RESUMEN
Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is one of the deadliest diseases in the world. In 2022, 6.7 million patients with T2D died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular factors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 mo to nondiabetic mice aged 6 mo and 20 mo. The comparison with the two nondiabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 mo present the same characteristics of ECM wear as those observed in mice aged 20 mo. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of patients with T2D.NEW & NOTEWORTHY Aortic elastic fibers of young (6-mo old) individuals with diabetes degrade prematurely and exhibit an appearance like that found in aged (20-mo old) nondiabetic mice. Exacerbated elastolysis and elastin-derived peptide production are characteristic elements, contributing to early aortic wall rigidity and hypertension development. Therefore, limiting this early aging could be a judicious therapeutic approach to reduce cardiovascular complications and premature death in patients with diabetes.
Asunto(s)
Aorta , Tejido Elástico , Matriz Extracelular , Síndrome Metabólico , Ratones Endogámicos C57BL , Rigidez Vascular , Animales , Tejido Elástico/metabolismo , Tejido Elástico/patología , Rigidez Vascular/fisiología , Ratones , Aorta/metabolismo , Aorta/patología , Aorta/fisiopatología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Síndrome Metabólico/fisiopatología , Elastina/metabolismo , Colágeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Envejecimiento/patología , Envejecimiento/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Envejecimiento Prematuro/metabolismo , Envejecimiento Prematuro/patología , Envejecimiento Prematuro/fisiopatologíaRESUMEN
Premature brain aging is associated with poorer cognitive reserve and lower resilience to injury. When there are focal brain lesions, brain regions may age at different rates within the same individual. Therefore, we hypothesize that reduced gray matter volume within specific brain systems commonly associated with language recovery may be important for long-term aphasia severity. Here we show that individuals with stroke aphasia have a premature brain aging in intact regions of the lesioned hemisphere. In left domain-general regions, premature brain aging, gray matter volume, lesion volume and age were all significant predictors of aphasia severity. Increased brain age following a stroke is driven by the lesioned hemisphere. The relationship between brain age in left domain-general regions and aphasia severity suggests that degradation is possible to specific brain regions and isolated aging matters for behavior.
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Afasia , Encéfalo , Humanos , Afasia/fisiopatología , Afasia/patología , Afasia/etiología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Encéfalo/patología , Encéfalo/fisiopatología , Envejecimiento Prematuro/fisiopatología , Envejecimiento Prematuro/patología , Imagen por Resonancia Magnética , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patología , Envejecimiento/patología , Índice de Severidad de la Enfermedad , Sustancia Gris/patología , Sustancia Gris/diagnóstico por imagen , AdultoRESUMEN
This review presents data from the literature on the characteristics of the course of chronic kidney disease from the perspective of the geriatric patient. Chronic kidney disease and progression of renal failure is a prototype model of premature and accelerated aging. Many authors have stated that a better mechanistic understanding of the phenomenon of premature aging, early diagnosis of chronic kidney disease, and a geriatric approach to the patient can improve the effectiveness of management and prolongation of life in this category of patients. Comprehensive geriatric assessment is one of the most important tools used by geriatricians and their teams to globally assess elderly patients and plan effective interventions. It is concluded that the use of comprehensive geriatric assessment in patients with chronic kidney disease may improve the clinical status of patients and allow selection of patients who may benefit most from renal replacement therapy compared to a conservative approach. And even in the early stages of chronic kidney disease, a comprehensive geriatric assessment may be useful in formulating a complete intervention plan and optimizing quality of life, autonomy, and prognosis. However, despite recognition of the importance of comprehensive geriatric assessment, the means to implement this tool in nephrology departments have not been developed and require special training programs and appropriate skills. It is concluded that much more needs to be done to realize the continuity of nephrologists and geriatricians in the provision of meaningful skilled care to older patients with chronic kidney disease.
