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DNA Damage Leads to Epigenetic Alterations

double strand breakdouble strand break

A team of researchers, including Dr. David Sinclair, has recently made a new study available as a preprint prior to peer review and publication in the journal Cell.

DNA damage and the double-strand break

Two of the primary hallmarks of aging are genomic instability, which consists of damage to our DNA, and epigenetic alterations, which are the changes in gene expression that occur with aging and are harmful to normal cell function.

The DNA in our cells is constantly being damaged on a daily basis. This damage comes from sources such as UV radiation from sunlight, exposure to radiation and chemical agents, and byproducts from our cells’ metabolism, including reactive oxygen species that are produced by the mitochondria and can strike and damage the DNA. The end result of this damage is double-strand breaks (DSBs) in the chromosome.

DSBs are a particular concern because if they are not repaired properly, they can cause deletions, translocations, or fusions in the DNA. These alterations are known collectively as genomic rearrangements and are typically seen in cancer cells.

DSBs are the most likely type of DNA damage linked to aging and are thought to occur at a rate of up to fifty times a day per cell. However, there is no need to panic because, thankfully, our bodies have evolved special checkpoint mechanisms that inspect the DNA for damage and facilitate its repair. Unfortunately, when the repair is imperfect, this can lead to mutations, and these are thought to gradually accrue as we age.

The link between DNA damage and epigenetic alterations

Despite it long having been the consensus that DNA damage and the resulting epigenetic changes are drivers of aging, some recent studies have questioned the importance of mutations in aging. For example, the number of mutations present in aged yeast cells is fairly low, and some genetically engineered strains of mice with high levels of free radicals or mutation rates do not appear to age prematurely, nor do they have shorter lifespans than their wild-type counterparts.

This appears to suggest that mutational load may not have such a strong influence on aging as was once thought, and the researchers of this new study consider further evidence suggesting the same. They also suggest that epigenetic alterations are perhaps the most important driver of aging and that, far from being random in nature, these changes are predictable and reproducible.

So, if this shift in gene expression is indeed one of the key drivers of aging (and there is plenty of supporting data to think it is), then what is causing the epigenome to change over time and what is the role of DNA damage in aging?

These researchers suggest that DSBs are a possible reason for epigenetic changes and show that there are clues to be found in yeast. In yeast cells, DSBs trigger a DNA damage signal that summons epigenetic regulators and takes them away from gene promoters to the site of the DSB on the DNA, where they then facilitate the repair of the break. The researchers suggest that after these repairs, the regulators responsible for repairing the DSBs return to their original locations on the genome, thus turning off the DNA damage signal, but this does not always happen.

The researchers suggest that with each successive cycle of DNA damage response and repair, the epigenetic landscape begins to change and regulators gradually become displaced, reaching a point where the DNA damage response remains active, leaving cells in a chronic state of stress. This stressed state then causes them to become dysfunctional and ultimately alters their cellular identity.

There are numerous hallmarks of aging in mammals, but no unifying cause has been identified. In budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly DNA double-strand breaks (DSBs). Mammals also undergo predictable epigenetic changes with age, including alterations to DNA methylation patterns that serve as epigenetic “age” clocks, but what drives these changes is not known. Using a transgenic mouse system called “ICE” (for inducible changes to the epigenome), we show that a tissue’s response to non-mutagenic DSBs reorganizes the epigenome and accelerates physiological, cognitive, and molecular changes normally seen in older mice, including advancement of the epigenetic clock. These findings implicate DSB-induced epigenetic drift as a conserved cause of aging from yeast to mammals.


If the researchers are correct, epigenetic drift initiated by DSBs is an evolutionarily conserved driver of aging from yeast all the way up to mammals. This research also confirms the link between DNA damage, and thus genomic instability, and epigenetic alterations and how the two collectively drive aging. This also has very interesting ramifications for therapies that reset the epigenome, such as partial cellular reprogramming.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
  1. jimofoz
    October 13, 2019

    Good summary Steve, appreciate it.

  2. October 15, 2019

    Sinclair Interview Excerpts

    Here is a 7 minute excerpt from my new film
    To Age or Not To Age wherein Sinclair explains his theory from the paper.

  3. October 15, 2019

    one other thing, David explains that the damage happens randomly (stochastic) but it is the “reaction that is predictable – because it is a defense mechanism.” It looks like a program but it’s not, in the sense of how
    Josh Mitteldorf would describe it.

    the full name of my film is “To Age or Not To Age – Transforming the Human Condition” and I am developing a series with a number of the scientists

    • October 16, 2019

      It does look like a program but it is most likely a quasi-program like Dr. David Gems has talked about. However, it seems likely at this point that epigenetic alterations are more than simply the hands of the clock and rather, they are the clock as increasing evidence suggests.

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