Mather, Armstrong, Thalamuthu & Kwok
Keywords: DNA methylation • epigenetic clock • exceptional longevity • longitudinal studies

With the advancement in science and technology, many clues are available, but not enough to have a clear picture of how DNA methylation loci are associated with “exceptional aging”.

There are two factors that are considered as causes of aging. One is the concept of entropy, where disorder accumulates and bodily parts wear out over time. Another is that aging happens according to an instruction set written in the genome. ¹⁾ Related to the hypothesis that aging has a programmed component, is epigenetics.

“Epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself.” ²⁾ Older persons express the same genes differently than a younger person. DNA contains the genetic code for both states, both young and old.

Gene expression can be altered by many means, including histone acetylation, chromatin remodeling, noncoding RNAs, and DNA methylation. DNA methylation has had the most study due to the ease in which it can be investigated, and is the focus of the article.

An organism can create a molecule used for its sustenance, by copying a segment of the DNA molecule as an RNA molecule, a process known as transcription. Transcription is affected by methylation.

Methylation can have many effects, depending on its location. Effects include disabling or slowing down transcription, therefore decreasing the supply of the particular molecule.

Because of the complexity of molecular interactions in an organism, cause and effect are difficult to establish. The article covers many other research studies trying to find patterns between methylation, health, and age. Research has hypothesized the existence of an epigentic clock that may be based on the methylation state.

Cross-sectional studies and Longitudinal studies were performed to know how epigenetic methylation effects aging. In cross-sectional studies, the young and old members of a population are compared. Longitudinal studies follows individual members of a population over an extended period of time, to see how aging affects their genome.

Most of the studies performed were cross-sectional, comparing younger and older cohorts, either as unrelated or family studies. These studies when performed showed changes in DNA that occurs during the aging process or changes that resulted in diseased gene causing longevity or early mortality. But cross-sectional studies had its own limitations like

1. Inter-individual variability. 2. Age specific differences. 3. Information obtained was not enough.

Ideally longitudinal study is more ideal as it is performed on the same population over a prolonged period of time by follow up, which helps in keeping the track down of the changes due to methylation and its effects on longevity. Limitations:

1. Logistic difficulties. 2. Lengthy procedure.

Epigenetic clocks & interpretation of data

Recent researches have been performed using DNA methylation profile to calculate the chronological age that has suggested the existence of Epigenetic clock;

• Bocklandt et al predicted the human age using DNA methylation profile in a study using saliva sample from 34 male monozygotic twin pairs between 21-45 years of age.
• Horvath et al researched on over 8000 samples revealing that DNA methylation age is zero for embryos.
• Hannum et al, further developed the concept of the epigenetic clock in a cohort of 656 participants aged 19–101 years from whole blood.
• Marioni et al calculated the difference between an individual’s chronological age and DNA methylation age (?age), and demonstrated that this difference could significantly predict all-causes of mortality in later life.
• Gross et al conducted an analysis on 137 HIV+ men. He found out HIV infection leads to an average advancement of 4.9 years, increasing expected mortality risk by 19%.

Hence these studies suggest that some of the epigenetic loci are altered with disease processes and ultimately with mortality.

UNRESOLVED ISSUES:

• Horvath et al studied on centenarians and younger individuals, suggesting that the chronological age was underestimated by 8.6 years. If this is the case then it could affect the power of our cross-sectional longevity studies to detect the loci.
• Gross et al demonstrated on HIV+ individuals suggesting that disease associated changes in epigenetic clock are not consistent in all cell types.
• Horvath et al performed on individual with Huntington’s disease demonstrating that epigenetic clock is differentially compromised in disease states. Therefore, the utilization of tissue-specific methylation clocks should be of relevance to the disease of interest. For example, tissue derived from brain would be of more relevance to neurological disorders.
• Some recent studies have shown that some positions in DNA acts differently than expected, it is still unknown that how would it react in long lived individual.
• The underlying causes that affect the epigenetic clock are still unknown. It is believed that the individuals who can regulate the DNA methylation the best have the slowest epigenetic clock.
• Limitations of technology and statistical analyses – There have been a rapid progress in science and technology but still we fall short to reach conclusive findings on aging and its application to control it to some extent.

Future perspective

Today we lack proper knowledge of DNA methylation loci that are associated with exceptional longevity. Future studies may help us identify these loci responsible for longevity.

With future research and advancement of science, we may be able to modify them and promote healthy aging.

This may help us in finding diseased genes and we can modify them accordingly, hence help us in improving living standards.