Asunto(s)
Evaluación Geriátrica , Insuficiencia Renal Crónica , Humanos , Evaluación Geriátrica/métodos , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/epidemiología , Anciano , Calidad de Vida , Envejecimiento/fisiología , Progresión de la Enfermedad , Envejecimiento Prematuro/fisiopatología , Envejecimiento Prematuro/etiología , Envejecimiento Prematuro/diagnóstico , Envejecimiento Prematuro/terapia , PronósticoRESUMEN
OBJECTIVES: To assess the mitochondrial dysfunction, oxidative stress and premature aging in children with nutritional rickets. METHODS: This cross-sectional study enrolled children aged 6 months - 5 years with nutritional rickets attending a tertiary care hospital between January 2021 and August 2022. Mitochondrial dysfunction, oxidative stress and premature aging were assessed by measuring the mitochondrial DNA (mtDNA) content, total antioxidant status (TAOS) and telomere length (TL) in 40 children with nutritional rickets and 40 age- and sex- matched healthy children without rickets (controls). RESULTS: The median (IQR) mtDNA content was significantly higher in children with rickets as compared to controls [152.27 (111.83, 218.66) vs 93.7 (72.5, 134.14); P < 0.001], implying mitochondrial dysfunction attributed to increased mitochondrial biogenesis in children with rickets. The median (IQR) TAOS ( mM Trolox equiv.) was significantly lower in children with rickets than controls [4.54 (3.93, 5.73) vs 7.86 (5.09, 9.58); P < 0.001)]. The median (IQR) TL in cases was significantly longer in children with rickets compared to controls [417.31 (111.83,218.66) vs 93.7 (72.5,134.14); P < 0.001] implying that children with rickets do not have premature aging. CONCLUSIONS: Children with rickets have high oxidative stress and mitochondrial dysfunction but no evidence of premature aging.
Asunto(s)
Envejecimiento Prematuro , Estrés Oxidativo , Raquitismo , Humanos , Estrés Oxidativo/fisiología , Raquitismo/fisiopatología , Estudios Transversales , Preescolar , Femenino , Masculino , Lactante , Envejecimiento Prematuro/fisiopatología , ADN Mitocondrial , Mitocondrias/metabolismo , Antioxidantes/metabolismo , Estudios de Casos y ControlesRESUMEN
Bedrest as an experimental paradigm or as an in-patient stay for medical reasons has negative consequences for cardiovascular health. The effects of severe inactivity parallel many of the changes experienced with natural aging but over a much shorter duration. Cardiac function is reduced, arteries stiffen, neural reflex responses are impaired, and metabolic and oxidative stress responses impose burden on the heart and vascular systems. The effect of these changes is revealed in studies of integrative function. Aerobic fitness progressively deteriorates with bedrest and tolerance of upright posture is rapidly impaired. In this review we consider the similarities of aging and bedrest-induced cardiovascular deconditioning. We concur with many recent clinical recommendations that early and regular mobility with upright posture will reduce likelihood of hospital-associated disability related to bedrest.
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Reposo en Cama , Humanos , Reposo en Cama/efectos adversos , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/etiología , Envejecimiento Prematuro/fisiopatología , Envejecimiento Prematuro/etiología , Descondicionamiento Cardiovascular/fisiología , Envejecimiento/fisiologíaRESUMEN
The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.
