Eotaxin-1/CCL11 promotes cellular senescence in human-derived fibroblasts through pro-oxidant and pro-inflammatory pathways.

Introduction: Eotaxin-1/CCL11 is a pivotal chemokine crucial for eosinophil homing to the lungs of asthmatic patients. Recent studies also suggest that CCL11 is involved in the aging process, as it is upregulated in elderly, and correlated with shorter telomere length in leukocytes from asthmatic children. Despite its potential pro-aging effects, the precise contribution of CCL11 and the underlying mechanisms involved in the promotion of cellular senescence remains unclear. Therefore, the primary goal of this study was to explore the role of CCL11 on senescence development and the signaling pathways activated by this chemokine in lung fibroblasts. Methods: To investigate the targets potentially modulated by CCL11, we performed an in silico analysis using PseudoCell. We validated in vitro the activation of these targets in the human lung fibroblast cell line MRC-5 following rhCCL11 exposure. Finally, we performed differential gene expression analysis in human airway epithelial cells of asthmatic patients to assess CCL11 signaling and activation of additional senescent markers. Results: Our study revealed that eotaxin-1/CCL11 promote reactive oxygen secretion (ROS) production in lung fibroblasts, accompanied by increased activation of the DNA damage response (DDR) and p-TP53 and γH2AX. These modifications were accompanied by cellular senescence promotion and increased secretion of senescence-associated secretory phenotype inflammatory cytokines IL-6 and IL-8. Furthermore, our data show that airway epithelial lung cells from atopic asthmatic patients overexpress CCL11 along with aging markers such as CDKN2A (p16INK4a) and SERPINE1. Discussion: These findings provide new insights into the mechanisms underlying the pro-aging effects of CCL11 in the lungs of asthmatic patients. Understanding the role of CCL11 on senescence development may have important implications for the treatment of age-related lung diseases, such as asthma.

Síndrome de Progeria Hutchinson-Gilford

El Síndrome de Progeria de Hutchinson- Gilford es una enfermedad que se caracteriza por el envejecimiento prematuro en niños, debido a una mutación en el gen de Lámina tipo A involucrado en la mitosis celular. En el presente trabajo, con el objetivo de dar difusión al conocimiento de esta enfermedad, se señalan los procesos involucrados en su desarrollo, así como los avances científicos y el alcance de nuevas ventanas terapéuticas. La revisión se realizó consultando artículos en español e inglés empleando los motores de búsqueda Pubmed y Google Académico. La actualización del personal de salud sobre las enfermedades genéticas congénitas es de vital importancia para mejorar su detección, atención y manejo.

Hutchinson-Gilford Progeria Syndrome is a disease characterized by premature aging in children, due to a mutation in the Lamina type A, gene involved in cellular mitosis. In the present work, with the aim of spreading the knowledge of this disease, the processes involved in its development, the scientific advances, and the scope of new therapeutic treatments were summarized. The review was carried out by consulting articles in Spanish and English using the Pubmed and Google Academic search engines. The updating of health personnel on congenital genetic diseases is of vital importance to improve their detection, care and management.

A Síndrome de Hutchinson-Gilford Progeria é uma doença caracterizada pelo envelhecimento prematuro em crianças, devido a uma mutação no gene lamina tipo A envolvido na mitose celular. No presente trabalho, como objetivo de divulgar o conhecimento desta doença, são indicados os processos envolvidos no seu desenvolvimento, bem como os avanços científicos e o âmbito de novas janelas terapêuticas. A análise foi realizada através da consulta de artigos em espanhol e inglês utilizando os motores de busca pubmed e Google Scholar. A atualização do pessoal de saúde sobre doenças genéticas congénitas é de importância vital para melhorar a sua deteção, cuidados e gestão.

