Focus on senescence: Clinical significance and practical applications

Journal of Internal Medicine, Год журнала: 2024, Номер 295(5), С. 599 - 619

Опубликована: Март 6, 2024

Abstract The older population is increasing worldwide, and life expectancy continuously rising, predominantly thanks to medical technological progress. Healthspan refers the number of years an individual can live in good health. From a gerontological viewpoint, mission extend spent health, promoting well‐being minimizing impact aging‐related diseases slow aging process. Biologically, malleable process characterized by intra‐ inter‐individual heterogeneous dynamic balance between accumulating damage repair mechanisms. Cellular senescence key component this process, with senescent cells different tissues organs, leading age‐related disease susceptibility over time. Removing from body or slowing down burden rate has been proposed as efficient way reduce age‐dependent deterioration. In animal models, senotherapeutic molecules lifespan either senolytic senomorphic activity. Much research shows that dietary physical activity‐driven lifestyle interventions protect against senescence. This narrative review aims summarize current knowledge on targeting risk models their translational potential for humans. We focused studies have examined role senotherapeutics modifying burdens. concludes general discussion mechanisms underlying unique trajectory its implications future research.

Язык: Английский

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Blood-brain barrier disruption: a culprit of cognitive decline?

Fluids and Barriers of the CNS, Год журнала: 2024, Номер 21(1)

Опубликована: Авг. 7, 2024

Cognitive decline covers a broad spectrum of disorders, not only resulting from brain diseases but also systemic diseases, which seriously influence the quality life and expectancy patients. As highly selective anatomical functional interface between circulation, blood-brain barrier (BBB) plays pivotal role in maintaining homeostasis normal function. The pathogenesis underlying cognitive may vary, nevertheless, accumulating evidences support BBB disruption as most prevalent contributing factor. This mainly be attributed to inflammation, metabolic dysfunction, cell senescence, oxidative/nitrosative stress excitotoxicity. However, direct evidence showing that causes is scarce, interestingly, manipulation opening alone exert beneficial or detrimental neurological effects. A overview present literature shows close relationship decline, risk factors disruption, well cellular molecular mechanisms disruption. Additionally, we discussed possible leading by potential therapeutic strategies prevent enhance repair. review aims foster more investigations on early diagnosis, effective therapeutics, rapid restoration against would yield better outcomes patients with dysregulated function, although their causative has yet been completely established.

Язык: Английский

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Elevated PDGF‐BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRβ Shedding from Pericytes

Advanced Science, Год журнала: 2023, Номер 10(20)

Опубликована: Апрель 27, 2023

Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain elusive. Here platelet-derived growth factor-BB (PDGF-BB) produced by preosteoclasts in is reported to promote age-associated hippocampal vascular impairment. Aberrantly elevated circulating PDGF-BB aged mice high-fat diet (HFD)-challenged correlates with capillary reduction, pericyte loss, increased blood-brain barrier (BBB) permeability their hippocampus. Preosteoclast-specific Pdgfb transgenic markedly high plasma concentration faithfully recapitulate BBB impairment cognitive decline. Conversely, preosteoclast-specific knockout have attenuated or HFD-challenged mice. Persistent exposure of brain pericytes concentrations upregulates matrix metalloproteinase 14 (MMP14), which promotes ectodomain shedding PDGF receptor β (PDGFRβ) from surface. MMP inhibitor treatment alleviates loss reduction conditional antagonizes leakage The findings establish role bone-derived mediating disruption identify ligand-induced PDGFRβ as feedback mechanism for downregulation consequent loss.

Язык: Английский

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Bone-derived PDGF-BB drives brain vascular calcification in male mice

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(23)

Опубликована: Окт. 10, 2023

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue well studied, but microvascular the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular male mice. Aged mice had higher serum PDGF-BB levels incidence compared with young mice, mainly thalamus. Transgenic preosteoclast-specific Pdgfb overexpression exhibited recapitulated age-associated thalamic calcification. Conversely, deletion displayed diminished In an ex vivo cerebral culture system, dose-dependently promoted Analysis osteogenic gene array single-cell RNA-Seq (scRNA-Seq) revealed upregulated multiple differentiation genes phosphate transporter Slc20a1 microvessels. Mechanistically, stimulated phosphorylation its receptor PDGFRβ (p-PDGFRβ) ERK (p-ERK), leading activation RUNX2. This activation, turn, induced transcription osteoblast PCs astrocytes. Thus, bone-derived by activating p-PDGFRβ/p-ERK/RUNX2 signaling cascade cells.

Язык: Английский

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“Bone-SASP” in Skeletal Aging

Calcified Tissue International, Год журнала: 2023, Номер 113(1), С. 68 - 82

Опубликована: Май 31, 2023

Abstract Senescence is a complex cell state characterized by stable cycle arrest and unique secretory pattern known as the senescence-associated phenotype (SASP). The SASP factors, which are heterogeneous tissue specific, normally include chemokines, cytokines, growth adhesion molecules, lipid components that can lead to multiple age-associated disorders eliciting local systemic consequences. skeleton highly dynamic organ changes constantly in shape composition. Senescent cells bone marrow produce diverse factors induce alterations of through paracrine effects. Herein, we refer cell-associated “bone-SASP.” In this review, describe current knowledge cellular senescence SASP, focusing on role senescent mediating pathologies during natural aging premature syndromes. We also summarize bone-SASP glucocorticoids-induced damage. addition, discuss development osteoarthritis, highlighting mechanisms drives subchondral metabolic syndrome-associated osteoarthritis.

