Introduction
In most countries, life expectancy has increased steadily over the past few decades. In fact, average life expectancy worldwide increased to 71 years in 2015, compared to 46 years in 1950 [1]. Nevertheless, aging is an inevitable event that affects most living organisms over time. For most people, aging means growing old, having wrinkled skin and gray hair, or even having grandchildren. However, physicians and biologists view aging as a complex, multifactorial biological process that involves a loss of physiological function that increases susceptibility to environmental stresses and age-related chronic diseases such as cancer, metabolic disorders (e.g., type II diabetes), cardiovascular disease, and neurodegenerative diseases [2,3,4,5].
In order to identify potential therapeutic targets with which to mitigate the aging process and the above-mentioned diseases, numerous studies have been carried out aimed at identifying the changes caused by this process. As a result, nine hallmarks of aging have been defined, including genomic instability, altered intercellular communication, stem cell exhaustion, cellular senescence, and epigenetic changes and deregulation [6]. Together with other factors, these features paved the way to identifying molecular events that lead to an aging phenotype.
How do epigenetic changes affect the aging process?
1. DNA methylation
Considering the importance of epigenetics and the great interest in developing therapies targeting epigenetic processes, great progress has been made in this field in the context of aging. In fact, DNA methylation - a biological process in which methyl groups are attached to the DNA molecule - has been used as an indicator of the chronological age of cells and tissues such as blood, liver and kidney and is therefore called the "epigenetic clock"[7]. Furthermore, changes in epigenetic patterns or so-called “epigenetic drift” is a well-known phenomenon that describes the gradual decrease in global DNA methylation with the aging process [8].
It is important to remember that DNA methylation patterns are not fixed but are reprogrammed at different stages of mammalian development. These patterns can change in response to various external and internal factors. However, it has been proven that global DNA hypomethylation (loss of methylation) is associated with aging [9,10]. This decrease in methylation is attributed to the progressive decline of the DNA methyltransferase DNMT1 [11]. Several genes show altered DNA methylation patterns with age, e.g. B. genes for tumor suppression (LOX), development and growth (IGF2) and metabolism (ELOVL2), which shed light on the increased susceptibility to diseases [12].
2. Histone modification
Similarly, aging has been shown to impact the histone components of chromatin. Histones can exhibit a variety of post-translational modifications, resulting in enormous functional complexity that is still not fully understood. These modifications have been shown to affect a variety of processes, e.g. B. on gene transcription, DNA repair, DNA replication and the condensation of chromatin [13,14]. The most important changes observed are the methylation and acetylation of lysine residues of histones [15,16]. The trends of age-related changes in histone methylation have been studied in detail. This means, for example, For example, the loss of certain trimethylation marks on H3 lysines (e.g. H3K9me3 and H3K237me3) suggests a general loss of heterochromatic structure with aging [17,18]. In addition, technological advances have revealed the possibility of extending lifespan in humans through sirtuins, a family of deacetylases with remarkable abilities to prevent disease and reverse aspects of aging in mice [19].
Changes in heterochromatin - condensed DNA that is not normally accessible for transcription - have been observed in several organisms and are considered a classic model to explain aging [20]. The gradual loss of heterochromatic regions is mainly due to the loss of core proteins of chromatin. This transition from highly condensed to weakly packed chromatin structures can lead to cellular dysfunction. As a result, various consequences have been observed, including altered chromatin architecture, decompression of silenced genes, and global changes in gene expression [21].
Conclusion
Aging is a good example of a process in which the study of epigenetics has made great progress and provided an explanation for many dilemmas. However, most of the changes that aging causes are not yet fully understood. Together with partners, MoleQlar Analytics aims to develop epigenetic biomarkers that will help us better understand why and how we age.
