Epigenetic mechanisms related to cognitive decline during aging

Abstract

Cognitive decline is a hallmark of the aging nervous system, characterized by increasing memory loss and a deterioration of mental capacity, which in turn creates a favorable context for the development of neurodegenerative diseases. One of the most detrimental alterations that occur at the molecular level in the brain during aging is the modification of the epigenetic mechanisms that control gene expression. As a result of these epigenetic‐driven changes in the transcriptome most of the functions of the brain including synaptic plasticity, learning, and memory decline with aging. The epigenetic mechanisms altered during aging include DNA methylation, histone modifications, nucleosome remodeling, and microRNA‐mediated gene regulation. In this review, we examine the current evidence concerning the changes of epigenetic modifications together with the molecular mechanisms underlying impaired neuronal gene transcription during aging. Herein, we discuss the alterations of DNA methylation pattern that occur in old neurons. We will also describe the most prominent age‐related histone posttranslational modifications in the brain since changes in acetylation and methylation of specific lysine residues on H3 and H4 are associated to functional decline in the old. In addition, we discuss the role that changes in the levels of certain miRNAs would play in cognitive decline with aging. Finally, we provide an overview about the mechanisms either extrinsic or intrinsic that would trigger epigenetic changes in the aging brain, and the consequences of these changes, i.e., altered transcriptional profile and reactivation of transposable elements in old brain.

Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice

“…In reference to this family of deacetylases, our results demonstrate decreased Sirt1, Sirt2 and Sirt6 gene expression in SAMP8 mice compared to SAMR1 and SAMR1 under CMS. Compelling evidence has proposed that methylation of H3K9 promotes DNA methylation maintenance in mammals and is a hallmark of heterochromatin formation and subsequent gene silencing [2,34,35]. As with histone phosphorylation, CMS treatment increased H3K9 methylation in SAMP8 animals but not in SAMR1, suggesting that even they showed more H3 acetylation, which also resulted in more methylation.…”

“…During aging, there are several epigenetic mechanisms altered, which include DNA methylation, histone modifications, nucleosome remodelling, and miRNA-mediated gene regulation [2,23]. In the present study, we evaluated three main epigenetic marks, which modulate chromatin structure and act as platforms for recruitment, assembly or retention of chromatin-associated factors: histone posttranslational modifications, DNA methylation and miRNA-mediated gene regulation.…”

“…In reference to other modifications, histone phosphorylation belongs to the cellular response to DNA damage, as phosphorylated histone H2A.X demarcates large chromatin domains around the site of DNA breakage [2]. Additionally, multiple studies have also shown that histone phosphorylation plays crucial roles in other nuclear processes, such as DNA replication because of apoptosis or DNA damage [36].…”

“…Environmental factors drive epigenetic modifications, resulting in phenotypic differences, which alter almost all tissues and organs. Although the brain is one of the most affected structures, such modifications lead to a progressive decline in the cognitive function and create a favourable context for the development of neurodegenerative diseases [2]. Aging is the most significant risk factor for most chronic diseases, such as age-related cognitive decline and Alzheimer's disease (AD) [3].…”

“…Epigenetics refers to potentially heritable and environmentally modifiable changes in gene expression mediated via non-DNA encoded mechanisms [5]. Recent evidence has demonstrated significant associations between epigenetic alterations and stress [2,6]. Potential threats cause a course of action releasing numerous transmitters and hormones throughout our body, particularly catecholamines and glucocorticoids.…”