Efectos patogénicos de los productos finales de glicación avanzada en el proceso de envejecimiento-enfermedad

RESUMEN Los productos finales de glicación avanzada -conocidos como productos de la reacción de Maillard-, formados por glicación directa no enzimática de azúcares reductores con grupos amino libres de proteínas, provocan cambios estructurales y funcionales en las mismas, cuya producción endógena es incrementada con la edad, el estrés oxidativo, así como por factores externos, provocando envejecimiento prematuro y enfermedades degenerativas. El objetivo de la revisión fue obtener una visión actualizada de los avances en investigaciones sobre los efectos de productos finales de glicación avanzada y su interrelación con el estrés oxidativo en el proceso de envejecimiento-enfermedad. En la revisión se consideraron los principales artículos más recientes sobre el tema en las bases de datos PubMed, SciELO, ClinicalKey y LILACS. Se evidencian los efectos patogénicos de los productos finales de glicación avanzada que contribuyen al estrés oxidativo y a la inflamación, de forma especial en el envejecimiento prematuro, diabetes, enfermedad cardiovascular y en otras enfermedades neurodegenerativas, como un aspecto preocupante en el tema del envejecimiento poblacional y su enorme costo para la sociedad futura.

ABSTRACT The advanced glycation end-products-known like products of the Maillard reaction-formed by a direct non-enzymatic glycation of reducing sugars with amino groups free of proteins, cause structural and functional changes in them, whose endogenous production is incremented with age, oxidative stress, as well as by external factors, causing premature aging and degenerative diseases. The objective of the review objective was to obtain an updated view of the advances in research on the effects of the advanced glycation end products and their interrelation with the oxidative stress in the aging-disease process. In the review the authors considered the most recent leading articles on the topic published in the databases PubMed, SciELO, ClinicalKey and LILACS. The pathogenic effects of the advanced glycation end products that contribute to oxidative stress and inflammation are evidenced, especially in premature aging, diabetes, cardiovascular disease and other neurodegenerative diseases, as a worrying aspect in the issue of population aging and its enormous cost for future society.

Hutchinson-Gilford Progeria Syndrome: Clinical and Molecular Characterization.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare congenital disease caused by mutations in the LMNA gene. Children with HGPS are phenotypically characterized by lipodystrophy, short height, low body weight, scleroderma, reduced joint mobility, osteolysis, senile facial features, and cardiovascular compromise that usually lead to death. We aimed to describe the case of a patient who reached above-average age expectancy for children with HGPS in Latin America and describe the clinical and molecular characteristics of the patient. A 14-year-old female patient was presented with progeria-compatible phenotypic characteristics. HGPS was confirmed via LMNA gene sequencing that detected a heterozygous c.1824C>T (p.Gly608Gly) mutation. The primary aim is to describe the HGPS case, the molecular gene mutation finding, and make a short review of the limited available treatment options for children with HGPS. Such as the farnesyl transferase inhibitors in conjunction with other pharmacological therapies that have insinuated improvement in health, and survival rate.

Immunosenescence profile and expression of the aging biomarker (p16INK4a) in testicular cancer survivors treated with chemotherapy.

BACKGROUND: Cytotoxic chemotherapy can cure advanced germ cell tumors. Nevertheless, cancer treatment may induce cellular senescence and accelerate molecular aging. The aging process implies an increase of cells expressing p16INK4a and changes in lymphocyte subpopulations. Our aim was to study the potential induction of premature immunosenescence in testicular cancer survivors (TCS) exposed to chemotherapy. METHODS: Case-control exploratory study of TCS treated with chemotherapy (≥3 BEP cycles, disease-free ≥3 months) compared with age matched healthy controls. Peripheral blood mononuclear cells were isolated, and lymphocyte subpopulations were analyzed by flow cytometry. CDKN2A/p16INK4a expression in T cells was measured using qPCR. The percentage of lymphocyte subpopulations and the CDKN2A/p16INK4a expression in TCS were compared with the control group using the Wilcoxon signed-rank test. RESULTS: We included 16 cases and 16 controls. The median age was 27 years (minimum 24, maximum 54) and the median time on surveillance was 26.5 months (minimum 3, maximum192). TCS had a lower percentage of total T cells and CD4+ T cells in total lymphocytes. Among the CD4+ T lymphocytes, TCS had less naïve CD4+ and increased memory CD4+ cells. Within the CD8+ T lymphocytes, TCS exhibited a decrease in the percentage of naïve cells and an increase in CD8 + CD45RA + CD57+ cells. TCS also exhibited decreased memory CD19+ B cells compared to the controls. The relative expression of CDKN2A/p16INK4a in T cells was increased in TCS (mean 1.54; 95% CI of the mean: 1.074-2.005; p = 0.048). CONCLUSION: In this exploratory study, TCS showed increased expression of CDKN2A/p16INK4a and a lymphocyte phenotype that has been associated with immunosenescence. Further studies are warranted to define the clinical implications of these alterations in TCS.

