RESUMEN
The blood-brain barrier (BBB) and blood-retinal barrier (BRB) constitute critical physiochemical interfaces, precisely orchestrating the bidirectional communication between the brain/retina and blood. Increased permeability or leakage of these barriers has been demonstrably linked to age-related vascular and parenchymal damage. While it has been suggested that the gradual aging process may coincide with disruptions in these barriers, this phenomenon is significantly exacerbated in individuals with age-related neurodegenerative disorders (ARND). This review focuses on the microvascular endothelium, a key constituent of BBB and BRB, highlighting the impact of endothelial senescence on barrier dysfunction and exploring recent discoveries regarding core pathways implicated in its breakdown. Subsequently, we address the "vascular senescence hypothesis" for ARND, with a particular emphasis on Alzheimer's disease and age-related macular degeneration, centered on endothelial senescence. Finally, we discuss potential senotherapeutic strategies targeting barrier dysfunction.
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Envejecimiento , Barrera Hematoencefálica , Barrera Hematorretinal , Endotelio Vascular , Humanos , Barrera Hematoencefálica/fisiopatología , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Barrera Hematorretinal/fisiología , Barrera Hematorretinal/metabolismo , Envejecimiento/fisiología , Envejecimiento/patología , Animales , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismo , Senescencia Celular/fisiología , Enfermedades Neurodegenerativas/fisiopatología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patologíaRESUMEN
Obesity, a global health crisis, disrupts multiple systemic processes, contributing to a cascade of metabolic dysfunctions by promoting the pathological expansion of visceral adipose tissue (VAT). This expansion is characterized by impaired differentiation of pre-adipocytes and an increase in senescent cells, leading to a pro-inflammatory state and exacerbated oxidative stress. Particularly, the senescence-associated secretory phenotype (SASP) and adipose tissue hypoxia further impair cellular function, promoting chronic disease development. This review delves into the potential of autophagy modulation and the therapeutic application of senolytics and senomorphics as novel strategies to mitigate adipose tissue senescence. By exploring the intricate mechanisms underlying adipocyte dysfunction and the emerging role of natural compounds in senescence modulation, we underscore the promising horizon of senotherapeutics in restoring adipose health. This approach not only offers a pathway to combat the metabolic complications of obesity, but also opens new avenues for enhancing life quality and managing the global burden of obesity-related conditions. Our analysis aims to bridge the gap between current scientific progress and clinical application, offering new perspectives on preventing and treating obesity-induced adipose dysfunction.
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Tejido Adiposo , Autofagia , Senescencia Celular , Obesidad , Senoterapéuticos , Humanos , Obesidad/tratamiento farmacológico , Senescencia Celular/fisiología , Senescencia Celular/efectos de los fármacos , Autofagia/fisiología , Autofagia/efectos de los fármacos , Senoterapéuticos/farmacología , Animales , AdipocitosRESUMEN
Senescent chondrocytes or signaling mechanisms leading to senescence are promising new therapeutic approaches for ameliorating cartilage degradation. Herein, we show that the transactive response DNA/RNA-binding protein (TDP-43) regulates chondrocyte senescence and ameliorates cartilage degradation. First, a significant decrease in TDP-43 was observed in 16-month-old mice compared with younger mice. Immunohistochemistry (IHC) analysis of mouse articular cartilage showed that p21, p16, p53, and matrix metalloprotein-13 (MMP13) were increased, but laminB1 and Collagen type II alpha1 1 chain (Col2a1) were decreased in 16-month-old mice. Furthermore, TDP-43 levels were decreased in vivo following D-galactose (D-gal) induction. Therefore, we investigated the role of TDP-43 in the senescent chondrocytes. ATDC5 cells were induced to overexpress TDP-43. Western blot analysis showed increased expression of laminB1, Ki67, and PCNA but decreased expression of p21, p16, p53, and MMP13. Senescence-associated-ß-galactosidase (SA-ß-Gal) assay, γH2AX staining, and EdU were performed to assess changes in chondrocytes, showing weaker SA-ß-Gal and γH2AX staining but stronger EdU and Alican Blue staining. However, TDP-43 deficiency had opposing effects, and similar to D-gal stimulation results. Taken together, our data verified that TDP-43 negatively correlated with senescence markers, positively correlated with cell proliferation markers, and could alleviate cartilage degradation induced by D-gal. This may be an essential mechanism of cellular senescence and cartilage degradation.
