Epigenetic alterations, as described in the Hallmarks of Aging [1], are age-related changes in gene expression that harm the fundamental functions of cells and increase the risk of cancer and other age-related diseases.

What are epigenetic alterations?

One of the proposed reasons we age is the changes to gene expression that our cells experience as we get older; these are commonly called epigenetic alterations. These alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases.

The DNA in each of our cells is the same, with only slight differences, so why do our various organs and tissues look so different, and how do cells know what to become?

Gene expression is modified by the addition of epigenetic markers to the DNA changing the pattern of gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. You might think of DNA as the building blocks and epigenetics as the instruction manual that explains how to assemble those blocks to make a certain structure to suit a particular situation.

This is how a cell in the liver knows that it needs to be a liver cell: the epigenetic instructions make sure that it is given the right guidance to become the correct cell type. At a basic level, these epigenetic instructions make sure that the genes needed to develop into a liver cell are turned on while the instructions specific to other types of cells are turned off.

However, as we age, our cells are exposed to environmental factors and are subject to negative changes in their genome through epigenetic mechanisms. Such changes accumulate over time and have been correlated with the decline observed in aging cells.

Epigenetic alterations in aging include changes to methylation patterns and in general, these correlate with a decrease in the amount of heterochromatin and an increase in chromosome fragility and transcriptional alterations (variance in gene expression), remodeling of chromatin (a DNA support structure that assists or impedes its transcription), and transcriptional noise.

How epigenetic alterations accumulate

Aging can cause alterations to our epigenome, which can lead to alterations in gene expression that can potentially change and ultimately compromise cell function. As an example, epigenetic alterations of the immune system can harm activation and suppress immune cells, thus causing our immune system to fail and leaving us vulnerable to pathogens. Inflammation is implicated in epigenetic alterations, and studies show that caloric restriction slows the rate of these epigenetic changes [2]. Metabolism and epigenetic alterations are closely linked with inflammation, facilitating a feedback loop leading to ever-worsening epigenetic alterations.

Alterations to gene expression patterns are an important driver of aging. These alterations involve changes to DNA methylation patterns, histone modification, transcriptional alterations (variance in gene expression) and remodeling of chromatin (a DNA support structure that assists or impedes its transcription).

In the cell, gene expression is activated by hypomethylation (a loss of methylation) or silenced by hypermethylation (an increase of methylation) at a gene location. Aging causes changes that reduce or increase methylation at different gene locations throughout the body. For example, some tumor suppressor genes become hypermethylated during aging, meaning that they cease functioning, which increases the risk of cancer [3].

Post-translational modifications of histones regulate gene expression by organizing the genome into active euchromatin regions, where DNA is accessible for transcription, or inactive heterochromatin regions, where DNA is compacted and less accessible for transcription. Aging causes these regions to change, which changes gene expression.

Aging also causes an increase in transcriptional noise, which is the primary cause of variance in the gene expression happening between cells [4]. Researchers compared young and old tissues from several species and identified age-related transcriptional changes in the genes encoding key components of inflammatory, mitochondrial, and lysosomal degradation pathways [5]. Finally, chromatin remodeling alters chromatin from a condensed state to a transcriptionally accessible state, allowing transcription factors and other DNA binding proteins to access DNA and control gene expression.

Conclusion

If we can find ways to reset age-related epigenetic alterations, we can potentially improve cell function, thus improving tissue and organ health.

One potential approach is the use of reprogramming factors, which reset cells to a developmental state, thus reverting epigenetic changes. We have been doing this for over a decade to create induced pluripotent stem cells, and recent work has seen a therapy based on that technique applied to living animals to reset their epigenetic alterations [6]. This reversed a number of age-related changes, and work is now proceeding with the goal of translating this to humans.

Epigenetic alterations might be considered like a program in a computer, but in this case, it is the cell, not a computer, being given instructions. Ultimately, damage causes changes that contribute to the cell moving from an efficient “program” of youth to a dysfunctional one of old age. If we can reset that program, we can potentially address this hallmark of aging, and a number of researchers are working on that right now.

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Maegawa, S., Lu, Y., Tahara, T., Lee, J. T., Madzo, J., Liang, S., … & Issa, J. P. J. (2017). Caloric restriction delays age-related methylation drift. Nature Communications, 8.

[3] Maegawa, S., Hinkal, G., Kim, H. S., Shen, L., Zhang, L., Zhang, J., … & Issa, J. P. J. (2010). Widespread and tissue specific age-related DNA methylation changes in mice. Genome research, 20(3), 332-340.

[4] Bahar, R., Hartmann, C. H., Rodriguez, K. A., Denny, A. D., Busuttil, R. A., Dollé, M. E., … & Vijg, J. (2006). Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature, 441(7096), 1011-1014.

[5] De Magalhães, J. P., Curado, J., & Church, G. M. (2009). Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics, 25(7), 875-881.

[6] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.