ABSTRACT
Aging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process. Modifications in transcriptional networks and chromatin structure might be central to age-related functional decline. A prevalent feature described during aging is the overall reduction in heterochromatin, specifically marked by the loss of repressive histone modification, Histone 3 lysine 9 trimethylation (H3K9me3). However, the role of H3K9me3 in aging, especially in mammals, remains unclear. Here we show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit reduced lifespan, lower body weight, increased frailty index, multi-organ degeneration, transcriptional changes with significant upregulation of transposable elements, and accelerated epigenetic age. Our data strongly supports the concept that the loss of epigenetic information directly drives the aging process. These findings reveal the importance of epigenetic regulation in aging and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline. Understanding the molecular mechanisms underlying the process of aging will be crucial for developing novel therapeutic strategies that can delay the onset of age-associated diseases and preserve human health at old age specially in rapidly aging societies.
ABSTRACT
We have generated using CRISPR/Cas9 technology a partially humanized mouse model of the neurometabolic disease phenylketonuria (PKU), carrying the highly prevalent PAH variant c.1066-11G>A. This variant creates an alternative 3' splice site, leading to the inclusion of 9 nucleotides coding for 3 extra amino acids between Q355 and Y356 of the protein. Homozygous Pah c.1066-11A mice, with a partially humanized intron 10 sequence with the variant, accurately recapitulate the splicing defect and present almost undetectable hepatic PAH activity. They exhibit fur hypopigmentation, lower brain and body weight and reduced survival. Blood and brain phenylalanine levels are elevated, along with decreased tyrosine, tryptophan and monoamine neurotransmitter levels. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Changes in the morphology of glial cells, increased GFAP and Iba1 staining signals and decreased myelinization are observed. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of chaperones DNAJC12 and HSP70 and increased autophagy markers LAMP1 and LC3BII, suggesting possible coaggregation of mutant PAH with chaperones and subsequent autophagy processing. This PKU mouse model with a prevalent human variant represents a useful tool for pathophysiology research and for novel therapies development.
Subject(s)
Disease Models, Animal , Phenylalanine Hydroxylase , Phenylketonurias , Animals , Mice , Phenylketonurias/genetics , Phenylketonurias/pathology , Phenylketonurias/metabolism , Humans , Phenylalanine Hydroxylase/genetics , Phenylalanine Hydroxylase/metabolism , Brain/metabolism , Brain/pathology , CRISPR-Cas Systems , Autophagy/genetics , Mutation , Liver/metabolism , Liver/pathologyABSTRACT
Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.
Subject(s)
Aging, Premature , Humans , Mice , Animals , Aging, Premature/genetics , Aging/genetics , DNA Repair/genetics , DNA Methylation/genetics , Proteins/genetics , Epigenesis, Genetic , DNAABSTRACT
Objetivo: Describir el espectro de aplicaciones no ginecológicas de la ultrasonografía transvaginal (TV), comparando su utilidad diagnóstica con la de otras técnicas de imagen. Material y métodos: 50 pacientes con patología peritoneal y/o pélvica fueron evaluados mediante ultrasonografía TV: cáncer de recto (n = 11) o de sigma (n = 10); diverticulitis de sigma (n = 11); apendicitis pélvica (n = 3); quistes entéricos (n = 2); implantes peritoneales (n = 5); enfermedad de Crohn (n = 3); litiasis ureteral (n = 3) y neoplasia de vejiga (n = 2). Comparamos estos hallazgos con los obtenidos mediante ultrasonografía abdominal, tomografía computarizada (TC) y enema de bario. Resultados: La ecografía TV es de utilidad para: a) la valoración de las estenosis rectales y neoplasias de sigma que son inaccesibles a la sonda transrectal, que obtiene una evaluación de la estadificación prequirúrgica similar a la aportada con la TC; b) diferenciar la etiología neoplásica o inflamatoria (diverticulitis) de las estenosis de sigma, no aclarada previamente con la ultrasonografía transabdominal, transrectal y/o la TC; c) evaluar las complicaciones rectales y/o perianales en la enfermedad de Crohn; d) el diagnóstico de apendicitis pélvica y/o diverticulitis, en asociación con la ecografía abdominal; e) caracterizar los implantes peritoneales malignos, y f) identificar litiasis y/o tumoraciones de vejiga y del uréter distal. Conclusión: La ecografía TV es una técnica complementaria a la ecografía transabdominal o transrectal en la valoración de patología no ginecológica, especialmente del tracto intestinal inferior, uréter distal, vejiga y cavidad peritoneal. Recomendamos su empleo cuando el diagnóstico no es concluyente, y en la valoración del peritoneo inferior/pélvico (AU)