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Envejecimiento , Cartílago Articular , Senescencia Celular , Condrocitos , Proteínas de Unión al ADN , Animales , Condrocitos/metabolismo , Senescencia Celular/fisiología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Cartílago Articular/metabolismo , Ratones , Envejecimiento/metabolismo , Ratones Endogámicos C57BL , Galactosa/metabolismo , Masculino , Proliferación CelularRESUMEN
Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin-FAK-ERK-Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.
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Proliferación Celular , Senescencia Celular , Proteína 1 de la Respuesta de Crecimiento Precoz , Miocitos Cardíacos , Regeneración , Animales , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Regeneración/fisiología , Senescencia Celular/fisiología , Miocitos Cardíacos/metabolismo , Ratones Endogámicos C57BL , Neovascularización Fisiológica/fisiología , Transducción de Señal , Fibroblastos/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Cultivadas , Animales Recién Nacidos , Modelos Animales de Enfermedad , Fenotipo Secretor Asociado a la Senescencia , Proteómica , Análisis de la Célula Individual , Masculino , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ratones Noqueados , Quinasa 1 de Adhesión FocalRESUMEN
Anterior cruciate ligament (ACL) injuries pose a significant challenge due to their limited healing potential, often resulting in premature arthritis. The factors and mechanisms contributing to this inadequate healing process remain elusive. During the acute phase of injury, ACL tissues express elevated periostin levels that decline over time. The functional significance of periostin in ligament biology remains understudied. In this study, we investigated the functional and mechanistic implications of periostin deficiency in ACL biology, utilizing ligament fibroblasts derived from patients and a murine model of ACL rupture. Our investigations unveiled that periostin knockdown compromised fibroblast growth characteristics, hindered the egress of progenitor cells from explants, and arrested cell-cycle progression, resulting in the accumulation of cells in the G0/G1 phase and moderate apoptosis. Concurrently, a significant reduction in the expression of cell-cycle and matrix-related genes was observed. Moreover, periostin deficiency triggered apoptosis through STAT3Y705/p38MAPK signaling and induced cellular senescence through increased production of reactive oxygen species (ROS). Mechanistically, inhibition of ROS production mitigated cell senescence in these cells. Notably, in vivo data revealed that ACL in Postn-/- mice exhibited a higher tearing frequency than wild-type mice under equivalent loading conditions. Furthermore, injured ACL with silenced periostin expression, achieved through nanoparticle-siRNA complex delivery, displayed an elevated propensity for apoptosis and senescence compared to intact ACL in C57BL/6 mice. Together, our findings underscore the pivotal role of periostin in ACL health, injury, and potential for healing.
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Lesiones del Ligamento Cruzado Anterior , Ligamento Cruzado Anterior , Senescencia Celular , Fibroblastos , Periostina , Especies Reactivas de Oxígeno , Animales , Femenino , Humanos , Masculino , Ratones , Ligamento Cruzado Anterior/metabolismo , Lesiones del Ligamento Cruzado Anterior/metabolismo , Lesiones del Ligamento Cruzado Anterior/patología , Apoptosis , Células Cultivadas , Senescencia Celular/fisiología , Fibroblastos/metabolismo , Ratones Endogámicos C57BL , Periostina/genética , Periostina/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Purpose: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to the development of numerous age-associated diseases. In this study, we investigated the link between cholesterol burden and the cellular senescence of photoreceptors. Methods: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) and G member 1 (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for the signs of cellular senescence. Real-time quantitative PCR and immunofluorescence were used to characterize the senescence profile of the retina and cholesterol-treated photoreceptor cell line (661W). Inducible elimination of p16(Ink4a)-positive senescent cells (INK-ATTAC) mice or the administration of senolytic drugs (dasatinib and quercetin: D&Q) were used to examine the impact of senolytics on AMD-like phenotypes in Abca1/g1-rod/-rod retina. Results: Increased accumulation of senescent cells as measured by markers of cellular senescence was found in Abca1/g1-rod/-rod retina. Exogenous cholesterol also induced cellular senescence in 661W cells. Selective elimination of senescent cells in Abca1/g1-rod/-rod;INK-ATTAC mice or by administration of D&Q improved visual function, lipid accumulation in retinal pigment epithelium, and Bruch's membrane thickening. Conclusions: Cholesterol accumulation promotes cellular senescence in photoreceptors. Eliminating senescent photoreceptors improves visual function in a model of retinal neurodegeneration, and senotherapy offers a novel therapeutic avenue for further investigation.
