ROLE OF EPIGENETIC ALTERATIONS IN AGE-ASSOCIATED CELLULAR DYSFUNCTION

Abstract

Aging is a multifaceted biological phenomenon that is marked by dysfunction of cells that progressively degenerate and in which epigenetics changes critically regulate the operation of the system. The DNA methylation patterns, histone modifications, and the establishment of chromatin structure have increasingly been implicated in the reduction of cellular homeostasis and the emergence of age-related phenotypes. The purpose of the present study was to explore the mechanisms of age-related cellular dysfunction that are mediated by epigenetic changes through reviewing the changes in DNA methylation and histone changes and their effects on gene expression and cellular senescence. The comparative analysis of the young and old human fibroblast cell lines was done by genome-wide DNA methylation profiling by bisulfite sequencing and histone modification analysis in chromatin immunoprecipitation assays. Quantitative real-time PCR was employed to measure the level of gene expression, and the dysfunction of the cell was assessed by senescence-associated β-galactosidase staining, reactive oxygen species tests and the measuring of the mitochondrial activity levels. The findings showed widespread global DNA hypomethylation and promoter specific hypermethylation of genes that regulate cell cycle and respond to stress in old cells. There were also changes in the pattern of histone modifications, such as less H3K9 acetylation and more H3K27 trimethylation. These epigenetic alterations were closely connected with inappropriate regulation of gene activity, augmented oxidative stress, mitochondrial malfunction, and higher indicators of cellular senescence. The results overall confirm that epigenetic changes are major causes of age-related cellular dysfunction and indicate that modulation of the epigenetic pathways could be used as a promising approach to therapeutic interventions to counteract aging and age-related diseases.