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Envejecimiento Prematuro , Envejecimiento , Encéfalo , Factores de Riesgo Cardiometabólico , Adulto , Factores de Edad , Envejecimiento/sangre , Envejecimiento/patología , Envejecimiento/fisiología , Envejecimiento Prematuro/sangre , Envejecimiento Prematuro/diagnóstico por imagen , Envejecimiento Prematuro/patología , Envejecimiento Prematuro/fisiopatología , Teorema de Bayes , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiología , Estudios Transversales , Imagen de Difusión Tensora , Femenino , Humanos , Estudios Longitudinales , Aprendizaje Automático , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Obesity is highly prevalent in schizophrenia, with implications for psychiatric prognosis, possibly through links between obesity and brain structure. In this longitudinal study in first episode of psychosis (FEP), we used machine learning and structural magnetic resonance imaging (MRI) to study the impact of psychotic illness and obesity on brain ageing/neuroprogression shortly after illness onset. METHODS: We acquired 2 prospective MRI scans on average 1.61 years apart in 183 FEP and 155 control individuals. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants and calculated BrainAGE by subtracting chronological from the estimated brain age. RESULTS: Individuals with FEP had a higher initial BrainAGE than controls (3.39 ± 6.36 vs 1.72 ± 5.56 years; ß = 1.68, t(336) = 2.59, P = .01), but similar annual rates of brain ageing over time (1.28 ± 2.40 vs 1.07±1.74 estimated years/actual year; t(333) = 0.93, P = .18). Across both cohorts, greater baseline body mass index (BMI) predicted faster brain ageing (ß = 0.08, t(333) = 2.59, P = .01). For each additional BMI point, the brain aged by an additional month per year. Worsening of functioning over time (Global Assessment of Functioning; ß = -0.04, t(164) = -2.48, P = .01) and increases especially in negative symptoms on the Positive and Negative Syndrome Scale (ß = 0.11, t(175) = 3.11, P = .002) were associated with faster brain ageing in FEP. CONCLUSIONS: Brain alterations in psychosis are manifest already during the first episode and over time get worse in those with worsening clinical outcomes or higher baseline BMI. As baseline BMI predicted faster brain ageing, obesity may represent a modifiable risk factor in FEP that is linked with psychiatric outcomes via effects on brain structure.
Asunto(s)
Envejecimiento Prematuro/patología , Progresión de la Enfermedad , Aprendizaje Automático , Obesidad/patología , Trastornos Psicóticos/patología , Adolescente , Adulto , Envejecimiento Prematuro/diagnóstico por imagen , Envejecimiento Prematuro/etiología , Envejecimiento Prematuro/fisiopatología , Índice de Masa Corporal , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Obesidad/complicaciones , Obesidad/diagnóstico por imagen , Obesidad/fisiopatología , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/fisiopatología , Factores de Riesgo , Adulto JovenRESUMEN
Cells respond to stress by activating a variety of defense signaling pathways, including cell survival and cell death pathways. Although cell survival signaling helps the cell to recover from acute insults, cell death or senescence pathways induced by chronic insults can lead to unresolved pathologies. Arterial hypertension results from chronic physiological maladaptation against various stressors represented by abnormal circulating or local neurohormonal factors, mechanical stress, intracellular accumulation of toxic molecules, and dysfunctional organelles. Hypertension and aging share common mechanisms that mediate or prolong chronic cell stress, such as endoplasmic reticulum stress and accumulation of protein aggregates, oxidative stress, metabolic mitochondrial stress, DNA damage, stress-induced senescence, and proinflammatory processes. This review discusses common adaptive signaling mechanisms against these stresses including unfolded protein responses, antioxidant response element signaling, autophagy, mitophagy, and mitochondrial fission/fusion, STING (signaling effector stimulator of interferon genes)-mediated responses, and activation of pattern recognition receptors. The main molecular mechanisms by which the vasculature copes with hypertensive and aging stressors are presented and recent advancements in stress-adaptive signaling mechanisms as well as potential therapeutic targets are discussed.
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Estrés del Retículo Endoplásmico/fisiología , Hipertensión/fisiopatología , Estrés Fisiológico/fisiología , Adaptación Fisiológica , Envejecimiento/fisiología , Envejecimiento Prematuro/fisiopatología , Animales , Muerte Celular , Supervivencia Celular , Senescencia Celular , Daño del ADN , Modelos Animales de Enfermedad , Humanos , Hipertensión/etiología , Mitocondrias/metabolismo , Dinámicas Mitocondriales , Estrés Oxidativo , Receptores de Reconocimiento de Patrones/metabolismo , Transducción de Señal , Estrés Mecánico , Respuesta de Proteína DesplegadaRESUMEN
Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminAG609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, ß-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.