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Transportador 1 de Casete de Unión a ATP , Senescencia Celular , Colesterol , Modelos Animales de Enfermedad , Ratones Noqueados , Degeneración Retiniana , Animales , Ratones , Senescencia Celular/fisiología , Colesterol/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Ratones Endogámicos C57BL , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Células Fotorreceptoras Retinianas Bastones/metabolismo , Células Fotorreceptoras Retinianas Bastones/patología , Células Fotorreceptoras Retinianas Bastones/fisiologíaRESUMEN
Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by abnormal accumulation of tau proteins and amyloid-ß, leading to neuronal death and cognitive impairment. Recent studies have implicated aging pathways, including dysregulation of tau and cellular senescence in AD pathogenesis. In AD brains, tau protein, which normally stabilizes microtubules, becomes hyperphosphorylated and forms insoluble neurofibrillary tangles. These tau aggregates impair neuronal function and are propagated across the brain's neurocircuitry. Meanwhile, the number of senescent cells accumulating in the aging brain is rising, releasing a pro-inflammatory SASP responsible for neuroinflammation and neurodegeneration. This review explores potential therapeutic interventions for AD targeting tau protein and senescent cells, and tau -directed compounds, senolytics, eliminating senescent cells, and agents that modulate the SASP-senomodulators. Ultimately, a combined approach that incorporates tau-directed medications and targeted senescent cell-based therapies holds promise for reducing the harmful impact of AD's shared aging pathways.
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Envejecimiento , Enfermedad de Alzheimer , Senescencia Celular , Proteínas tau , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Proteínas tau/metabolismo , Senescencia Celular/fisiología , Senescencia Celular/efectos de los fármacos , Envejecimiento/metabolismo , Animales , Encéfalo/metabolismoRESUMEN
BACKGROUND: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI. RESULTS: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI. CONCLUSIONS: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.
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Células Epiteliales Alveolares , Senescencia Celular , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Humanos , Masculino , Ratones , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de la radiación , Células Epiteliales Alveolares/patología , Células Cultivadas , Senescencia Celular/efectos de la radiación , Senescencia Celular/fisiología , Quinasa del Factor 2 de Elongación/metabolismo , Quinasa del Factor 2 de Elongación/genética , Lesión Pulmonar/metabolismo , Lesión Pulmonar/genética , Lesión Pulmonar/patología , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/genética , Proteína 1 de Unión a Repeticiones Teloméricas/genética , Proteína 1 de Unión a Repeticiones Teloméricas/metabolismoRESUMEN
PURPOSE: Latent TGF-ß binding protein 4 (LTBP4) is involved in the production of elastin fibers and has been implicated in LTBP4-related cutis laxa and its complication, emphysema-like changes. Various factors have been implicated in the pathogenesis of emphysema, including elastic degeneration, inflammation, cellular senescence, mitochondrial dysfunction, and decreased angiogenesis in the lungs. We investigated the association between LTBP4 and emphysema using human lung fibroblasts with silenced LTBP4 genes. METHODS: Cell contraction, elastin expression, cellular senescence, inflammation, anti-inflammatory factors, and mitochondrial function were compared between the LTBP4 small interfering RNA (siRNA) and control siRNA. RESULTS: Under the suppression of LTBP4, significant changes were observed in the following: decreased cell contractility, decreased elastin expression, increased expression of the p16 gene involved in cellular senescence, increased TNFα, decreased GSTM3 and SOD, decreased mitochondrial membrane potential, and decreased VEGF expression. Furthermore, the decreased cell contractility and increased GSTM3 expression observed under LTBP4 suppression were restored by the addition of N-acetyl-L-cysteine or recombinant LTBP4. CONCLUSION: The decreased elastin expression, cellular senescence, inflammation, decreased antioxidant activity, mitochondrial dysfunction, and decreased VEGF expression under reduced LTBP4 expression may all be involved in the destruction of the alveolar wall in emphysema. Smoking is the most common cause of emphysema; however, genetic factors related to LTBP4 expression and other factors may also contribute to its pathogenesis.