Metabolomic profiling suggests systemic signatures of premature aging induced by Hutchinson-Gilford progeria syndrome.

INTRODUCTION: Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder. HGPS children present a high incidence of cardiovascular complications along with altered metabolic processes and an accelerated aging process. No metabolic biomarker is known and the mechanisms underlying premature aging are not fully understood. OBJECTIVES: The present work aims to evaluate the metabolic alterations in HGPS using high resolution mass spectrometry. METHODS: The present study analyzed plasma from six HGPS patients of both sexes (7.7 ± 1.4 years old; mean ± SD) and eight controls (8.6 ± 2.3 years old) by LC-MS/MS in high-resolution non-targeted metabolomics (Q-Exactive Plus). Targeted metabolomics was used to validate some of the metabolites identified by the non-targeted method in a triple quadrupole (TSQ-Quantiva). RESULTS: We found several endogenous metabolites with statistical differences between control and HGPS children. Multivariate statistical analysis showed a clear separation between groups. Potential novel metabolic biomarkers were identified using the multivariate area under ROC curve (AUROC) based analysis, showing an AUC value higher than 0.80 using only two metabolites, and tending to 1.00 when increasing the number of metabolites in the AUROC model. Taken together, changed metabolic pathways involve sphingolipids, amino acids, and oxidation of fatty acids, among others. CONCLUSION: Our data show significant alterations in cellular energy use and availability, in signal transduction, and lipid metabolites, adding new insights on metabolic alterations associated with premature aging and suggesting novel putative biomarkers.

Sarcopenia-related parameters in adults with Down syndrome: A cross-sectional exploratory study.

BACKGROUND: People with Down syndrome (DS) experience premature aging. Whether this accelerated aging also involves early declines in muscle mass, strength and physical performance is presently unclear. The present study investigated the prevalence of sarcopenia parameters in adults with DS. In addition, the relationship between well-established muscle mass indexes and a set of body composition, functional, biological, and clinical parameters was explored. METHODS: One hundred-five adults with DS participated in the study. Demographic, clinical, anthropometric, and functional parameters were assessed. Lean body mass (LBM) was estimated using bioelectrical impedance analysis. Bone mineral density (BMD) of the hip and the spine was measured through dual X-ray absorptiometry. For the analysis, participants were categorized into two subgroups (i.e., low and high) for each LBM-related measurement (i.e., crude LBM, LBM to body mass index ratio, and skeletal muscle index) according to their median values. RESULTS: The mean age of participants was 38.4 ±â€¯12.1 years, with 43 men (41%). Muscle mass, handgrip strength, and gait speed were lower than established cutoffs for sarcopenia. All muscle mass indexes were negatively correlated with age. However, only crude LBM and the skeletal muscle index were correlated with a set of anthropometric parameters and BMD. CONCLUSION: Findings from this exploratory study indicate that adults with DS show muscle mass indexes and physical performance levels similar to or lower than older adults with sarcopenia. The assessment of muscle mass and functional status should therefore be included in the routine evaluation of this population starting at young age.

Síndrome de Werner: a propósito de un caso probable / Werner's syndrome, about a probable case

Resumen: el síndrome de Werner es una patología poco frecuente, de herencia autosómica recesiva, caracterizado por signos de envejecimiento prematuro y tendencia a desarrollar tumores malignos. El diagnóstico de esta enfermedad es principalmente clínico, con hallazgos predominantes como talla baja y envejecimiento precoz. En este artículo se presenta el caso de un paciente de 49 años de edad, con signos tempranos de envejecimiento desde los 15 años y ateroesclerosis temprana asociada, que lo lleva a amputación quirúrgica de extremidad inferior derecha. De acuerdo con los criterios diagnósticos del síndrome de Werner este es el primer caso probable en el suroccidente colombiano. (AU)