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Aminopropionitrilo/farmacocinética , Progeria/tratamiento farmacológico , Proteína-Lisina 6-Oxidasa/antagonistas & inhibidores , Envejecimiento Prematuro/genética , Envejecimiento Prematuro/fisiopatología , Aminopropionitrilo/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Cardiopatías/fisiopatología , Cardiopatías/terapia , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Progeria/metabolismo , Progeria/fisiopatología , Proteína-Lisina 6-Oxidasa/genética , Proteína-Lisina 6-Oxidasa/metabolismo , Rigidez Vascular/efectos de los fármacos , Rigidez Vascular/fisiologíaRESUMEN
Importance: Individuals with mental disorders are at an elevated risk of developing chronic age-related physical diseases. However, it is not clear whether psychopathology is also associated with processes of accelerated aging that precede the onset of age-related disease. Objective: To test the hypothesis that a history of psychopathology is associated with indicators of accelerated aging at midlife. Design, Setting, and Participants: This prospective cohort study was based on the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand. Members were followed up to age 45 years (until April 2019). Data were analyzed from January 6 to December 7, 2020. Exposures: Mental disorders were assessed in 6 diagnostic assessments from ages 18 to 45 years and transformed through confirmatory factor analysis into continuous measures of general psychopathology (p-factor) and dimensions of internalizing, externalizing, and thought disorders (all standardized to a mean [SD] of 100 [15]). Main Outcomes and Measures: Signs of aging (biological pace of aging; declines in sensory, motor, and cognitive functioning; and facial age) were assessed up to age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports. Results: Of the original 1037 cohort participants, 997 were still alive at age 45 years, of whom 938 (94%) were assessed (474 men [50.5%]). Participants who had experienced more psychopathology exhibited a faster pace of biological aging (ß, 0.27; 95% CI, 0.21-0.33; P < .01); experienced more difficulties with hearing (ß, 0.18; 95% CI, 0.12-0.24; P < .01), vision (ß, 0.08; 95% CI, 0.01-0.14; P < .05), balance (ß, 0.20; 95% CI, 0.14-0.26; P < .01), and motor functioning (ß, 0.19; 95% CI, 0.12-0.25; P < .01); experienced more cognitive difficulties (ß, 0.24; 95% CI, 0.18-0.31; P < .01); and were rated as looking older (ß, 0.20; 95% CI, 0.14-0.26; P < .01). Associations persisted after controlling for sex, childhood health indicators, maltreatment, and socioeconomic status and after taking into account being overweight, smoking, use of antipsychotic medication, and the presence of physical disease. Tests of diagnostic specificity revealed that associations were generalizable across externalizing, internalizing, and thought disorders. Conclusions and Relevance: In this cohort study, a history of psychopathology was associated with accelerated aging at midlife, years before the typical onset of age-related diseases. This link is not specific to any particular disorder family but generalizes across disorders. Prevention of psychopathology and monitoring of individuals with mental disorders for signs of accelerated aging may have the potential to reduce health inequalities and extend healthy lives.
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Envejecimiento Prematuro/epidemiología , Envejecimiento Prematuro/fisiopatología , Síntomas Conductuales/epidemiología , Adolescente , Adulto , Cohorte de Nacimiento , Niño , Preescolar , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Adulto JovenRESUMEN
Prenatal hypoxia is among leading causes of progressive brain pathologies in postnatal life. This study aimed to analyze the characteristics of the hippocampal glutamatergic system and behavior of rats in early (2 weeks), adult (3 months) and advanced (18 months) postnatal ontogenesis after exposure to prenatal severe hypoxia (PSH, 180 Torr, 5% O2, 3 h) during the critical period in the formation of the hippocampus (days 14-16 of gestation). We have shown an age-dependent progressive decrease in the hippocampal glutamate levels, a decrease of the neuronal cell number in the CA1 hippocampal region, as well as impairment of spatial long-term memory in the Morris water navigation task. The gradual decrease of glutamate was accompanied by decreased expression of the genes that mediate glutamate metabolism and recycling in the hippocampus. That deficiency apparently correlated with an increase of the metabotropic glutamate receptor type 1 (mGluR1) and synaptophysin expression. Generation of the lipid peroxidation products in the hippocampus of adult rats subjected to prenatal severe hypoxia (PSH rats) was not increased compared to the control animals when tested in a model of glutamate excitotoxicity induced by severe hypoxia. This demonstrates that excessive glutamate sensitivity in PSH rats does not compensate for glutamate deficiency. Our results show a significant contribution of the glutamate system dysfunction to age-associated decrease of this mediator, cognitive decline, and early neuronal loss in PSH rats.
