Hallmarks of ageing in human skeletal muscle and implications for understanding the pathophysiology of sarcopenia in women and men

Clinical Science, Journal Year: 2023, Volume and Issue: 137(22), P. 1721 - 1751

Published: Nov. 1, 2023

Abstract Ageing is a complex biological process associated with increased morbidity and mortality. Nine classic, interdependent hallmarks of ageing have been proposed involving genetic biochemical pathways that collectively influence trajectories susceptibility to pathology in humans. skeletal muscle undergoes profound morphological physiological changes loss strength, mass, function, condition known as sarcopenia. The aetiology sarcopenia whilst research this area growing rapidly, there relative paucity human studies, particularly older women. Here, we evaluate how the nine classic ageing: genomic instability, telomere attrition, epigenetic alterations, proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication contribute pathophysiology We also highlight five novel particular significance inflammation, neural extracellular matrix reduced vascular perfusion, ionic dyshomeostasis, discuss are interconnected. Their clinical relevance translational potential considered.

Language: Английский

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Ageing reduces persistent inward current contribution to motor neurone firing: Potential mechanisms and the role of exercise

The Journal of Physiology, Journal Year: 2023, Volume and Issue: 601(17), P. 3705 - 3716

Published: July 24, 2023

Abstract Nervous system deterioration is a primary driver of age‐related motor impairment. The neurones, which act as the interface between central nervous and muscles, play crucial role in amplifying excitatory synaptic input to produce desired neuronal firing output. For this, they utilise their ability generate persistent (long‐lasting) depolarising currents that increase cell excitability, both amplify prolong output activity neurones for given input. Modulation these inward (PICs) contributes neurones’ capacities attain required frequencies rapidly modulate them competently complete most tasks. Thus, PICs are adequate movement generation. Impairments intrinsic neurone properties can impact unit capacity, with convincing evidence indicating PIC contribution reduced older adults. Indeed, this could be an important mechanism underpinning reductions strength physical function. Furthermore, resistance training has emerged promising intervention counteract age‐associated impairments, changes being correlated improvements muscular function after training. In review, we present current knowledge magnitude decline during ageing discuss whether serotonergic noradrenergic onto voltage‐gated calcium channel dysfunction or inhibitory impairments candidates that: (i) explain (ii) underpin enhanced following image

Language: Английский

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Alterations in neuromuscular junction morphology with ageing and endurance training modulate neuromuscular transmission and myofibre composition

The Journal of Physiology, Journal Year: 2024, Volume and Issue: 603(1), P. 107 - 125

Published: Jan. 3, 2024

Abstract Both ageing and exercise training affect the neuromuscular junction (NMJ) structure. Morphological alterations in NMJ have been considered to influence transmission myofibre properties, but direct link between morphology function has yet be established. We measured transmission, composition structure of 5‐month‐old (young) 24‐month‐old untrained (aged control) trained trained) mice. Aged mice were subjected 2 months endurance before measurement. Neuromuscular was evaluated vivo as ratio ankle plantar flexion torque evoked by sciatic nerve stimulation that muscle stimulation. The significantly lower aged than young at high‐frequency stimulations, showing a significant positive correlation with voluntary grip strength. degree pre‐ post‐synaptic overlap also positively correlated ratio. found proportion fast‐twitch fibres soleus decreased age, age‐related denervation occurred preferentially fibres. Age‐related shift partially prevented training. These results suggest deterioration impairs alters composition, these can structural amelioration Our findings highlight importance major determinant skeletal muscles clinical significance countermeasure. image Key points plays an essential role maintenance properties. show is impaired recovered training, which contributes associated NMJ. toward slower phenotype are study provides substantial evidence exercise‐induced properties morphological changes

Language: Английский

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How do neurons age? A focused review on the aging of the microtubular cytoskeleton

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(9), P. 1899 - 1907

Published: Dec. 14, 2023

Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in neuronal cytoskeleton, mainly underpinned by protein modifications to destabilization of microtubules, central pathogenesis disease. This accompanied morphological defects across somatodendritic compartment, axon, synapse. However, knowledge what occurs microtubule cytoskeleton morphology neuron during physiological aging comparatively poor. Several recent studies have suggested there an age-related increase phosphorylation key stabilizing tau, modification, which known destabilize indicates potentially structures reliant on become functionally compromised normal aging. The current literature shows reductions synaptic spine density shifts conformation might explain functional deficits. microtubular actin with increasing age extremely limited. When considering regression dendrites loss dendritic length volume reported whilst reduction soma volume/size often seen. research into cytoskeletal change limited handful demonstrating mislocalizations microtubule-associated proteins just one study directly exploring integrity microtubules. In axonal diameter appearance swellings but like dendrites, investigates microtubules others reporting or mislocalization proteins. Though these are general trends reported, clear disparities between model organisms brain regions worthy further investigation. Additionally, longitudinal neuronal/cytoskeletal should also investigate whether changes contribute not vulnerability decline nervous system function behavioral output all experience. will highlight utility, if any, fortification promotion healthy potential protection against review seeks summarize currently about hope uncovering mechanisms underpinning