Язык: Английский

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Crosstalk between bone and brain in Alzheimer's disease: Mechanisms, applications, and perspectives

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(8), С. 5720 - 5739

Опубликована: Июнь 2, 2024

Abstract Alzheimer's disease (AD) is a neurodegenerative that involves multiple systems in the body. Numerous recent studies have revealed bidirectional crosstalk between brain and bone, but interaction bone AD remains unclear. In this review, we summarize human of association provide an overview their interactions underlying mechanisms AD. We review effects on from aspects pathogenic proteins, risk genes, neurohormones, neuropeptides, neurotransmitters, brain‐derived extracellular vesicles (EVs), autonomic nervous system. Correspondingly, elucidate involvement pathogenesis AD, including bone‐derived hormones, marrow‐derived cells, EVs, inflammation. On basis brain, propose potential strategies for management with hope offering novel perspectives its prevention treatment. Highlights The along consequent changes may involve disturbing homeostasis. Degenerative disorders influence progression through series pathophysiological mechanisms. Therefore, relevant intervention be beneficial comprehensive

Язык: Английский

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The Soluble Platelet‐Derived Growth Factor β Receptor Induces Postoperative Delirium by Downregulating the Clearance of β‐Amyloid in the Brain

Brain and Behavior, Год журнала: 2025, Номер 15(5)

Опубликована: Май 1, 2025

ABSTRACT Purpose: To investigate the relationship between soluble platelet‐derived growth factor β receptor (sPDGFRβ) in cerebrospinal fluid (CSF) and Alzheimer's disease (AD) biomarkers, to determine whether high CSF sPDGGFRβ is a potential risk for postoperative delirium (POD), evaluate its predictive effect, so as provide reference clinical prevention treatment. Patients Methods: samples were collected preoperatively from cognitively normal participants aged 50–90 years undergoing knee/hip replacement surgery under spinal‐epidural anesthesia. The concentrations of sPDGFRβ, β‐amyloid 42 (Aβ42), total tau protein (Ttau), phosphorylated (Ptau) detected by enzyme‐linked immunosorbent assay (ELISA). confusion assessment method (CAM) was used developed POD after surgery, they divided into group non‐POD (NPOD). AD analyzed. Results: level marker brain pericyte injury, significantly increased patients ( p < 0.05), difference still statistically significant adjusting multiple confounders 0.05). Aβ42 showed mediating effect sPDGFRβ (22.45%). combination biomarkers predicted better than that or alone. Conclusion: results suggest increase associated with an due blood–brain barrier (BBB) dysfunction reduced clearance. In this study, correlation investigated first time, providing new index prediction. However, paper did not study other relevant indicators BBB lacked follow‐up, which could be further improved future.

Язык: Английский

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RAGE in circulating immune cells is fundamental for hippocampal inflammation and cognitive decline in a mouse model of latent chronic inflammation

Brain Behavior and Immunity, Год журнала: 2023, Номер 116, С. 329 - 348

Опубликована: Дек. 22, 2023

Язык: Английский

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Improving the reliability of T₂measurement in magnetic resonance imaging

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 10, 2024

Abstract Magnetic resonance imaging (MRI) is a versatile technique broadly utilized in research and clinic. Among the information available from MRI measurements, transversal relaxation time (T 2 ) basic but critical one to reflect microstructure microenvironment at molecular level. A popular method estimate T employing series of evolution (TE) values and, thereafter, fitting with exponential model (termed as fitting). Despite popularity using fitting, there lack knowledge how related experimental parameters, such signal-to-noise (SNR), number TE utilized, dynamic range TE, repetition each affect measurement reproducibility. In this study, we performed Monte Carlo simulations investigate SNR, number, range, influence reliability measurement, which was indexed by coefficient variations. Good ≤5.0% variation can be achieved when normalized noise level below 2.2%. Optimal for measuring under evaluation. increased reduce

Язык: Английский

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Bone-derived PDGF-BB enhances hippocampal non-specific transcytosis through microglia-endothelial crosstalk in HFD-induced metabolic syndrome

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Апрель 29, 2024

Abstract Background It is well known that high-fat diet (HFD)-induced metabolic syndrome plays a crucial role in cognitive decline and brain-blood barrier (BBB) breakdown. However, whether the bone-brain axis participates this pathological process remains unknown. Here, we report platelet-derived growth factor-BB (PDGF-BB) secretion by preosteoclasts bone accelerates neuroinflammation. The expression of alkaline phosphatase (ALPL), nonspecific transcytosis marker, was upregulated during HFD challenge. Main body Preosteoclast-specific Pdgfb transgenic mice with high PDGF-BB concentrations circulation recapitulated HFD-induced neuroinflammation shift. knockout were partially rescued from hippocampal shifts HFD-challenged mice. elevation aggravated microglia-associated interleukin-1β (IL-1β) secretion, which increased ALPL shift through enhancing protein 1 (SP1) translocation endothelial cells. Conclusion Our findings confirm bone-secreted region challenge identify novel mechanism microglia-endothelial crosstalk syndrome.

Язык: Английский

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