2016-11-18
Mather, Armstrong, Thalamuthu & Kwok
Keywords: DNA methylation • epigenetic clock • exceptional longevity • longitudinal studies
https://doi.org/10.2217/epi-2016-0137

With the advancement in science and technology, many clues are available, but not enough to have a clear picture of the cause of aging, or the genomic traits of individuals that will live long healthy lives. Scientists have not succeeded in discovering genes associated with exceptional longevity. Attempts have been made to find other genome attributes that lead to longevity, besides genes or other DNA sequences.

DNA does not live in a void by itself. Kwok et al overview studies pertaining to molecules that attach to DNA. In particular, studies of DNA methylation, the adding of methyl groups to a cytosine base of DNA. Methylation can change the activity of molecular interactions with a DNA segment.

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.

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. Kwok et al cover many other research studies trying to find patterns between methylation, health, and age. Research has hypothesized the existence of an epigentic clock which may be based on the methylation state.

Cross-sectional studies and Longitudinal studies have been performed to investigate how epigenetic methylation affects aging. In cross-sectional studies, the young and old members of a population are compared. Longitudinal studies follow the same 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 or twins. These studies showed possible differences in the genome from the aging process, or they showed differences resulting from disease.

Cross-sectional studies have inherent limitations:
1. The genomes of different persons makes it hard to set a baseline.
2. A higher number of confounding variables and lack of scientific_controls.
3. Insufficient information for statistically meaningful conclusions.

Whereas cross-sectional studies look at different genomes of different ages at one point in time, longitudinal studies have the advantage of looking at how individual genomes change over long periods of time.

Longitudinal study limitations:
1. Lack of standardization in methods for collection/extracting of blood or genetic material, and storage thereof.
2. Lack of standardization for methylation analysis.
3. Time commitment for a study, and unknown time period for statistical significance.

DNA methylation profiles estimate a chronological age, suggesting a conceptual epigenetic clock.

There are regions of stochastic, or random, methylation along the chromosomes. However, some isolated regions show a consistent decline in methylation density with age. In exceptionally long lived individuals, there are regions that decline less rapidly, suggesting younger epigenetic age and long-lived phenotype.

Embryonic stem cells have the highest amount of chromosomal methylation. Highly methylated chromosomes are more tightly condensed, with less surface area for molecular interactions effectuating less active or disabled gene sites.

In the lab, scientists can convert somatic_cells into stem cells of pluripotent nature. These cells also have a methylated state resembling embryonic stem cells. This methylated state can be thought of as having a “DNA methylation age” of zero.

When scientists work with tissue cultures, the cells in the culture also have altered methylation over time, and is associated with the passage_number. “The DNA methylation profiles of mammalian cell lines differ from those of the primary tissues from which they were derived, exhibiting increasing divergence from the in vivo methylation profile with extended time in culture.” ³⁾

There has been efforts into finding key locations, or loci, along the chromosome, in hopes of isolating or reducing the complexity of a statistical model of aging. These loci are compared to a person's calendar age.

Individuals that skew from the mean towards a younger “DNA methylation age”, compared to their physical age, tend to live longer lives.

While the studies may aspire to find a biological process for aging, currently the methylated loci are only age indicators, like measuring the amount of wrinkles on a person's face, or the quality of one's teeth.

• 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, 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%.

• 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.

(UNDER CONSTRUCTION)

— Marcos Reyes 2019/07/30 04:38
— Sobia Syed 2019/07/30 04:38

https://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070