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Senescencia Celular , Fibroblastos , Proteínas de Unión a TGF-beta Latente , Humanos , Proteínas de Unión a TGF-beta Latente/genética , Proteínas de Unión a TGF-beta Latente/metabolismo , Senescencia Celular/fisiología , Fibroblastos/metabolismo , Elastina/metabolismo , ARN Interferente Pequeño , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/genética , Enfisema Pulmonar/patología , Células Cultivadas , Pulmón/metabolismo , Pulmón/patología , Enfisema/metabolismo , Enfisema/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Lymphatic aging represented by cellular and functional changes, is involved in increased geriatric disorders, but the intersection between aging and lymphatic modulation is less clear. Lymphatic vessels play an essential role in maintaining tissue fluid homeostasis, regulating immune function, and promoting macromolecular transport. Lymphangiogenesis and lymphatic remodeling following cellular senescence and organ deterioration are crosslinked with the progression of some lymphatic-associated diseases, e.g., atherosclerosis, inflammation, lymphoedema, and cancer. Age-related detrimental tissue changes may occur in lymphatic vessels with diverse etiologies, and gradually shift towards chronic low-grade inflammation, so-called inflammaging, and lead to decreased immune response. The investigation of the relationship between advanced age and organ deterioration is becoming an area of rapidly increasing significance in lymphatic biology and medicine. Here we highlight the emerging importance of lymphangiogenesis and lymphatic remodeling in the regulation of aging-related pathological processes, which will help to find new avenues for effective intervention to promote healthy aging.
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Envejecimiento , Linfangiogénesis , Vasos Linfáticos , Humanos , Linfangiogénesis/fisiología , Envejecimiento/fisiología , Envejecimiento/metabolismo , Envejecimiento/patología , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patología , Vasos Linfáticos/fisiopatología , Animales , Inflamación/metabolismo , Inflamación/patología , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/fisiopatología , Senescencia Celular/fisiología , Linfedema/metabolismo , Linfedema/patología , Linfedema/fisiopatologíaRESUMEN
Human aging is linked to bone loss, resulting in bone fragility and an increased risk of fractures. This is primarily due to an age-related decline in the function of bone-forming osteoblastic cells and accelerated cellular senescence within the bone microenvironment. Here, we provide a detailed discussion of the hypothesis that age-related defective bone formation is caused by senescence of skeletal stem cells, as they are the main source of bone forming osteoblastic cells and influence the composition of bone microenvironment. Furthermore, this review discusses potential strategies to target cellular senescence as an emerging approach to treat age-related bone loss.
