Impact of epigenetic mechanisms on age-related diseases

Aging is a biological process characterized by the progressive decline of physiological functions along with an increased risk of the development of severe diseases such as cardiovascular disease, cancer, diabetes, frailty and others. Previous studies have identified several hallmarks of aging which include genomic instability, stem cell exhaustion, senescence, epigenetic deregulation and altered intercellular communication.

Longevity.Technology: Recent studies have indicated that epigenetic deregulation can impact gene expression which in turn can regulate age-related diseases. Alteration of epigenetic mechanisms makes the cells vulnerable to transcriptional processes that favor age-related diseases [1]. A few of the common epigenetic events include histone and DNA modification, non-coding RNAs and ATP-dependent chromatin remodeling complexes.

A new review in Cells by Annamaria la Torre, Filomena Lo Vecchio and Antonio Greco of Casa Sollievo della Sofferenza describes different epigenetic regulatory mechanisms and their impact on age-associated diseases.

Epigenetic mechanisms

DNA methylation

DNA methylation is one of the most studied epigenetic mechanisms. It occurs at the level of DNA and regulates the expression of genes. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and carry out the transfer of a methyl group onto the 5th carbon of particular stretches of DNA called CpG islands [2].

DNA methylation is reported to regulate transcriptional initiation activity while DNA hypomethylation is associated with higher transcriptional activity. The ten–eleven translocation (TET) carries out the catalyzation of the hypomethylation using α-ketoglutarate, Fe(II), and oxygen as substrates.

Histone modifications

Packaging of the eukaryotic genome into a complex structure known as chromatin ensures the compactness of the genome as well as the accessibility of RNA polymerases and regulatory proteins to the DNA. The nucleosome is the fundamental unit of the chromatin which is made up of an octamer of histones comprising two copies each of histone H2A, H2B, H3, H4, and other variants of histones and surrounded by 147 DNA base pairs [2]. A histone linker H1 binds to the DNA that moves in and out of its 1.65 turns around the nucleosome. Histones undergo several modifications such as acetylation, methylation, phosphorylation, ubiquitination, ribosylation and sumoylation. These modifications help in the existence of various spatial chromatin rearrangements which in turn influence the interaction of the DNA with RNA polymerase II and other transcription factors.

Histone methylation

Histone methylation is involved in the silencing or activation of gene transcription depending on the number of methyl groups attached to specific amino acid residues (lysine and arginine). Histone methyltransferases (HMTs) carry out the methylation of the residues where lysine can be mono-, di- and trimethylated and arginine can be monomethylated, or asymmetrically/symmetrically dimethylated. Although initially methylation was assumed to be irreversible, the identification of two families of histone demethylases proved it to be otherwise.

Histone acetylation

Histone acetylation promotes a more relaxed chromatin structure and initiates transcriptional processes by removing positive charges from lysine residues at histone tails. Histone deacetylation promotes a closed chromatin structure which suppresses the transcriptional processes. Histone acetylation is carried out by histone acetyltransferases (HATs) and deacetylation by histone deacetylases (HDACs).

Histone phosphorylation

Histone phosphorylation is a post-transcriptional modification carried out by various enzymes. Histone phosphorylation is associated with gene expression, transcription regulation, and DNA damage response (DDR).

Histone ribosylation

Histone H1 as well as all the core histones can undergo ribosylation. Identification of About 22 members of the ADP ribosyltransferase (ART) superfamily, as well as several members of the sirtuin (SIRT) family, has taken place that possess mono-ADP-ribosylation properties. Histone ribosylation has been reported to play important roles in transcription and replication.

Histone ubiquitination and sumoylation

Histone ubiquitination takes place with the help of E1-activating enzymes,

E2 conjugation and E3 ligases. These result in the addition of ubiquitin (Ub) to a lysine (Lys) residue on proteins or Ub itself, leading to the formation of polyUb chains. On the contrary, deubiquitinating enzymes (DUBs) carry out the removal of Ubs from the residues.

Histone sumoylation is another post-traditional modification that has been discovered recently. Their effects on gene expression and chromatin organization are not as well known as other post-transcriptional modifications.

Epigenetic changes in cellular senescence

Several human studies and in vivo models of aging have indicated that the epigenome undergoes a progressive loss in configuration during aging. External stimuli can also cause the perturbation of chromatin configuration which in turn impacts expression of genes associated with lifespan and aging.

