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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Effects of Exercise Intervention for the Management of Delirium in Hospitalized Older Adults: A Randomized Clinical Trial

Journal of the American Medical Directors Association, Journal Year: 2024, Volume and Issue: 25(8), P. 104980 - 104980

Published: April 7, 2024

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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Peripheral Regulation of Central Brain-Derived Neurotrophic Factor Expression through the Vagus Nerve

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3543 - 3543

Published: Feb. 10, 2023

The brain-derived neurotrophic factor (BDNF) is an extensively studied neurotrophin es sential for both developing the brain and maintaining adult function. In hippocampus, BDNF critical neurogenesis. Adult hippocampal neurogenesis involved not only in memory formation learning ability, but also mood regulation stress responses. Accordingly, decreased levels of BDNF, accompanied by low neurogenesis, occurs brains older adults with impaired cognitive function those patients major depression disorder. Therefore, elucidating mechanisms that maintain biologically clinically important. It has been revealed signalling from peripheral tissues contribute to expression across blood-brain barrier. Moreover, recent studies indicated evidence neuronal pathways can be a mechanism which signal expression. this review, we give overview current status central signalling, special interest signals via vagus nerve. Finally, discuss relationship between age-associated control

Language: Английский

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Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 111970 - 111970

Published: Jan. 1, 2023

Protein quality control is important for healthy aging and dysregulated in age-related diseases. The autophagy-lysosome ubiquitin-proteasome are key proteostasis, but it remains largely unknown whether other proteolytic systems also contribute to maintain proteostasis during aging. Here, we find that expression of enzymes (proteases/peptidases) distinct from the declines skeletal muscle Drosophila. Age-dependent protease downregulation undermines as demonstrated by increase detergent-insoluble poly-ubiquitinated proteins pathogenic huntingtin-polyQ levels response knockdown. Computational analyses identify transcription factor Ptx1 (homologous human PITX1/2/3) a regulator expression. Consistent with this model, protein aging, RNAi counteracts age-associated Moreover, improves protease-dependent manner extends lifespan. These findings indicate proteases their transcriptional modulator ensure

Language: Английский

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Peripheral to brain and hippocampus crosstalk induced by exercise mediates cognitive and structural hippocampal adaptations

Life Sciences, Journal Year: 2024, Volume and Issue: 352, P. 122799 - 122799

Published: June 7, 2024

Language: Английский

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Exercise-driven cellular autophagy: A bridge to systematic wellness

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Exercise enhances health by supporting homeostasis, bolstering defenses, and aiding disease recovery. It activates autophagy, a conserved cellular process essential for maintaining balance, while dysregulated autophagy contributes to progression. Despite extensive research on exercise independently, their interplay remains insufficiently understood. This review explores the molecular mechanisms of exercise-induced in various tissues, focusing key transduction pathways. examines how different types trigger specific autophagic responses, balance addressing systemic dysfunctions. The also highlights signaling pathways involved, roles protecting organ function, reducing risk, promoting longevity, offering clear understanding link between autophagy. Exercise-induced is governed highly coordinated dynamic integrating direct indirect mechanical forces biochemical signals, linking physical activity across multiple systems. Its activation influenced modality, intensity, duration, individual biological characteristics, including age, sex, muscle fiber composition. Aerobic exercises primarily engage AMPK mTOR pathways, mitochondrial quality homeostasis. Anaerobic training PI3K/Akt signaling, modulating molecules like FOXO3a Beclin1 drive repair. In pathological contexts, proteostasis, tissue regeneration, benefiting conditions sarcopenia, neurodegeneration, myocardial ischemia, metabolic disorders, cancer. However, excessive may lead overactivation, leading atrophy or cardiac remodeling. underscores critical need balanced regimens maximize therapeutic efficacy minimizing risks. Future should prioritize identifying reliable biomarkers, optimizing protocols, with pharmacological strategies enhance outcomes.

Language: Английский

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Myokines and the Brain: A Novel Neuromuscular Endocrine Loop

Journal of Neuropsychiatry, Journal Year: 2025, Volume and Issue: 37(1), P. A4 - 4

Published: Jan. 1, 2025

Language: Английский

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Metabolomic insight into the link of intermuscular fat with cognitive performance: the Health ABC Study

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract There is growing evidence that higher intermuscular fat (IMF) associated with worse processing speed, measured by the digit symbol substitution test (DSST) in older adults. However, underlying biological mechanisms are not well understood. Considering both muscle and brain metabolically active organs, we sought to identify metabolites may explain IMF-DSST association. We assessed 613 plasma 2388 participants from Health, Aging, Body Composition Study (mean age ± SD 74.7 2.9 years, 50% men, 63% white), using liquid chromatography-mass spectrometry. confirmed IMF was DSST scores (standardized beta (95% CI) − 0.08 (− 0.12, 0.03), p < 0.001). Sixty-six were significantly DSST. Four of 66 attenuated association ≥ 10%: levels adrenic acid (polyunsaturated fatty acid), lower C20:5 lysophosphatidylcholine (lysophospholipid), 1-methylnicotinamide (vitamin B3-related myokine), maslinic (triterpene) Together, they explained 41% Pathway enrichment analyses identified two significant shared pathways: unsaturated metabolism citrate (TCA) cycle. This study provides hypothesis-generating a set circulating related acids, energy metabolism, myokines partially inverse speed. The findings, if further independent studies, advance our understanding molecular pathways muscle-brain crosstalk. Whether early predictors future decline speed should be investigated.

Language: Английский

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Pan-PTM profiling identifies post-translational modifications associated with exceptional longevity and preservation of skeletal muscle function in Drosophila

npj Aging, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 30, 2025

Skeletal muscle weakness is a major component of age-associated frailty, but the underlying mechanisms are not completely understood. Drosophila has emerged as useful model for studying skeletal aging. In this organism, previous lab-based selection established strains with increased longevity and reduced functional decline compared to parental strain. Here, we have applied computational pipeline (JUMPptm) retrieving information on 8 post-translational modifications (PTMs) from proteomes 2 long-lived corresponding strain in young old age. This pan-PTM analysis identified 2470 modified sites (acetylation, carboxylation, deamidation, dihydroxylation, mono-methylation, oxidation, phosphorylation, ubiquitination) several classes proteins, including evolutionarily conserved contractile proteins metabolic enzymes. PTM consensus sequences further highlight amino acids that enriched adjacent site, thus providing insight into flanking residues influence distinct PTMs. Altogether, these analyses identify PTMs associated during aging may underlie negligible senescence lab-evolved strains.

Language: Английский

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