Asunto(s)
Envejecimiento Prematuro/fisiopatología , Región CA1 Hipocampal/metabolismo , Ácido Glutámico/metabolismo , Hipoxia/fisiopatología , Envejecimiento Prematuro/etiología , Envejecimiento Prematuro/patología , Sistema de Transporte de Aminoácidos A/metabolismo , Animales , Animales Recién Nacidos , Región CA1 Hipocampal/patología , Femenino , Hipoxia/complicaciones , Hipoxia/patología , Masculino , Prueba del Laberinto Acuático de Morris/fisiología , Embarazo , Ratas , Receptores AMPA/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Progeroid disorders make up a heterogeneous group of very rare hereditary diseases characterized by clinical signs that often mimic physiological aging in a premature manner. Apart from Hutchinson-Gilford progeria syndrome, one of the best-investigated progeroid disorders, a wide spectrum of other premature aging phenotypes exist, which differ significantly in their clinical presentation and molecular pathogenesis. Next-generation sequencing (NGS)-based approaches have made it feasible to determine the molecular diagnosis in the early stages of a disease. Nevertheless, a broad clinical knowledge on these disorders and their associated symptoms is still fundamental for a comprehensive patient management and for the interpretation of variants of unknown significance from NGS data sets. This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well-known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options.
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Envejecimiento Prematuro/genética , Envejecimiento/genética , Progeria/genética , Envejecimiento/patología , Envejecimiento Prematuro/diagnóstico , Envejecimiento Prematuro/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Patología Molecular , Fenotipo , Progeria/diagnóstico , Progeria/fisiopatologíaRESUMEN
PURPOSE: Xeroderma pigmentosum (XP) is an autosomal recessive disease with defective DNA repair, a markedly increased risk of skin cancer, and premature aging. Reports from North Africa have described thyroid nodules in XP patients, but thyroid nodule prevalence has never been determined in XP patients enrolled in our natural history study at the National Institutes of Health (NIH). METHODS: We performed thyroid ultrasound examinations on all 29 XP patients examined from 2011 to 2019 and assessed nodule malignancy using the Thyroid Imaging Reporting and Data System. Thyroid nodule prevalence was also obtained from comparison cohorts. DNA sequencing was performed on thyroid tissue from XP patients who had surgery for thyroid cancer. RESULTS: Thyroid nodules were identified in 18/29 XP patients (62%). The median age of patients with thyroid nodules in our XP cohort (20 years) was younger than that of three comparison groups: 36 years (California study-208 subjects), 48 years (Korean study-24,757 subjects), and 52 years (NIH-682 research subjects). Multiple (2-4) thyroid nodules were found in 12/18 (67%) of the patients with nodules. Autopsy examination revealed follicular adenomas in 4/8 (50%) additional XP patients. DNA sequencing revealed rare mutations in two other XP patients with papillary thyroid cancer. CONCLUSIONS: XP patients have an increased incidence of thyroid nodules at an early age in comparison to the general population. These finding confirm another premature aging feature of XP.