To date, four epigenetic alterations have been reported that are associated with aging. The first one is nucleosome repositioning and histone loss. Other epigenetic alterations include abnormal chromatin accessibility, replacement of the recognized histones with different histone variants, and local DNA hypermethylation and global DNA hypomethylation especially at CpG islands near genes that control differentiation and development.

Epigenetic changes in age-related diseases

The human body is unable to maintain homeostasis and becomes more vulnerable to diseases, injury and stress with age. Moreover, there is a decline in regeneration and reproduction, making older people more susceptible to age-related diseases [2].

Tumors

The incidence of cancer has been reported to increase exponentially with age in many mammalian species. This is most often due to the accumulation of several molecular lesions such as epigenetic and/or genetic alterations. Several epigenetic alterations such as global hypomethylation and local CpG island hypermethylation that are associated with aging also play an important role in the occurrence of cancer. Moreover, cellular senescence has been reported to play a dual role in cancer, it safeguards against cancer as well as can lead to increased cancer aggressiveness. Another epigenetic alteration that is associated with cancer is histone modification.

Cardiovascular disease

Cardiovascular disease (CVD) leading to heart failure and ultimately death is a significant cause of mortality and morbidity globally. Obesity, hypertension, the age of an individual, and diabetes are three of the most prevalent risk factors for CVD. Several studies have reported CVD is associated with exposure to chemical stimuli present in the environment which could result due to a combination of gene alterations and epigenetic effects. The epigenetic alterations that are most often associated with CVD are histone methylation, DNA methylation, and histone acetylation.

Alzheimer’s disease

More than 55 million people have Alzheimer’s disease globally, which is also the most common cause of dementia. Recent studies have reported several epigenetic alterations in AD. Histone deacetylation and DNA hypermethylation are the two most common epigenetic alterations that have been reported among AD patients. Many studies have also indicated DNA methylation modifications in specific genes to be associated with AD pathology.

Parkinson’s disease

Parkinson’s disease is a neurodegenerative condition that has a multifactorial origin. Parkison’s disease develops due to the impact of several environmental factors on epigenetic machinery. The two most common alterations that have been reported among PD patients are histone modifications and abnormal DNA methylation patterns.

Diabetes

Type 2 diabetes (T2D) is characterized by high blood glucose levels and impaired insulin secretion from the pancreatic beta cells. Although diabetes is a genetic disease, environmental factors also play a role in its progression by influencing epigenetic changes. DNA methylation is a commonly reported epigenetic alteration that was observed to regulate the expression of essential diabetes-related genes such as the INS 1 (insulin), PDX-1 (pancreatic and duodenal homeobox 1) gene, and others.

Sarcopenia

Sarcopenia is a condition that leads to malnutrition, loss of mobility, and an inactive lifestyle. It is characterized by loss of muscle strength, mass, and function. Recent studies indicate that epigenetic processes play an important role in the development of sarcopenia. Several studies have reported differential DNA methylation patterns of genes that are involved in muscle function in people affected by sarcopenia.

Osteoporosis

Osteoporosis is a condition characterized by the destruction of bone microstructure and decreased bone mineral density (BMD), leading to an increased risk of bone fracture and bone fragility. Several studies have reported differences in DNA methylation patterns of certain gene promoter regions associated with bone remodeling, osteogenic differentiation, osteogenesis, and other bone metabolism-related processes. Moreover, upregulation of histone H3K27me3 was observed during the process of osteogenesis.

Authors’ findings

This review suggests that several epigenetic alterations that occur with age make cells vulnerable to transcriptional modifications that are associated with the development and profession of age-related diseases. But it is leveraging the knowledge of these alterations that could be a gamechanger, both in terms of prediction of disease and development of treatment.

As the authors put it: “Given the reversible nature of epigenetic mechanisms, understanding these alterations will provide promising avenues for therapeutics against age-related decline and diseases. Furthermore, with the advent of high-throughput epigenome mapping technologies, identifying the “epigenomic identity card” of each disease and even of each patient will offer a possibility for discovering new diagnostic, predictive, and prognostic, molecular biomarkers that will have a huge impact on patient outcomes [2].”

[1] https://link.springer.com/article/10.1007/s40520-019-01430-0
[2] https://www.mdpi.com/2073-4409/12/8/1163