Epigenetic alterations: Small changes affecting health and longevity

Highlights:

• Epigenetic alterations are changes that influence gene activity without affecting the DNA sequence
• Environmental changes impact epigenetic alterations
• DNA methylation, histone modifications, and microRNA expression are among the most well-established epigenetic alterations
• Epigenetic alterations are one of the hallmarks of aging

Introduction

Conrad Waddington first introduced the term “epigenetics” in the early 1940s. Epigenetics is defined as changes in genetic functionality without alterations in the deoxyribonucleic acid (DNA) sequence. It means that these changes are reversible, yet they influence how the body reads a DNA sequence and expresses genes. Several known epigenetic changes include DNA methylation, histone modification, and alterations in micro-ribonucleic acid (miRNA) expression. Literature has highlighted that epigenetic modifications are influenced by diet, tobacco smoking, physical activity, infections, and others. Additionally, they have been identified to induce many conditions like cancer and mental disorders and are a hallmark of aging. Epigenetic alterations were also found to play a role in developmental biology, which was initially thought to be solely influenced by genetics.

DNA methylation and epigenetic alterations

DNA methylation, as a process, was discovered in the 1940s. It involves transferring a methyl group from methionine to the fifth atom of cytosine (a DNA base) to form 5-methylcytosine (1). This process is catalyzed by DNA methyltransferases, a family of enzymes. The outcome of this process is essential for the regulation of gene expression, embryonic development, genomic stability, aging, and chromatin structure integrity (1, 2).

The process of DNA methylation can be influenced by factors like diet, physical activity, environmental elements, and others (3). The said factors also play a role in and affect the lifespan. This is backed by literature highlighting the epigenetic differences between monozygotic twins, despite having a similar epigenetic profile at birth (3). It is important to note that changes in DNA methylation occur early in life and start at conception (4). In this context, literature has highlighted that childhood is characterized by a rapid increase in levels of DNA methylation, which tend to stabilize by adulthood, both in the brain and blood. In the stage beyond adulthood, DNA methylation in the blood tends to decrease (4, 5).

With time, DNA methylation patterns tend to change, leading to the development of many age-related diseases (6). One example of such a condition is cancer, where a disturbance in DNA methylation occurs (7). In this case, both hypomethylation and hypermethylation at different locations are evident. The former occurs across the genome, leading to instability and inefficient gene repression, while the latter occurs at the CG islands (a region in DNA where cytosine nucleotide is followed by that of guanine in a linear sequence) (7). The process of hypermethylation reported with the aging process has been known to affect numerous CG islands that influence genes involved in tumor suppression, DNA repair, and others. Examples include the RASSF1A, a gene that is involved in cell cycle control in healthy cells, which progressively gets methylated due to increased adiposity and age (7).

Alterations in DNA methylation also influence age-related non-cancerous conditions. For example, such changes are linked to conditions like Alzheimer’s disease (AD). This has been confirmed by Silva et al., who found that elderly patients with AD have a higher methylation frequency in the hTERT (human telomerase reverse transcriptase gene) compared to controls (8). An example of a non-cancerous condition with hypomethylation is Parkinson’s disease (PD). PD is caused by mutations in the alpha-synuclein gene, which, if disrupted by mutations, leads to the accumulation of Lewy bodies (spherical masses made of aggregated alpha-synuclein) (7, 9). It is important to note that alpha-synuclein protein accumulates with aging; however, in patients with PD, the clearance mechanism is severely impaired (10). Demethylation of the CG islands located in the first intron (a polynucleotide sequence that does not code for proteins) of the alpha-synuclein gene has been found to be associated with increased alpha-synuclein (a neuronal soluble protein that plays a role in neurotransmission) accumulation (9). The role of DNA methylation in other age-related conditions like osteoarthritis, renal diseases, type 2 diabetes has also been highlighted in the literature (7).

Histone modifications as key players in epigenetics

Histones are basic protein units that form condensed chromatin structures together with DNA. Nuclear DNA is not in the form of free linear strands but is highly condensed by wrapping around histones. In addition to supporting the DNA, histones have various functions like regulation of gene expression, DNA repair, and DNA replication processes (11). There are four canonical (core) histones, including H2A, H2B, H3, and H4. All histones are subject to post-transcriptional modifications, like acetylation, methylation, phosphorylation, and others, occurring at histone tails (12). Literature has highlighted that in most instances, histone acetylation is associated with higher gene expression, while methylation has been found to promote or repress gene expression, depending on the target being methylated (13).

The methylation process occurs in various parts of histones, and the location and degree of methylation influence the outcome (14). In this context, abnormal histone methylation has been implicated in cancer, where it was found to be correlated with increased rates of cancer recurrence and associated with poor survival. For example, point mutations in EZH2 (a gene involved in production of an enzyme called a histone methyltransferase) have been suggested to play a role in B cell lymphomas (14). Likewise, histone acetylation has also been suggested to play a role in conditions like cancer, neurodegenerative disorders, and others (15). An example is the reduction of H4K16 (epigenetic alteration occurring at the core histone H4, where acetylation takes place at the sixteenth lysine residue) acetylation, which has been implicated in several cancer types.

