Causes and Consequences of Age-Related Changes in DNA Methylation: A Role for ROS?

Abstract

Recent genome-wide analysis of C-phosphate-G (CpG) sites has shown that the DNA methylome changes with increasing age, giving rise to genome-wide hypomethylation with site‑specific incidences of hypermethylation. This notion has received a lot of attention, as it potentially explains why aged organisms generally have a higher risk of age-related diseases. However, very little is known about the mechanisms that could cause the occurrence of these changes. Moreover, there does not appear to be a clear link between popular theories of aging and alterations in the methylome. Some of the most fruitful of these theories attribute an important role to reactive oxygen species, which seem to be responsible for an increase in oxidative damage to macromolecules, such as DNA, during the lifetime of an organism. In this review, the connection between changes in DNA methylation and these reactive oxygen species is discussed, as well as the effect of these changes on health. Deeper insights into the nature, causes and consequences of the aging methylome might provide a deeper understanding of the molecular mechanisms of aging and eventually contribute to the development of new diagnostic and therapeutic tools.

Methylation of Apoptosis-Associated Speck-Like Protein With a Caspase Recruitment Domain and Outcomes in Heart Failure

“…Previous studies have established that there is a decrease in global DNA methylation with age, 25–27 but this relationship has not been established in HF. The age-related changes in healthy adults are likely not relevant in chronic HF.…”

“…Global methylation studies show varying DNA methylation with age, 25–27 exercise, 28,29 diet, 30–32 and environmental factors. 33–35 While NLRP3 and caspase-1 have inflammatory functions independent of the inflammasome, ASC functions only as an adapter protein as part of the inflammasome; the level of CpG methylation of ASC may control inflammasome formation.…”

Central nervous system toxicity of metallic nanoparticles

“…50 Under physiological conditions, ROS are present in every cell, being produced by the mitochondrial and cytoplasmic oxidation processes. A low to moderate ROS concentration is essential to maintain normal physiological processes.…”

“…46 In addition, Mohammadipour et al 47 observed reduced hippocampal cell proliferation and decreased spatial memory, inhibitory memory, and learning ability in rat offspring after the maternal administration of TiO 2 NPs during pregnancy. In that study, rats were exposed to 100 mg/kg body weight of TiO 2 NPs every day, which is equivalent to ~6,000 mg/60 kg of body weight for humans, far lower than the LD 50 (dose required to kill 50% of a population of test animals) of TiO 2 for rats (12,000 mg/kg body weight) per the 1969 guidelines of the World Health Organization (WHO). Although this dose was less than the dose reported by the WHO, it still had side effects on the hippocampus.…”

Association of semen cytokines with reactive oxygen species and histone transition abnormalities

“…A molecular study suggested that oxidative stress and ROS can impair the process of DNA methylation by inhibiting substrate synthesis or decreasing the activity of epigenetic enzymes such as DNMT and HDAC [28–31]. It is unclear if ROS can impair the histone-to-protamine transition in a similar manner and further investigation is thus warranted.…”