aging age-associated diseases. The ubiquitin-proteasome autophagy-lysosome play key roles in but, addition to these systems, human genome encodes for ~600 proteases, also known as peptidases. Here, we examine role proteases age-related neurodegeneration. Proteases are present across cell compartments, including extracellular space, their substrates encompass cellular constituents, proteins with signaling functions, Proteolytic processing by can lead changes activity localization or degradation. cooperate systems but have independent proteolytic that impact all hallmarks aging. Specifically, regulate mitochondrial function, DNA damage repair, senescence, nutrient sensing, stem properties regeneration, protein stress responses, intercellular signaling. capacity functions translates into important preserving tissue homeostasis during Consequently, influence onset progression pathologies determinants health span. how certain promote Alzheimer's, Huntington's, and/or Parkinson's disease whereas other protect from Mechanistically, cleavage pathogenic hence impede pathogenesis. Alternatively, generate substrate byproducts increased toxicity, which progression. Altogether, studies indicate importance

Language: Английский

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The proteasome: A key modulator of nervous system function, brain aging, and neurodegenerative disease

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: April 13, 2023

The proteasome is a large multi-subunit protease responsible for the degradation and removal of oxidized, misfolded, polyubiquitinated proteins. plays critical roles in nervous system processes. This includes maintenance cellular homeostasis neurons. It also long-term potentiation via modulation CREB signaling. possesses promoting dendritic spine growth driven by localization to spines an NMDA/CaMKIIα dependent manner. Proteasome inhibition experiments varied organisms has been shown impact memory, consolidation, recollection extinction. further circadian rhythm through range ‘clock’ genes, glial function. function impaired as consequence both aging neurodegenerative diseases. Many studies have demonstrated impairment 26S brain other tissues age, disassembly favor 20S proteasome. Some show augmentation correct age-related deficits. In amyotrophic lateral sclerosis Alzheimer’s, Parkinson’s Huntington’s disease distinct mechanisms with impacts on susceptibility progression. Age neurodegenerative-related deficits constitutive are often accompanied increase alternative form called immunoproteasome. article discusses role system. We then describe how dysfunction contributes disease.

Language: Английский

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An adaptive stress response that confers cellular resilience to decreased ubiquitination

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 14, 2023

Abstract Ubiquitination is a post-translational modification initiated by the E1 enzyme UBA1, which transfers ubiquitin to ~35 E2 ubiquitin-conjugating enzymes. While UBA1 loss cell lethal, it remains unknown how partial reduction in activity endured. Here, we utilize deep-coverage mass spectrometry define E1-E2 interactome and determine proteins that are modulated knockdown of each human cells. These analyses UBA1/E2-sensitive proteome specificity protein modulation. Interestingly, profound adaptations peroxisomes other organelles triggered decreased ubiquitination. cargo receptor PEX5 depends on its mono-ubiquitination for binding peroxisomal importing them into peroxisomes, find UBA1/E2 induces compensatory upregulation PEX necessary docking membrane. Altogether, this study defines homeostatic mechanism sustains import cells with ubiquitination capacity.

Language: Английский

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Preconditioning Exercise Inhibits Neuron Ferroptosis and Ameliorates Brain Ischemia Damage by Skeletal Muscle–Derived Exosomes via Regulating miR-484/ACSL4 Axis

Antioxidants and Redox Signaling, Journal Year: 2024, Volume and Issue: unknown

Published: March 28, 2024

Although there is evidence that patients with stroke who exercise regularly before have a better prognosis than those do not exercise, the detailed mechanism remains unclear. Moreover, neuronal death plays central role in neurological dysfunction caused by ischemic stroke. Thus, we investigated whether could reduce stroke-induced and its associated mediators current study.

Language: Английский

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Stress responses induced by perturbation of the ubiquitin–proteasome system

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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