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Epigenetic Alteration: A Hallmark of Aging

Non-inheritable changes to the genome that do not change the sequence of the DNA itself are epigenetic alterations, which come in many forms. Epigenetic alteration has been shown to influence aging in humans and various model organisms.

Epigenetic alterations consists of a variety of changes that can ocurr in the genome. Unlike DNA mutations, these epigenetic alterations are reversible. Examples of epigenetic alterations include DNA methylation, histone modification, and chromatin remodeling. Many enzymes like methyltransferases, (de)methylases, (de)acetylases, and heterochromatin remodeling proteins are under investigation for their ability to alter DNA and their potential to influence lifespan.

Investigation into methylation patterns of the genome during aging suggest that there are various hypermethylated regions that show up through the aging process, which refutes the previous belief that aging was due to a general demethylation of the genome. Based on the 2013 review The Hallmarks of Aging, there has been no definitive experimentation done correlating increased lifespan to methylation patterns of the genome.

Manipulation of histones by underexpression of the modifying enzymes H3K4 and H3k27 in nematodes and flies, respectively, results in a decrease in longevity, suggesting that histone modification may have direct correlation to lifespan. In vertebrates, a class of proteins called sirtuins, also found in red wine, improve health during aging, rather than increasing longevity, by stabilizing the genome, aiding glucose homeostasis, and deacetylation of mitochondrial proteins.

Through chromatin remodeling, different parts of the genome are exposed and available for transcription, or for methylation. In a study done with flies underexpressing a heterochromatin remodeling protein 1a, lifespan and health was greatly reduced. Chromatin remodeling may also have a direct effect on telomere building and length, which is another hallmark of aging.

Updates in Research Since The 2014 Hallmarks of Aging Review

DNA Methylation

As the genome becomes methylated or demethylated, the organization of chromatin can be effected and/or genes can be repressed or activated which may change the proteome of the cell which may result in physiological aging. Current novel research into the effects of DNA methylation by Horvath, et al done in a 2014 published journal article predicts age based on the level of DNA methylation as a function of BMI units, suggesting that obesity causes epigenetic alterations of the DNA that accelerate physiological aging in liver tissue . In addition to this, it has been shown that other environmental factors other than diet, like smoking habits and exercise habits, can affect epigenetics in a way that results in accelerated physiological aging. Furthermore, decreased epigenetic regulation by methylomes has been determined to be reduced with age in human epidermal tissue samples by statistical analyses . Research done by Borman, et al in 2016 also suggests, in accordance with Horvath, that DNA methylation can be a predictor of age, but in skin tissue. Both sets of research make use of microarrays and public datasets, current technology that allows for the analysis of thousands of methylation sites among thousands of individuals, genes, and tissues.

Histone Modification

In the sub-category, histone modification, of epigenetic alterations, more current research by Zhang, et al. in a 2015 published article shows that nuclear structure and epigenomic organization can be altered by a lack of functional WRN gene, associated with the premature aging disorder Werner syndrom, shown by a down-regulation of the H3K9me3 heterochromatin mark. The WRN protein associates with heterochromatin proteins and nuclear lamina proteins that control the structure of the genome. It is well known and characterized that disorder of nuclear lamina proteins is also a hallmark of aging. In the disease Hutchinson-Gilford Progeria Syndrome (HGPS) characterized by severe premature ageing phenotype, the H3K9me3 and H3K27 are, again, shown to be downregulated . However, Arancio, et al also notes that the heterochromatic marker H4K20me3 is upregulated in HGPS cells, which marks telomeric heterochromatin, and that "histone H4K16 hypoacetylation is associated with premature senescence." These research highlight the interconnection between different types of epigenetic alterations and between other hallmarks of aging, like telomere shortening, which remind us that aging is a complex process that most likely is not caused by any single phenomenon.

Chromatin Remodeling

As exemplified above, histone modification is intimately associated with chromatin remodeling, since the main units of chromatin are histone proteins on which the DNA is wrapped around to create dense compact chromatin, eventually leading to the most condensed and readily divisible form: chromosomes. Recent study of the effects of chromatin remodeling shows that loss of local interactions between chromatin and TADs (topologically associating domains) or LMNB1 leads to a change in the physical compactness of the DNA unique in senescent cells . LMNB1 is one of four lamin proteins found in the nuclear architecture, and alternative splicing of the mRNA of these genes can lead to defective lamins, causing laminopathies resulting in premature physiological aging.