Abstract: Werner syndrome is a rare, autosomal recessive pathology, characterized by signs of premature aging and tendency to develop malignant tumors. The diagnosis is principally clinical, with predominating findings as short stature and precocious aging. In this article, it's presented the case of a 49-year-old patient with early signs of aging from the age of 15 years and associated early atherosclerosis that leads to the right lower limb surgical amputation. According to the diagnostic criteria of Werner syndrome, this is the first probable case in the Colombian Southwest. (AU)

Functional lung rejuvenation in obese patients after bariatric surgery / Rejuvenescimento pulmonar funcional em pacientes obesos após cirurgia bariátrica

Summary Objective: To determine the lung age (LA) in obese people before and after bariatric surgery, compare the LA with the chronological age (CA) before and after the peration, and verify whether there was a functional pulmonary rejuvenation after it. Methods: A prospective longitudinal study including 43 morbidly obese patients who underwent bariatric surgery. The patients underwent clinical and spirometric evaluation in two stages, before and after the surgery. In both stages, LA, CA and spirometric variables were measured. Results: A significant improvement in the spirometric variables (FVC; FEV1; and FEV1/FVC ratio) was found after the operation (p≤ 0.0001). Comparing the LA before (50.93±13.36 years) and after the surgery (39.02±12.95 years), there was an important reduction of 11.90±9.12 years (95CI:9.10-14.71; p≤0.0001) in LA after surgery. The difference between LA and CA before surgery was 12.20± 11.71 years (95CI:8.60-15.81) with significant difference (p≤0.0001), and the difference between LA and CA after surgery was -1.95±11.83 years (95CI: -5.59-1.69) with no significant difference (p≤0.28). Regarding LA, we observed a pulmonary aging of 12.20±11.71 years before the surgery and a pulmonary rejuvenation of 11.90±9.12 years after it. Conclusion: Morbid obesity is responsible for early damage and functional accelerated pulmonary aging. After the correction of the body weight by surgery, there is a functional pulmonary rejuvenation demonstrated by the normalization of LA in relation to CA.

Resumo Objetivo: determinar a idade pulmonar (IP) em obesos no pré e pós-operatório de cirurgia bariátrica, comparar a IP com a idade cronológica (IC) antes e após a cirurgia, e verificar se houve rejuvenescimento pulmonar funcional após a cirurgia. Métodos: estudo longitudinal, prospectivo, envolvendo 43 pacientes obesos mórbidos submetidos à cirurgia bariátrica. Os pacientes foram submetidos à avaliação clínica e espirométrica antes e após a cirurgia, sendo determinadas IP, IC e variáveis espirométricas. Resultados: observou-se melhora significativa nas variáveis espirométricas (VEF1, CVF e razão VEF1/CVF) após a cirurgia (p≤0,0001). Comparando a IP antes (50,93±13,36 anos) e após a cirurgia (39,02±12,95 anos), observou-se redução significativa da IP no pós-operatório de 11,90±9,12 anos (IC 95% 9,10-14,71; p≤0,0001). A diferença entre IP e IC no pré-operatório foi de 12,20±11,71 anos (IC 95% 8,60-15,81) com diferença significativa (p≤0,0001). A diferença entre IP e IC no pós-operatório foi de -1,95±11,83 anos (IC 95% -5,59-1,69), sem apresentar diferença significativa (p≤0,28). Quando comparamos a IP antes e após a cirurgia, observamos um envelhecimento pulmonar de 12,20±11,71 anos antes e um rejuvenescimento pulmonar de 11,90±9,12 anos após a cirurgia. Conclusão: a obesidade mórbida causa dano precoce e envelhecimento pulmonar funcional acelerado. Após a correção do peso corpóreo pela cirurgia, há um rejuvenescimento pulmonar funcional, mostrado pela normalização da IP em relação à IC.