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Envejecimiento , Senescencia Celular , Osteoblastos , Humanos , Senescencia Celular/fisiología , Envejecimiento/metabolismo , Envejecimiento/fisiología , Envejecimiento/patología , Osteoblastos/metabolismo , Animales , Osteoporosis/metabolismo , Osteoporosis/patología , Células Madre/metabolismo , Células Madre/patología , Osteogénesis/fisiología , Huesos/metabolismo , Huesos/patologíaRESUMEN
BACKGROUND: Sleep is a fundamental and complex physiological process whose duration decreases and characteristics change with age. Around 50 % of children will experience sleep disturbances at some point in their early life. Sleep disturbances can result in a number of deleterious consequences, including alterations in the levels of cellular senescence (CS) markers. CS is a complex process essential for homeostasis characterized by the irreversible loss of cell proliferation capacity; however, the accumulation of senescent cells can lead to age-related diseases. OBJECTIVE: In this review, our objective was to gather information about the relationship between sleep duration, sleep-disordered breathing (SDB) and cellular senescence markers, namely: oxidative stress, inflammation, insulin-like growth factor 1 (IGF-1), and growth hormone (GH) in newborns, children, and teenagers. METHODS: To achieve this, we searched six databases: MEDLINE, Scopus, LILACS, Web of Science, Embase, and SciELO, and identified 20 articles that met our inclusion criteria. RESULTS: Our results show that better sleep quality and duration and, both the surgical and non-surgical treatment of sleep disorders are associated with a reduction in oxidative stress, inflammation, and telomeric attrition levels. Furthermore, our results also show that surgical treatment for SDB significantly reduced the levels of cellular senescence markers. Further studies need to be conducted in this area, particularly longitudinal studies, for a greater understanding of the mechanisms involved in the relationship between sleep and senescence. CONCLUSION: Better sleep quality and duration were associated with less oxidative stress, inflammation, and telomeric attrition and a higher level of IGF-1 in children and teenagers.
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Senescencia Celular , Factor I del Crecimiento Similar a la Insulina , Estrés Oxidativo , Síndromes de la Apnea del Sueño , Humanos , Niño , Síndromes de la Apnea del Sueño/fisiopatología , Síndromes de la Apnea del Sueño/complicaciones , Adolescente , Senescencia Celular/fisiología , Estrés Oxidativo/fisiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Sueño/fisiología , InflamaciónRESUMEN
Cellular longevity is regulated by both genetic and environmental factors. However, the interactions of these factors in the context of aging remain largely unclear. Here, we formulate a mathematical model for dynamic glucose modulation of a core gene circuit in yeast aging, which not only guided the design of pro-longevity interventions but also revealed the theoretical principles underlying these interventions. We introduce the dynamical systems theory to capture two general means for promoting longevity-the creation of a stable fixed point in the "healthy" state of the cell and the "dynamic stabilization" of the system around this healthy state through environmental oscillations. Guided by the model, we investigate how both of these can be experimentally realized by dynamically modulating environmental glucose levels. The results establish a paradigm for theoretically analyzing the trajectories and perturbations of aging that can be generalized to aging processes in diverse cell types and organisms.
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Glucosa , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Glucosa/metabolismo , Modelos Biológicos , Redes Reguladoras de Genes , Senescencia Celular/fisiología , Senescencia Celular/genética , Longevidad/fisiología , Longevidad/genética , AmbienteRESUMEN
In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.
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Senescencia Celular , Células Endoteliales de la Vena Umbilical Humana , Uniones Intercelulares , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Senescencia Celular/fisiología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Uniones Intercelulares/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Estrés Oxidativo , Diabetes Mellitus/metabolismo , Glucosa/metabolismoRESUMEN
How do variations in nutrient levels influence cellular lifespan? A dynamical systems model of a core circuit involved in yeast aging suggests principles underlying lifespan extension observed at static and alternating glucose levels that are reminiscent of intermittent fasting regimens.
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Senescencia Celular , Saccharomyces cerevisiae , Saccharomyces cerevisiae/fisiología , Saccharomyces cerevisiae/genética , Senescencia Celular/fisiología , Glucosa/metabolismo , Modelos Biológicos , Análisis de la Célula Individual/métodosRESUMEN
Human skin ageing is closely related to the ageing of the whole organism, and it's a continuous multisided process that is influenced not only by genetic and physiological factors but also by the cumulative impact of environmental factors. Currently, there is a scientific community need for developing skin models representing ageing processes to (i) enhance understanding on the mechanisms of ageing, (ii) discover new drugs for the treatment of age-related diseases, and (iii) develop effective dermo-cosmetics. Bioengineers worldwide are trying to reproduce skin ageing in the laboratory aiming to better comprehend and mitigate the senescence process. This review provides details on the main ageing molecular mechanisms and procedures to obtain in vitro aged skin models.
