**1. Introduction**

Ageing is considered as a complex and multi-factorial biological process driven by diverse molecular pathways and biochemical events shared by all living organisms [1]. It is characterized by the deterioration in the maintenance of homeostatic processes over time, which leads to functional decline and the increased risks of diseases and death [2]. It is also known as a general and complex biological process that predisposes humans to many complex diseases, including neurodegenerative diseases, type 2 diabetes, and various types of cancers.

Numerous studies have focused on the decipherment of the hallmarks of ageing in order to identify potential therapeutic targets to mitigate the ageing process. These hallmarks include stem cell exhaustion, altered intercellular communication, senescence, genomic instability, and recently epigenetic deregulation [3]. The end result of epigenetic changes alters the local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. DNA accessibility is a determinant of genetic expression in the human genome. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the lifespan.

In eukaryotes, the physiological and cellular mechanisms of ageing are conserved. However, various molecular mechanisms of ageing come from a variety of eukaryotic models, like *Saccharomyces cerevisiae*, *Caenorhabditis elegans*, *Drosophila melanogaster*, *Mus musculus*, mammalian tissue culture and human premature ageing [4]. Several distinct mechanisms underlying this process have been reported. Among them, the genetic screening and naturally occurring mutations have identified hundreds of genes involved in different pathways that affect ageing, of which insulin-like growth factor 1 (IGF-1) signalling, target of Rampamicyn (TOR) signalling, autophagy pathway, mitochondrial respiration signalling pathway, and hypoxia-inducible factor 1 (HIF-1) pathways [5].

Recently, researchers have tended to hold a comprehensive view to explain the complex interaction of genetic and environmental factors. Epigenetics, which can be defined as the study of stable genetic modifications that result in changes in gene expression and function without a corresponding alteration in the DNA sequence [6], has been found to be a necessary component to establish the overall understanding of ageing. Evidences have shown that epigenetic alterations can be regarded as a trigger of ageing pathway mechanisms, namely [7] histone modifications, which are supposed to be the essential component of epigenetic regulation and broadly studied. Nowadays, histone methylation occupies a crucial role during the development of organisms. Regulators of histone methylation have been mainly associated with ageing in worms and flies [8]. By RNAi screening of *C. elegans* genes, histone methyltransferase and demethylase genes have been identified as the key modulator of lifespan. These modifications are involved both in gene silencing, generally associated with transcriptional repression (H3K27me3), and in gene activation, associated with gene expression (H3K4me3) [9, 10], among them are SET-domain genes.

Since their discovery, SET-domain genes have attracted significant interest in multiple areas of biology and medicine, including endocrinology, growth, metabolism, nutrition, ageing, and oncology. The signalling pathways elicited by SET-domain genes have been extensively characterized in biochemical and molecular terms over the past years. However, fundamental questions regarding basic differences between the mechanisms of action of SET-domain genes and the closely related role in ageing are yet to be resolved. More recently, a study carried out by Su et al. 2018 [11] observed that a SET-domain protein, *set-18*, which is presented as a novel H3K36 dimethyltransferase in *C. elegans*, is specifically expressed in muscle, and its expression level is gradually increased during ageing. The mutation on this gene extended *C. elegans* lifespan and increased its oxidative stress resistance. However, the mechanism in which this gene is implicated remains unknown [4].

This chapter will provide a collection of information dealing with the role of epigenetic modifications involved in ageing process and highlights the significant role of histone methylation of SET-domain with an emphasis on the *set-18* gene. Among all the epigenetics modifications affecting organism lifespan, the histone methylation and demethylation stand out as a highly conserved and critical mechanism.

### **2. The effect of histone modification in ageing regulation**

Although many studies have shown the molecular mechanism of ageing and the regulatory pathways, it appears that just in the past decade scientists have begun to understand that dynamic histone modification may be involved in the regulation of

#### *Epigenetic Modifications Involved in Ageing Process: The Role of Histone Methylation… DOI: http://dx.doi.org/10.5772/intechopen.100476*

the ageing process of organisms. Histone proteins, in contrast to DNA, are subject to a huge number of modifications that contain methylation, acetylation, ubiquitination, and phosphorylation [8]. Researchers have observed that histone modifications undergo alterations during the ageing process. Although these alterations are the causes or consequences of ageing are still debatable, it is widely accepted that there is a certain connection between them as shown in **Figure 1**.

Recent findings revealed that epigenetic factors that regulate histone methylation, a type of chromatin modification, can affect the lifespan of organisms. While acetylation of histone tails is largely ephemeral in nature. Histone methylation is widely observed to be a mark that confers long-standing epigenetic memory [12, 13]. This histone modification is accomplished by the catalysis of histone methyltransferase (HMT). According to the different methylation sites, it is mainly divided into histone lysine modification and arginine modification. Histone lysine methylation occurs at three different levels: monomethylation modification, dimethylation modification, and trimethylation modification. This modification is highly conserved between single-celled organisms and different species of mammals [4].

Most of the known targeted lysine of histone methyltransferase occurs on histone H3, which thereby serves as a conduit of epigenetic regulation. Mostly, lysine methylation at histone H3, lysine 9(H3K9), H3K27 or H4K20 act as gene silencing, whereas H3K4, H3K36 or H3K79 are associated with the actively transcribed genes [14]. Histone methylations, especially histone 3 lysine 4 trimethylation (H3K4me3) activation and H3K27me repressing, are epigenetic modifications with close ties to transcription and have been directly linked to lifespan regulation in many organisms [15]. These alterations are not only hallmarks to monitor and evaluate the course of ageing, but also the potential targets of anti-ageing treatments.

The age-dependent variations of histone marks increase the instability of the genome and influence the expression of corresponding genes, and the accumulated genomic instability in old cells can lead to oxidative stress and lifespan reduction.

Mounting evidence has reported the correlation between oxidative stress, ageing and epigenetic modifications. To date, histone methylation is a classic epigenetic mark recognized to be involved in gene expression and has key functions in ageing control [16–19]. By RNAi screening of *C. elegans*, histone methyltransferases and demethylases have been identified as key modulators of lifespan. These include H3K27 demethylase UTX-1. H3K9 trimethyltransferase *set-26* and H3K4 trimethylation complex *set-2*/ASH2/WDR-5 [11] are SET-domain proteins.