Progeria:: enfermedad coronaria e insuficiencia cardíaca en paciente joven

La progeria es una enfermedad caracterizada por el envejecimiento prematuro en los primeros años de vida. El diagnóstico es fundamentalmente clínico y la supervivencia más allá de la adolescencia es inusual. En más del 80% de los casos la muerte se debe a complicaciones cardiovasculares. Se presenta el caso clínico de un paciente masculino de 26 años de edad, diagnosticado de progeria, que cursa internación por infarto agudo de miocardio ínfero-latero-dorsal con compromiso eléctrico y hemodinámico del ventrículo derecho. En resumen, los pacientes con progeria suelen presentarse con enfermedad coronaria a edades tempranas. Los registros de estos grupos de pacientes informan que la gran mayoría fallecen durante la adolescencia a causa de enfermedad coronaria. Mostramos un caso de un paciente joven con enfermedad coronaria severa que debuta con un infarto agudo de miocardio con resolución favorable.

Progeria: coronary artery disease and heart failure in a young patient Progeria is a disease characterized by premature aging in the first years of life. The diagnosis is essentially clinical and survival beyond adolescence is unusual. In over 80% of cases death due to cardiovascular complications. The case report of a male patient of 26 years old, diagnosed with progeria, coursing hospitalization for acute inferio-latero-dorsal myocardial infarction with electric and hemodynamic right ventricular involvement is presented. In summary, patients with progeria usually appear with coronary disease at early ages. The records of these groups of patients report that the vast majority die during adolescence due to coronary disease. We report a case of a young patient with severe coronary artery disease who presents with an acute myocardial infarction with favorable resolution.

Progeria: doença arterial coronariana e insuficiência cardíaca em um paciente jovem Progeria é uma doença caracterizada pelo envelhecimento prematuro nos primeiros anos de vida. O diagnóstico é essencialmente clínico e sobrevivência além da adolescência é incomum. Em mais de 80% dos casos de morte devido a complicações cardiovasculares. É apresentado um caso clínico de um paciente do sexo masculino de 26 anos, diagnosticado com progeria, correndo hospitalização por infarto agudo do miocárdico ínfero-látero-dorsal com comprometimento elétrico e hemodinâmico do ventrículo direito. Em resumo, os pacientes com progeria geralmente aparecem com doença coronariana em idades precoces. Os registros desses grupos de pacientes relatam que a grande maioria morre durante a adolescência devido a doença coronária. Relatamos o caso de um jovem paciente com doença arterial coronariana grave, que debuta com um infarto agudo do miocárdio com resolução favorável.

Progeria:: enfermedad coronaria e insuficiencia cardíaca en paciente joven

La progeria es una enfermedad caracterizada por el envejecimiento prematuro en los primeros años de vida. El diagnóstico es fundamentalmente clínico y la supervivencia más allá de la adolescencia es inusual. En más del 80% de los casos la muerte se debe a complicaciones cardiovasculares. Se presenta el caso clínico de un paciente masculino de 26 años de edad, diagnosticado de progeria, que cursa internación por infarto agudo de miocardio ínfero-latero-dorsal con compromiso eléctrico y hemodinámico del ventrículo derecho. En resumen, los pacientes con progeria suelen presentarse con enfermedad coronaria a edades tempranas. Los registros de estos grupos de pacientes informan que la gran mayoría fallecen durante la adolescencia a causa de enfermedad coronaria. Mostramos un caso de un paciente joven con enfermedad coronaria severa que debuta con un infarto agudo de miocardio con resolución favorable.(AU)

Progeria: coronary artery disease and heart failure in a young patient Progeria is a disease characterized by premature aging in the first years of life. The diagnosis is essentially clinical and survival beyond adolescence is unusual. In over 80% of cases death due to cardiovascular complications. The case report of a male patient of 26 years old, diagnosed with progeria, coursing hospitalization for acute inferio-latero-dorsal myocardial infarction with electric and hemodynamic right ventricular involvement is presented. In summary, patients with progeria usually appear with coronary disease at early ages. The records of these groups of patients report that the vast majority die during adolescence due to coronary disease. We report a case of a young patient with severe coronary artery disease who presents with an acute myocardial infarction with favorable resolution.(AU)

