Role of Epigenetics in Aging and Longevity by Rishi Mehta

Introduction

Aging is a universal and multifaceted process that leads to a decline in bodily functions over time and eventually leads to death. The phenomenon of aging is usually associated with genetic and metabolic factors, however, it can also be understood through epigenetic factors. Epigenetics include a wide variety of variables like DNA methylation, histone modifications, and non-coding RNA, all of which can impact aging and longevity. These epigenetic factors are extremely dynamic as changes in lifestyle or environment can lead to drastic changes in one’s epigenome. These changes have a direct impact on aging and when unregulated can lead to diseases and intensify aging. In this paper, we will talk about the factors that affect aging by looking at epigenetics, factors affecting epigenetic markers, inheritance, methods to slow down aging, and pharmacological intervention to improve longevity.

Overview of Epigenetics

Epigenetics is the process by which gene expression is controlled without modifying an

organism’s DNA sequence (26). Rather than changing the DNA sequence, these mechanisms act on top of that sequence, to change gene transcription, thereby altering gene expression (8). It controls cell differentiation and can impact an organism’s development. Epigenetic markers are chemical modifications to DNA that determine genetic expression without changing the DNA sequence (28). They have the potential to express or silence genes by acting as a layer of instructions (43). Changes like histone acetylation, methylation, phosphorylation, and ubiquitination change the way genes are expressed (39). These changes also impact histones by regulating chromatin accessibility, non-coding regions of DNA like micro RNA (miRNA), and chromatin remodelling (39). Epigenetic markers also play a crucial role in regulating and maintaining cell identity, as

seen in the way in which red blood cells express the gene HBB to produce hemoglobin protein and enable oxygen transport (26). While this gene is present in all cells, the epigenetic markers prevent its expression from taking place.

Epigenetic markers that affect longevity

Longevity is best understood through biological age. Unlike chronological age, which is the age of a person based on the time of their birth, biological age showcases the age of cells and tissues based on a person’s DNA (38).

As a person ages, programmed cell death or apoptosis increases significantly (32). This leads to a wide variety of physical changes in the body. These changes include a great reduction in bone density due to reduced absorption of calcium from food, loss of muscle mass due to lower testosterone and growth hormone levels, diminished vision and hearing, loss of skin elasticity due to lower levels of collagen, and an overall reduction in the rate of bodily functions (46). Biological age is greatly determined by epigenetic markers. As aging takes place, the upregulation and downregulation of a variety of epigenetic markers occurs. This leads to changes in the epigenome called epigenetic alterations (14). These alterations due to aging also lead to epigenomic and genomic instability, loss of chromatin, cellular senescence, disabled autophagy, deregulated nutrient sensing, telomere degradation, and inflammation (14). These markers are of the following types: Acetyl groups, Methyl groups, Phosphate groups, and Ubiquitin groups.

Histone acetylation is the addition of Acetyl-CoA groups to the lysine sites in the genetic code using histone acetyltransferases as a catalyst (51). DNA methylation refers to the addition of methyl groups to the genome leading to silencing of genes. This methylation usually takes place on cytosine sites called CpG sites (16). Phosphorylation is the process by which transcriptional activation takes place due to the addition of a phosphate group. This process has been best studied on histone 3 (34). Finally, ubiquitination is the addition of the ubiquitin to histone core proteins (30). It is a form of post transcriptional modification that impacts gene expression (42).

These epigenetic markers, especially DNA methylation, greatly impact aging (20). Higher rates of DNA methylation are associated with an increase in inflammation as well as a faster rate of aging (54). Apart from epigenetic markers, telomeres also play a role in determining an individual's biological age. Telomeres are short repetitive sequences of DNA at the end of

chromosomes and play a crucial role in protecting the chromosome (1). As a person’s biological age increases, the size of the telomeres reduces, which leads to increase in the cells and tissues aging (1). Another factor that can be used to determine aging is telomerase action. Telomerase is used by the body to maintain the length of telomeres and thus protect chromosomes (15). As a person ages, telomerase activity drastically declines which leads to telomere shortening, making it a clear indicator of aging (36). Thus, DNA methylation, telomeric length, and telomerase action play a role in determining a person’s age.

Please click on the link for the full report