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Envejecimiento Prematuro/fisiopatología , Nódulo Tiroideo/epidemiología , Xerodermia Pigmentosa/complicaciones , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Maryland/epidemiología , Persona de Mediana Edad , Pronóstico , Nódulo Tiroideo/etiología , Nódulo Tiroideo/patología , Adulto JovenRESUMEN
Hutchinson-Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid LmnaG609G/G609G mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr-/- mice, a commonly used preclinical atherosclerosis model. Ldlr-/-LmnaG609G/G609G mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr-/-LmnaG609G/G609G mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr-/-LmnaG609G/G609G mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr-/-LmnaG609G/G609G mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies.
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Modelos Animales de Enfermedad , Músculo Liso Vascular/metabolismo , Progeria/metabolismo , Envejecimiento Prematuro/metabolismo , Envejecimiento Prematuro/fisiopatología , Animales , Aorta/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/fisiopatología , Femenino , Lamina Tipo A/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Miocitos del Músculo Liso/metabolismo , Lámina Nuclear/metabolismo , Placa Aterosclerótica/metabolismo , Progeria/fisiopatología , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMEN
Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.
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Autofagia/fisiología , Diferenciación Celular/fisiología , Epidermis/fisiología , Envejecimiento de la Piel/fisiología , Pigmentación de la Piel/fisiología , Piel/fisiopatología , Adulto , Envejecimiento Prematuro/metabolismo , Envejecimiento Prematuro/fisiopatología , Autofagia/genética , Diferenciación Celular/genética , Línea Celular , Epidermis/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Queratinocitos/citología , Queratinocitos/fisiología , Lentigo/genética , Lentigo/metabolismo , Lentigo/fisiopatología , Masculino , Persona de Mediana Edad , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Proteínas Quinasas Asociadas a Fase-S/genética , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Piel/metabolismo , Envejecimiento de la Piel/genética , Pigmentación de la Piel/genéticaRESUMEN
Life history theory argues that exposure to early life adversity (ELA) accelerates development, although existing evidence for this varies. We present a meta-analysis and systematic review testing the hypothesis that ELA involving threat (e.g., violence exposure) will be associated with accelerated biological aging across multiple metrics, whereas exposure to deprivation (e.g., neglect, institutional rearing) and low-socioeconomic status (SES) will not. We meta-analyze 54 studies (n = 116,010) examining associations of ELA with pubertal timing and cellular aging (telomere length and DNA methylation age), systematically review 25 studies (n = 3,253) examining ELA and neural markers of accelerated development (cortical thickness and amygdala-prefrontal cortex functional connectivity) and evaluate whether associations of ELA with biological aging vary according to the nature of adversity experienced. ELA overall was associated with accelerated pubertal timing (d = -0.10) and cellular aging (d = -0.21), but these associations varied by adversity type. Moderator analysis revealed that ELA characterized by threat was associated with accelerated pubertal development (d = -0.26) and accelerated cellular aging (d = -0.43), but deprivation and SES were unrelated to accelerated development. Systematic review revealed associations between ELA and accelerated cortical thinning, with threat-related ELA consistently associated with thinning in ventromedial prefrontal cortex, and deprivation and SES associated with thinning in frontoparietal, default, and visual networks. There was no consistent association of ELA with amygdala-PFC connectivity. These findings suggest specificity in the types of early environmental experiences associated with accelerated biological aging and highlight the importance of evaluating how accelerated aging contributes to health disparities and whether this process can be mitigated through early intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Asunto(s)
Experiencias Adversas de la Infancia , Envejecimiento Prematuro/fisiopatología , Envejecimiento/fisiología , Encéfalo/crecimiento & desarrollo , Maltrato a los Niños , Inseguridad Alimentaria , Carencia Psicosocial , Violencia , Adolescente , Biomarcadores , Senescencia Celular/fisiología , Niño , Metilación de ADN , Humanos , Pubertad/fisiología , Clase SocialRESUMEN
