Epigenetic Alterations and Aging

Epigenetic transformations are a series of processes occurring in the cell nucleus which by modulating gene expression can create cell diversity without altering the DNA sequence. These events include methylation of cytosine (CM) in DNA, post-translational histone modification, and chromatin remodeling. These interactions comprise the epigenome, a dynamic system that is modified by factors such as the environment, health, and aging. Here we address some epigenetic events in the context of human aging.

DNA Methylation

In mammals, CM mainly occurs in inter/intragenic CpG dinucleotide islands (CpGi). During aging, the global CM level decreases, particularly at repetitive regions, whereas hypermethylation increases at CPGi near gene-rich areas [2]. CM variations contribute to the dynamic control of gene expression, as shown by the demethylation rate of naïve and rapid proliferating human T lymphocyte genomes.

A study with mice of different lifespan suggested that the CM rate varies inversely with age. Similar changes appear correlated with donor age in cultured human epithelial cells [7]. The CM loss occurs primarily in the densely methylated repeat fraction of the genome, which predominantly consists of transposable elements. Demethylation may lead to genome destabilization. DNA methylation is a widely accepted defense mechanism for transposon repression, thus possibly keeping in check the inflammaging response [3].

In humans, studies on monozygotic twin pairs showed that inter-individual differences in locus-specific CM increase with age. The change was mainly associated with individual environmental factors. Selective gene methylation occurs upon aging. Thus, tumor suppressor genes become hypermethylated in tumor cells and normal aging cells. Likewise, the promoter CpGi sequence of tumor suppressors (p16, and TIG1) and transcription factor (RUNX3) genes that is normally unmethylated in human stomach epithelial cells before the 50-year age, becomes progressively methylated from 50 to 80-year [10]. DNA methylation patterns appear to depend on both tissue and age. In human tissues, there is a distinct correlation between age and CM levels: the degree of methylation increased in CpGi loci, whereas it decreased in non-CpGi loci.

The methylation status of the CpGi loci that correlate significantly with aging is the fundamental epigenetic mark used for predicting chronological and biological age (epigenetic clock) [3]. Thus, the classical “Horvath” clock, based on changes at 353 CpGi sites, predicts biological age with 96% accuracy in different human tissues and cell types [12].

Histone modifications

Histones are modified post-translationally by acetylation, methylation, phosphorylation, and ubiquitylation, creating histone marks [5]. Alkylation marks are referred based on the specific histone, modified amino acid position, and the number of alkylating units.

The involvement of histone alkylation with aging is widely recognized. There is a global increase in transcriptionally activating marks, such as H3K4me3 and H4K16ac, and a decrease in the silencing marks H3K9me3, H3K27me3, H4K20me2, and H3K56ac13. However, there are differences in the specific pattern of histone modifications, probably due to locus-specific mark variations [2]. Thus, aged mouse stem cells and senescent human fibroblasts have an overall increased abundance of H3K27me3, but showing areas where this mark decreases [14,15].

Alterations in the activity or abundance of alkyltransferases or dealkylases significantly affect the longevity of different organisms. Accordingly, knockout of the SET-26 methyltransferase and polycomb increase the lifespan in nematodes and flies, respectively2. Overexpression of the H3K27 or KDM7 demethylases increases the longevity in nematodes and mice [16,17]. Deletion of SAS2, which encodes the HAT enzyme that acetylates H4K16, extends the lifespan in yeasts.

Within the same context, the overexpression of a sirtuin deacetylase (Sir2) extends longevity in various animal models. SIR2 relocalizes to regions of DNA instability [2] and modulates H4K16Ac levels18. Like SIRT1, SIRT6, another mammalian sirtuin that deacetylates H3K9Ac and H3K56Ac [18], increases lifespan in mouse cells.

Chromatin remodeling

Nuclear DNA wraps histones into an octamer complex forming the nucleosome2. CM and histone modifications occur at multiple sites within the nucleosome, thereby affecting gene expression by regulating the binding of transcriptional complexes (chromatin remodeling). They result in a raised genomic instability and modifications of gene function typified by loss of silencing, enhanced translation, and increased retrotransposon activity.

Distinct epigenetic alterations occur with aging, such as CM and histone mark variations, changes in nucleosome positioning and occupancy, loss of core histones, and increased histone variants. These modifications can be reprogrammed, reversing many age-related phenotypes20, which might offer new ways for therapy of age-associated diseases, the safe approach to healthy aging, rejuvenation, and increased longevity.

Researchers have used "blood factors" in rats to apparently rejuvenate organs in rats.


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