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Senescencia Celular , Envejecimiento de la Piel , Piel , Humanos , Senescencia Celular/fisiología , Envejecimiento de la Piel/fisiología , Modelos Biológicos , Envejecimiento/fisiologíaRESUMEN
Parkinson's disease (PD) is an age-related movement disorder caused by the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) of the midbrain, however, the underlying cause(s) of this DA neuron loss in PD is unknown and there are currently no effective treatment options to prevent or slow neuronal loss or the progression of related symptoms. It has been shown that both environmental factors as well as genetic predispositions underpin PD development and recent research has revealed that lysosomal dysfunction and lipid accumulation are contributors to disease progression, where an age-related aggregation of alpha-synuclein as well as lipids have been found in PD patients. Interestingly, the most common genetic risk factor for PD is Glucosylceramidase Beta 1 (GBA), which encodes a lysosomal glucocerebrosidase (GCase) that cleaves the beta-glucosidic linkage of lipids known as glucocerebrosides (GluCer). We have recently discovered that artificial induction of GluCer accumulation leads to cellular senescence of DA neurons, suggesting that lipid aggregation plays a crucial role in the pathology of PD by driving senescence in these vulnerable DA neurons. Here, we discuss the relevance of the age-related aggregation of lipids as well as the direct functional link between general lipid aggregation, cellular senescence, and inflammaging of DA neurons. We propose that the expression of a cellular senescence phenotype in the most vulnerable neurons in PD can be triggered by lysosomal impairment and lipid aggregation. Importantly, we highlight additional data that perilipin (PLIN2) is significantly upregulated in senescent DA neurons, suggesting an overall enrichment of lipid droplets (LDs) in these cells. These findings align with our previous results in dopaminergic neurons in highlighting a central role for lipid accumulation in the senescence of DA neurons. Importantly, general lipid droplet aggregation and global lysosomal impairment have been implicated in many neurodegenerative diseases including PD. Taken together, our data suggest a connection between age-related lysosomal impairment, lipid accumulation, and cellular senescence in DA neurons that in turn drives inflammaging in the midbrain and ultimately leads to neurodegeneration and PD.
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Senescencia Celular , Neuronas Dopaminérgicas , Enfermedad de Parkinson , Neuronas Dopaminérgicas/metabolismo , Humanos , Senescencia Celular/fisiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/genética , Animales , Metabolismo de los Lípidos , Glucosilceramidasa/metabolismo , Glucosilceramidasa/genética , Envejecimiento/metabolismo , Lisosomas/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genéticaRESUMEN
The regenerative ability of limb bones after injury decreases during aging, but whether a similar phenomenon occurs in jawbones and whether autophagy plays a role in this process remain unclear. Through retrospective analysis of clinical data and studies on a mouse model of jawbone defects, we confirmed the presence of delayed or impaired bone regeneration in the jawbones of old individuals and mice. Subsequently, osteoblasts (OBs) derived from mouse jawbones were isolated, showing reduced osteogenesis in senescent osteoblasts (S-OBs). We observed a reduction in autophagy within both aged jawbones and S-OBs. Additionally, pharmacological inhibition of autophagy in normal OBs (N-OBs) led to cell aging and decreased osteogenesis, while autophagic activation reversed the aging phenotype of S-OBs. The activator rapamycin (RAPA) increased the autophagy level and bone regeneration in aged jawbones. Finally, we found that fatty acid-binding protein 3 (FABP3) was degraded by autolysosomes through its interaction with sequestosome 1 (P62/SQSTM1). Autophagy inhibition within senescent jawbones and S-OBs led to the excessive accumulation of FABP3, and FABP3 knockdown partially rescued the decreased osteogenesis in S-OBs and alleviated age-related compromised jawbone regeneration. In summary, we confirmed that autophagy inhibition plays an important role in delaying bone regeneration in aging jawbones. Autophagic activation or FABP3 knockdown can partially rescue the osteogenesis of S-OBs and the regeneration of aging jawbones, providing insight into jawbone aging.