Progeria: doenþa arterial coronariana e insuficiÛncia cardíaca em um paciente jovem Progeria é uma doenþa caracterizada pelo envelhecimento prematuro nos primeiros anos de vida. O diagnóstico é essencialmente clínico e sobrevivÛncia além da adolescÛncia é incomum. Em mais de 80% dos casos de morte devido a complicaþ§es cardiovasculares. E apresentado um caso clínico de um paciente do sexo masculino de 26 anos, diagnosticado com progeria, correndo hospitalizaþÒo por infarto agudo do miocárdico ínfero-látero-dorsal com comprometimento elétrico e hemodinÔmico do ventrículo direito. Em resumo, os pacientes com progeria geralmente aparecem com doenþa coronariana em idades precoces. Os registros desses grupos de pacientes relatam que a grande maioria morre durante a adolescÛncia devido a doenþa coronária. Relatamos o caso de um jovem paciente com doenþa arterial coronariana grave, que debuta com um infarto agudo do miocárdio com resoluþÒo favorável.(AU)

Síndrome de Cockayne: informe de dos casos clínicos y revisión de la literatura / Cockayne syndrome: report of two clinical cases and review of the literature

Introducción: el síndrome de Cockayne es un trastorno genético autosómico recesivo, caracterizado por detención del crecimiento, retraso del desarrollo, envejecimiento prematuro y fotosensibilidad. La prevalencia es de 1/100.000 nacidos vivos; es más frecuente en el sexo masculino con una relación 3:1. Desde el punto de vista genético se han descrito dos grupos: A: mutación del gen CSA (CKN1, ERCC8) en el cromosoma 5q12; B: mutación del gen CSB (ERCC6) en el cromosoma 10q11. Presentamos dos casos diagnosticados sobre bases clínicas pero en los que carecemos de estudios genéticos. Caso 1. Niña escolar producto de padres consanguíneos quien desde el nacimiento presenta hipotonía e hipomotilidad, retardo global del desarrollo, déficit pondoestatural, cara envejecida, rasgos dismórficos, fotosensibilidad, espasticidad e hipoacusia neurosensorial y hallazgos tomográficos característicos del síndrome. Actualmente está en rehabilitación. Caso 2. Adolescente de sexo femenino con crisis convulsivas desde los dos meses, poco progreso en el desarrollo psicomotor y pondoestatural, rasgos dismórficos y cara envejecida, hipoacusia neurosensorial bilateral, distonías repetitivas; en varias oportunidades sufrió procesos infecciosos respiratorios uno de los cuales, con neumonía bilateral, la llevó a la muerte a los 14 años. Conclusión: se presentan estos casos y se revisa la literatura para llamar la atención sobre este síndrome de modo que se lo sospeche tempranamente en pacientes con retardo del desarrollo psicomotor, envejecimiento prematuro y fotosensibilidad. El diagnóstico temprano es la base para brindar consejería genética a los padres.

Introduction: Cockayne syndrome is an autosomal, recessive genetic disorder, characterized by poor growth, development impairment, premature aging, and photosensitivity. Prevalence is 1/100.000 live births, and it is more frequent in males with a ratio of 3:1. From the genetic point of view two groups have been described: Group A: mutation of the CSA gene (CKN1, ERCC8) on chromosome 5q12. Group B: mutation of the CBS gene (ERCC6) on chromosome 10q11. We report two cases that were diagnosed solely on clinical bases because no genetic studies were available. Case 1. A school-girl, born from consanguineous parents. Since birth she has suffered from hypotonia and hypomotility. She has development delay, low weight and height gain, aged face, dysmorphic features, photosensitivity, spasticity, sensorineural hearing loss, and typical findings in the CT scan. She is currently on rehabilitation. Case 2. A female teenager with seizures from the age of two months; she made slow progress in psychomotor development, and had low weight and height gain. Her features were dysmorphic and her face aged. She had bilateral sensorineural hearing loss, and repeated dystonias. She suffered from repeated respiratory infections and died, aged 14, from respiratory failure secondary to bilateral pneumonia. Conclusion: We report these two cases and a review of the literature in order to attract attention to Cockayne syndrome so that early diagnoses can be made in children with psychomotor development delay, premature aging and photosensitivity. Early diagnoses are the basis for genetic counseling.