Acortamiento de telómeros en enfermedades neurodegenerativas: implicaciones terapéuticas / Telomere attrition in neurodegenerative disorders: therapeutic implications

Introducción: Varias enfermedades neurodegenerativas están asociadas a la ocurrencia de acortamiento de los telómeros, y los convierten en biomarcadores y dianas terapéuticas potenciales. Objetivo: Reflejar la relevancia del acortamiento de los telómeros para enfermedades neurodegenerativas, y destacar sus implicaciones Material y métodos: Se realizó una revisión bibliográfica durante los meses de septiembre de 2019 a enero de 2020. Fueron consultadas bases de datos de referencia, con el uso de descriptores y operadores booleanos. La estrategia de búsqueda avanzada para la selección de los artículos fue empleada, teniendo en cuenta la calidad metodológica o validez de los estudios. Desarrollo: Fueron identificadas evidencias sólidas de asociación entre el acortamiento de los telómeros y las enfermedades de Alzheimer y Huntington, que sugieren un papel relevante de la biología de los telómeros en la fisiopatología de estas enfermedades. Las evidencias disponibles hasta el momento no permiten establecer la relevancia de la biología de los telómeros en la fisiopatología de la Enfermedad de Parkinson o de la esclerosis lateral amiotrófica. Se obtuvieron evidencias de la utilidad de terapias orientadas a la prevención del acortamiento de los telómeros para el tratamiento de enfermedades neurodegenerativas. Conclusiones: El acortamiento de los telómeros es de relevancia fisiopatológica y clínica para las enfermedades de Alzheimer y Huntington, mientras que existen evidencias insuficientes para establecer su importancia en la Enfermedad de Parkinson y la esclerosis lateral amiotrófica. El uso de estrategias para estimular la actividad de la telomerasa tiene potenciales aplicaciones terapéuticas en el contexto de enfermedades neurodegenerativas(AU)

Introduction: Several neurodegenerative disorders are associated with telomere attrition, turning telomeres into potential biomarkers and potential therapeutic targets. Objective: To assess the relevance of telomere attrition for neurodegenerative disorders, highlighting its therapeutic implications. Material and methods: A literature review was carried out from September 2019 to January 2020. Several databases were searched by using descriptors and Boolean operators. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies. Results: Strong evidence for an association between telomere attrition and Alzheimer and Huntington diseases was obtained, suggesting a potential importance of telomere biology in the physiopathology of these diseases. Current evidence does not allow establishing the relevance of telomere attrition in the physiopathology of Parkinson´s disease or Amyotrophic Lateral Sclerosis. Evidence was obtained for the usefulness of therapies for the prevention of telomere attrition in the treatment of neurodegenerative disorders. Conclusions: Telomere attrition has physiopathological and clinical relevance in Alzheimer´s and Huntington´s diseases, though current evidence is not enough to establish its role in Parkinson's disease and Amyotrophic Lateral Sclerosis. Strategies that enhance telomerase activity have therapeutic potential in the context of neurodegenerative disorders(AU)

Telomere length and childhood trauma in Colombians with depressive symptoms

Objective: Childhood trauma and telomere length (TL) are important risk factors for major depressive disorder. We examined whether there was an association between childhood trauma and TL in a sample of Colombians who were assessed for depressive symptoms. Methods: We applied the Center for Epidemiologic Studies Depression scale, the Patient Health Questionnaire-9, the Hospital Anxiety and Depression scale and the Childhood Trauma Questionnaire to 92 Colombian subjects (mean age = 21). TL was measured with quantitative PCR. Spearman's correlation coefficient (rs) was used to analyze the relationship between childhood trauma scores and TL. Results: We found a significant correlation between TL and sexual abuse scores (rs = 0.428, p = 0.002) in individuals with higher depressive symptom scores. Conclusion: This is the first report of a significant association between TL and sexual abuse in a Latin American sample and provides additional evidence about the role of childhood trauma and TL in neuropsychiatric disorders.