The present study aimed to explore the relationship between electrocardiographic (ECG) and pulse wave analysis variables in patients with hypertension (HT) and high normal blood pressure (HNBP). A total of 56 consecutive, middle-aged hypertensive and HNBP patients underwent pulse wave analysis and standard 12-lead ECG. Pulse wave velocity (PWV), heart rate, intrinsic heart rate (IHR), P wave and QT interval durations were as follows: 7.26 ± 0.69 m/s, 69 ± 11 beats/minute, 91 ± 3 beats/minute, 105 ± 22 mm and 409 ± 64 mm, respectively. Significant correlations were obtained between PWV and IHR and P wave duration, respectively, between early vascular aging (EVA) and P wave and QT interval durations, respectively. Linear regression analysis revealed significant associations between ECG and pulse wave analysis variables but multiple regression analysis revealed only IHR as an independent predictor of PWV, even after adjusting for blood pressure variables and therapy. Receiver-operating characteristic (ROC) curve analysis revealed P wave duration (area under curve (AUC) = 0.731; 95% CI: 0.569-0.893) as a predictor of pathological PWV, and P wave and QT interval durations were found as sensitive and specific predictors of EVA. ECG provides information about PWV and EVA in patients with HT and HNBP. IHR and P wave durations are independent predictors of PWV, and P wave and QT interval may predict EVA.
Asunto(s)
Envejecimiento Prematuro/fisiopatología , Electrocardiografía , Frecuencia Cardíaca , Hipertensión/fisiopatología , Análisis de la Onda del Pulso , Enfermedades Vasculares/fisiopatología , Adulto , Presión Sanguínea/fisiología , Estudios Transversales , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/diagnóstico , Masculino , Persona de Mediana Edad , Valores de Referencia , Rigidez Vascular/fisiologíaRESUMEN
Hypertension has been described as a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated and exacerbated in hypertension. Nonetheless, the precise mechanisms that underlie the aged phenotype of arteries from hypertensive patients and animals remain elusive. Classically, the aged phenotype is the buildup of cellular debris and dysfunctional organelles. One means by which this can occur is insufficient degradation and cellular recycling. Mitophagy is the selective catabolism of damaged mitochondria. Mitochondria are organelles that contribute importantly to the determination of cellular age via their production of reactive oxygen species (ROS; Harman's free radical theory of aging). Therefore, the accumulation of dysfunctional and ROS-producing mitochondria could contribute to the acceleration of vascular age in hypertension. This review will address and critically evaluate the current literature on mitophagy in vascular physiology and hypertension.
Asunto(s)
Envejecimiento Prematuro/fisiopatología , Células Endoteliales/metabolismo , Hipertensión/fisiopatología , Mitofagia , Miocitos del Músculo Liso/metabolismo , Envejecimiento Prematuro/metabolismo , Animales , Autofagia/fisiología , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatología , Humanos , Hipertensión/metabolismo , Mitocondrias/metabolismo , Músculo Liso Vascular , Especies Reactivas de Oxígeno/metabolismoRESUMEN
We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Genome-wide total RNA-seq was performed and the expression patterns of protein-coding genes and non-coding RNAs were compared between hearts from naturally aging mice, mice with cardiac-specific deficiency of a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity and mice with reduced telomere length. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. Additionally, these mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Our data demonstrate very limited similarities between the transcriptomes of all our murine aging models and question their reliability to study human cardiovascular senescence.
Asunto(s)
Envejecimiento Prematuro/genética , Envejecimiento/genética , Corazón/crecimiento & desarrollo , Miocardio/metabolismo , Proteínas/genética , Envejecimiento/metabolismo , Envejecimiento Prematuro/metabolismo , Envejecimiento Prematuro/fisiopatología , Animales , Femenino , Humanos , Ictiosis Lamelar/genética , Ictiosis Lamelar/metabolismo , Ictiosis Lamelar/fisiopatología , Masculino , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas/metabolismo , Telómero/genética , Telómero/metabolismo , Acortamiento del Telómero , TranscriptomaRESUMEN
Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)-kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23-klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.