Global loss of core histones is one of the features associated with aging in various organisms, including humans (16). On the contrary, elevated histone expression has been shown to prolong the lifespan in organisms like Saccharomyces cerevisiae (15). Research highlights that alteration in levels of histone methylation, acetylation, and other post-translational modifications lead to loss of stable (permanent) and dynamic marks on basic histones, suggesting a role in organismal aging (14, 15). For example, the link between histone acetylation and general metabolism is mediated by sirtuins (a family of proteins that play a role in metabolism and aging). This relation could be influenced by caloric restriction, which was found to improve longevity via overexpression of Sir2 deacetylase (15).

Epigenetic alterations mediated by microRNA

miRNAs are RNA molecules that are about 22 nucleotides in length and profoundly affect gene expressions (17). When miRNAs bind to their target messenger RNA, they cause its degradation and can also affect its translation. miRNAs play an important role in cancer and have been found to act on tumor suppressor genes and oncogenes (17). For example, miR-21, a miRNA with antiapoptotic activity, has been found to be upregulated in breast cancers (17). Research highlights that miRNA expression is increased with age; this coincides with the downregulation of target genes (18). In the same context, studies have shown that the miRNAs influence the mammalian target of rapamycin (mTOR), which is involved in longevity and lifespan, therefore affecting the aging process (19).

Factors influencing epigenetics

Contrary to traditional belief, individuals have more control over their health because genes are not the sole contributors to overall well-being. Accumulating body of evidence suggests that factors like psychological stress, alcohol, environmental pollutants exposure, and other elements influence epigenetic changes (20).

Nutrition is among the most investigated factors and it has been mentioned that nutritional modification could impact epigenetic alterations, thus promoting diseases or protecting against them (20). For example, research has highlighted that polyunsaturated fatty acids, which play a role in modulating DNA methylation and influencing the inflammatory pathway, may promote anti-cancer activity through decreasing inflammation and dampening the effect of the nuclear factor kappa B (NF-κB) pathway in transgenic mice (21, 22). NF-κB is a protein transcription factor that regulates immune and inflammatory responses (23). In humans, the Mediterranean diet (rich in fruits, vegetables, legumes, nuts, fish, and unsaturated fats) has been found to confer epigenetic rejuvenation properties based on DNA methylation results of 120 participants (24). Folic acid and vitamin B12 play an important role in the methylation process through their role in methionine formation, where the latter acts as a methyl donor (25). Their deficiency has been linked to an abnormal methylation process, leading to diseases like cancer.

Physical activity has also been implicated in epigenetic alterations. In this context, exercise was found to influence the expression patterns of miRNAs in leukocytes, which play a role in acute and chronic inflammation (26). A study by Radom-Aizik et al. involving twelve healthy participants found that young males performing ten 2-minute bouts of cycle ergometer exercise with 1-minute rest in between led to an alteration in the levels of 34 miRNAs (27). The changes in miRNA levels, whether in the form of increase or decrease, influence inflammatory pathways involved in cancer, immune response, among others. In this context, miRNAs play an important role in regulating the inflammation clearance process to prevent the uncontrolled progress of inflammatory reactions (28).

Tobacco smoke is known to contain a mixture of organic and inorganic chemicals that contribute to a number of diseases, like cancer (20). According to literature, cigarette smoke contributes to a reduction in levels of certain histone modifications, like the H4K16 acetylation and H4K20 trimethylation, in respiratory cells (29). These histone modifications were also evident in lung cancer tissues (20). In addition to the previous, a systematic review that evaluated 80 studies highlighted that tobacco smoke also influences DNA methylation processes and miRNA expression (30). The study further explained that the negative impact of smoke could start early during maternal life. In addition to validating the previous, Murphy et al. highlighted that the epigenetic changes are more evident in males (31).

Other factors like psychological stress have also been implicated in epigenetic alterations and were linked to aging as well. Additionally, stress has also been associated with increased risk for cardiometabolic diseases, mood disorders, and others (32). Evidence from the literature suggests that psychological stress induces DNA methylation, leading to accelerated epigenetic aging (33). The possible mechanism behind this is DNA methylation leading to alteration in expression of genes like NR3C1 (nuclear receptor subfamily 3 group C member 1, a gene that codes for the glucocorticoid receptor and is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues) (34).The use of a DNA methylation-based epigenetic clock has been suggested to be a more useful measure of biological age than telomere length, which is also negatively influenced by stress (32).

Conclusions

Epigenetic alterations are changes that take throughout life and start at the very early stages. They involve a change in the chemical structure rather than the sequence of DNA. They have been implicated in health, where they have been found to be involved in cancer and numerous illnesses. Epigenetic alterations contribute to these conditions by altering the function of their targets. In addition, they play a role in the aging process, as they represent one of its hallmarks (35). In this context, abnormal changes in methylation and acetylation of histones or DNA and chromatin remodeling have been suggested to accelerate the aging process and various age-related conditions (35, 36). 

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