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Today’s open access paper reviews what is known of the connections between epigenetic aging and the nuclear DNA damage that occurs across a lifetime, and particularly in later life. Some of this DNA damage is more evidently connected with the epigenetic regulation that determines the packaging and structure of nuclear DNA, such as the activity of transposable elements, restrained in youth, but unleashed to copy themselves in later life, damaging genes as they do so. It is important to note that the relationship of cause and consequence between nuclear DNA damage and epigenetic change is likely a two-way street, particularly given the comparatively recent discovery that repeated double strand break repair causes epigenetic alterations characteristic of aging.
While nuclear DNA damage raises the risk of cancer, such as via damage to cancer suppression genes, it is fortunately largely irrelevant, occurring in cells that have only a few replications left before hitting the Hayflick limit, and will therefore soon be removed from tissues, or in parts of the genome that are inactive. Outside of the cancer risk, and the epigenetic change noted above, it can be argued that only DNA damage in stem cells and progenitor cells is relevant to aging, as these mutations can spread throughout a tissue. The pattern of mutations in a tissue, some of which will potentially alter cell behavior in damaging ways, is known as somatic mosaicism. Proving that this causes issues beyond cancer risk is ever a challenge, however. A great many harmful processes operate in aged tissues, and determining the relative impact of any one of those processes is very difficult, absent a way to fix it in isolation of all other processes of aging.
Epigenetics, DNA damage, and aging
The biology of aging is very complex, and the heterogeneity of aging is abundantly clear. Over a decade ago, nine hallmarks of aging were identified at the cellular and molecular level. The universality of the hallmarks of aging across species suggests their causal role in driving aging. However, establishing cause and consequence has proved challenging. Notably, more than one of the hallmarks reflect alterations to the nuclear genome, the integrity of which is vital to cell function. Here, we focus on the relationship of two hallmarks of aging affecting the nuclear genome: macromolecular damage and epigenetic alterations.
In eukaryotes, epigenetic modifications are critical because of their effects on gene transcriptional regulation. During development, different cell types establish and maintain specific epigenetic landscapes that dictate their cell fate. With aging, pronounced epigenetic alterations occur, including changes to DNA methylation and histone modifications, two key regulators of gene expression. Concurrent with these changes, spontaneous DNA lesions occur every single day within each of the 10^13 cells that constitute a human body. These lesions stall DNA and RNA polymerases, provoking a DNA damage response (DDR) that halts the cell cycle, enabling DNA repair.
Excessive or chronic DDR triggers irrevocable cell fate decisions, e.g., apoptosis and senescence. These two hallmarks of aging are intimately intertwined: DNA repair alters the epigenome and the epigenome impacts DNA repair efficiency. Furthermore, epigenetic marks to DNA can promote DNA damage. Genotoxic stress (DNA damage) is accepted as playing a causal role in cancer and in aging. Epigenome instability is established to play a causal role in cancer, but the mechanism by which epigenetic changes might play a causal role in aging are not well defined. Given the plethora of epigenetic clocks that correlate with chronological and even biological age, the causal relationship likely exists. Herein, we examine the current state of evidence that epigenetic alterations contribute to driving aging biology. In addition, because epigenetic changes impact genome stability, we explore the relationship between epigenetic marks and DNA damage.