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Envejecimiento , Autofagia , Regeneración Ósea , Proteínas de Unión a Ácidos Grasos , Osteoblastos , Osteogénesis , Animales , Femenino , Humanos , Masculino , Ratones , Envejecimiento/fisiología , Envejecimiento/metabolismo , Autofagia/fisiología , Senescencia Celular/fisiología , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Maxilares , Ratones Endogámicos C57BL , Osteoblastos/metabolismo , Osteogénesis/fisiologíaRESUMEN
Senescence is an irreversible arrest of the cell cycle that can be characterized by markers of senescence such as p16, p21, and KI-67. The characterization of different senescence-associated phenotypes requires selection of the most relevant senescence markers to define reliable cytometric methodologies. Mass cytometry (a.k.a. Cytometry by time of flight, CyTOF) can monitor up to 40 different cell markers at the single-cell level and has the potential to integrate multiple senescence and other phenotypic markers to identify senescent cells within a complex tissue such as skeletal muscle, with greater accuracy and scalability than traditional bulk measurements and flow cytometry-based measurements. This article introduces an analysis framework for detecting putative senescent cells based on clustering, outlier detection, and Boolean logic for outliers. Results show that the pipeline can identify putative senescent cells in skeletal muscle with well-established markers such as p21 and potential markers such as GAPDH. It was also found that heterogeneity of putative senescent cells in skeletal muscle can partly be explained by their cell type. Additionally, autophagy-related proteins ATG4A, LRRK2, and GLB1 were identified as important proteins in predicting the putative senescent population, providing insights into the association between autophagy and senescence. It was observed that sex did not affect the proportion of putative senescent cells among total cells. However, age did have an effect, with a higher proportion observed in fibro/adipogenic progenitors (FAPs), satellite cells, M1 and M2 macrophages from old mice. Moreover, putative senescent cells from muscle of old and young mice show different expression levels of senescence-related proteins, with putative senescent cells of old mice having higher levels of p21 and GAPDH, whereas putative senescent cells of young mice had higher levels of IL-6. Overall, the analysis framework prioritizes multiple senescence-associated proteins to characterize putative senescent cells sourced from tissue made of different cell types.
Asunto(s)
Biomarcadores , Senescencia Celular , Citometría de Flujo , Músculo Esquelético , Animales , Senescencia Celular/fisiología , Ratones , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Citometría de Flujo/métodos , Biomarcadores/metabolismo , Femenino , Masculino , Ratones Endogámicos C57BL , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Análisis de la Célula Individual/métodosRESUMEN
Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, however, its exact mechanism remains unknown. This study aimed to evaluate whether clusterin is essential to the development of SAE during the aging process of astrocytes. In the study, septic mice were established with cecal ligation and puncture (CLP) and lipopolysaccharides were applied to astrocytes in vitro. Evan's blue dye was used in vivo to show blood-brain barrier (BBB) permeability. A morris water maze test was conducted to assess cognitive functions of the mice. Clusterin-knockout mice were used to examine the effect of clusterin on sepsis. The astrocytes were transfected with lentivirus expressing clusterin cDNA for clusterin overexpression or pYr-LV-clusterin small hairpin RNA for clusterin knockdown in vitro . The expression of clusterin, p-p53, p21, GDNF, and iNOS was detected. he CLP mice exhibited a higher clusterin expression in hippocampus tissue, aging astrocytes, lower GDNF expression and higher iNOS expression, accompanied with BBB damage and cognitive deficiency. Following clusterin knockout, this pathological process was further enhanced. In vitro , following lipopolysaccharides treatment, astrocytes exhibited increased clusterin, p-p53, p21, iNOS and decreased GDNF. Following clusterin knockdown, the cells exhibited a further increase in p-p53, p21, and iNOS and decrease in GDNF. Clusterin overexpression, however, helped inhibit astrocytes aging and neuroinflammation evidenced by decreased p-p53, p21, iNOS and increased GDNF. The present study has revealed that clusterin may exert its neuroprotective effect by preventing aging in astrocytes, suppressing the secretion of iNOS and promoting GNDF release.