Telomere length and hTERT in mania and subsequent remission

Objective: The findings of telomere length (TL) studies in bipolar disorder (BD) are controversial. The aim of the present study was to detect TL, human telomerase reverse transcriptase (hTERT), and brain derived neurotrophic factor (BDNF) in severe mania and subsequent remission. Methods: Twenty-one medication-free male patients and 20 age and gender matched controls were recruited. The patients were followed in the inpatient clinic, and comparisons were made between the same patients in their remission state and controls. Patients received lithium plus antipsychotics during the follow-up period. Quantitative real-time polymerase chain reaction was performed to verify leukocyte TL and whole blood hTERT gene expression levels. Serum BDNF levels were verified by enzyme-linked immunosorbent assay (ELISA). Results: Compared to controls, manic patients presented shorter telomeres (p < 0.001) whose length increased with treatment (p = 0.001). Patients in the late stages showed shorter TL than those in the early stages and controls (p < 0.001). hTERT gene expression levels were up-regulated in mania and remission compared to controls (p = 0.03 and p = 0.01, respectively). BDNF changes did not reach statistically significant levels. Conclusions: TL and hTERT gene expression might reflect a novel aspect of BD pathophysiology and TL might represent a novel biomarker for BD staging.

Telomere length analysis in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia Binet A

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic clinical entity characterized by the proliferation of monoclonal B cells not meeting the diagnosis criteria for chronic lymphocytic leukemia (CLL). MBL may precede the development of CLL, but the molecular mechanisms responsible for disease progression and evolution are not completely known. Telomeres are usually short in CLL and their attrition may contribute to disease evolution. Here, we determined the telomere lengths of CD5+CD19+ cells in MBL, CLL, and healthy volunteers. Twenty-one CLL patients, 11 subjects with high-count MBL, and 6 with low-count MBL were enrolled. Two hundred and sixty-one healthy volunteers aged 0 to 88 years were studied as controls. After diagnosis confirmation, a flow cytometry CD19+CD5+-based cell sorting was performed for the study groups. Telomere length was determined by qPCR. Telomere length was similar in the 3 study groups but shorter in these groups compared to normal age-matched subjects that had been enrolled in a previous study from our group. These findings suggest that telomere shortening is an early event in CLL leukemogenesis.

Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease

Objective: Bipolar disorder (BD) has been associated with increased rates of age-related diseases, such as type II diabetes, metabolic syndrome, osteoporosis, and cardiovascular disorders. Several biological findings have been associated with age-related disorders, including increased oxidative stress, inflammation, and telomere shortening. The objective of this study was to compare telomere length among participants with BD at early and late stages and age- and gender-matched healthy controls. Methods: Twenty-six euthymic subjects with BD and 34 healthy controls were recruited. Genomic DNA was extracted from peripheral blood and mean telomere length was measured using real-time quantitative polymerase chain reaction. Results: Telomere length was significantly shorter in both the early and late subgroups of BD subjects when compared to the respective controls (p = 0.002 and p = 0.005, respectively). The sample size prevented additional subgroup analyses, including potential effects of medication, smoking status, and lifestyle. Conclusion: This study is concordant with previous evidence of telomere shortening in BD, in both early and late stages of the disorder, and supports the notion of accelerated aging in BD.

The reduction of serum aminotransferase levels is proportional to the decline of the glomerular filtration rate in patients with chronic kidney disease

OBJECTIVE: This study sought to determine the serum aminotransferase levels of patients with predialysis chronic kidney disease and establish their relationships with serum creatinine levels and glomerular filtration rate. METHODS: Patients with chronic kidney disease were evaluated between September 2011 and May 2012. Aminotransferase and creatinine serum levels were measured using an automated kinetic method, and glomerular filtration rates were estimated using the Cockroft-Gault and Modification of Diet in Renal Disease formulas to classify patients into chronic kidney disease stages. RESULTS: Exactly 142 patients were evaluated (mean age: 64±16 years). The mean creatinine serum level and glomerular filtration rate were 3.3±1.2 mg/dL and 29.1±13 mL/min/1.73 m2, respectively. Patients were distributed according to their chronic kidney disease stages as follows: 3 (2.1%) patients were Stage 2; 54 (38%) were Stage 3; 70 (49.3%) were Stage 4; and 15 (10.5%) were Stage 5. The mean aspartate aminotransferase and alanine aminotransferase serum levels showed a reduction in proportion to the increase in creatinine levels (p=0.001 and p=0.05, respectively) and the decrease in glomerular filtration rate (p=0.007 and p=0.028, respectively). Alanine aminotransferase and aspartate aminotransferase serum levels tended to be higher among patients classified as stage 2 or 3 compared with those classified as stage 4 or 5 (p=0.08 and p=0.06, respectively). CONCLUSIONS: The aspartate aminotransferase and alanine aminotransferase serum levels of patients with predialysis chronic kidney disease decreased in proportion to the progression of the disease; they were negatively correlated with creatinine levels and directly correlated with glomerular filtration rate. .