Language: Английский

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News from the old: aging features in the intracardiac, musculoskeletal, and enteric nervous systems

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102690 - 102690

Published: Feb. 1, 2025

Aging strongly affects the peripheral nervous system (PNS), triggering alterations that vary depending on innervated tissue. The most frequent alteration in nerve aging is reduced fiber and glial density which can lead to abnormal functionality. Interestingly, activation of a destructive phenotype takes place macrophages across PNS while number neuronal bodies unique feature some enteric ganglia. Single cell/nucleus RNA-sequencing has unveiled striking complexity cell populations nerves, these refined type annotations could facilitate better understanding aging. While effects senescence individual types requires further characterization, use senolytics appears improve general function models Here, we review current age-related changes intracardiac, musculoskeletal, sub-sections PNS, highlighting their commonalities differences.

Language: Английский

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Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes

Biogerontology, Journal Year: 2023, Volume and Issue: 25(2), P. 341 - 360

Published: Nov. 21, 2023

Abstract Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays crucial role in maintaining the length telomeres, which are specialised protective caps at end chromosomes. The lack vitro aging models, particularly for central nervous system (CNS), has impeded progress understanding and age-associated neurodegenerative diseases. In this study, we aimed to explore possibility inducing aging-associated features cell types CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, utilised CRISPR/Cas9 generate hiPSCs with loss telomerase function shortened telomeres. Through directed differentiation, generated motor neurons astrocytes investigate whether telomere could lead phenotypes. Our findings revealed that telomeres characteristics both including increased senescence, heightened inflammation, elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted fundamental TERT neural progenitor (NPC) proliferation neuronal differentiation. This serves as proof concept can effectively induce phenotypes, thereby providing valuable tool decline Graphical abstract

Language: Английский

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Muscle fibroblasts and stem cells stimulate motor neurons in an age and exercise‐dependent manner

Aging Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Abstract Exercise preserves neuromuscular function in aging through unknown mechanisms. Skeletal muscle fibroblasts (FIB) and stem cells (MuSC) are abundant skeletal reside close to junctions, but their relative roles motor neuron maintenance remain undescribed. Using direct cocultures of embryonic rat neurons with either human MuSC or FIB, RNA sequencing revealed profound differential regulation the transcriptome, FIB generally favoring growth cell migration production ribosomes translational machinery. Conditioned medium from was superior preserving increasing maturity. Lastly, we established importance donor age exercise status found an age‐related distortion interaction that fully mitigated by lifelong physical activity. In conclusion, show synergistically stimulate viability neurons, which is further amplified regular exercise.

Language: Английский

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Muscle Fibroblasts and Stem Cells Stimulate Motor Neurons in An Age and Exercise-Dependent Manner

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Exercise preserves neuromuscular function in ageing through unknown mechanisms. Skeletal muscle fibroblasts (FIB) and stem cells (MuSC) are abundant skeletal reside close to junctions, but their relative roles motor neuron maintenance remain undescribed. Using direct co-cultures of embryonic rat neurons with either human MuSC or FIB, RNA sequencing revealed profound differential regulation the transcriptome, FIB generally favoring growth cell migration production ribosomes translational machinery. Conditioned medium from was superior preserving increasing maturity. Lastly, we established importance donor age exercise status found an age-related distortion interaction that fully mitigated by lifelong physical activity. In conclusion, show synergistically stimulate viability neurons, which is further amplified regular exercise.

Language: Английский

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Age-related increase in the excitability of mouse layer V pyramidal neurons in the primary motor cortex is accompanied by an increased persistent inward current

GeroScience, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 30, 2024

Language: Английский

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Aging spinal cord microglia become phenotypically heterogeneous and preferentially target motor neurons and their synapses

Glia, Journal Year: 2023, Volume and Issue: 72(1), P. 206 - 221

Published: Sept. 22, 2023

Microglia have been found to acquire unique region-dependent deleterious features with age and diseases that contribute neuronal dysfunction degeneration in the brain. However, it remains unknown whether microglia exhibit similar phenotypic heterogeneity spinal cord. Here, we performed a regional analysis of cord 3-, 16-, 23-, 30-month-old mice. Using light electron microscopy, discovered an increasingly activated phenotype during course aging regardless location. causes ventral but not dorsal horn lose their spatial organization. Aged also aggregate around somata motor neurons increase contacts synapses, which shown be lost age. These findings suggest may affect ability receive relay commands aging. To generate additional insights about microglia, RNA-sequencing on FACS-isolated from 18-, 22-, 29-month-old We transcriptional identity as those brain includes altered expression genes roles microglia-neuron interactions inflammation. By 29 months age, changes known predicted cause senescence alter lysosomal ribosomal regulation. Altogether, this work provides foundation target ameliorate aged-related cord, particularly circuit.

Language: Английский

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