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Genomic Instability and Downstream Effects

Broken DNABroken DNA

A new open-access review published in Trends in Cell Biology sheds light on both the causes and consequences of genomic instability, the DNA damage that is one of the primary hallmarks of aging.

Sources of Damage

A substantial portion of genomic instability is caused by unwanted reactions with chemicals that we need to survive.

Oxidation is probably the most well-known source of age-related damage. While human beings require oxygen to live, oxygen is a very reactive element; it naturally forms reactive oxidation species (ROS) that react with DNA itself. Additionally, other compounds that have been oxidized by ROS can bind to DNA, creating toxic adducts that impair its function. ROS are also responsible for a large part of mitochondrial dysfunction, another of the hallmarks of aging, as the mitochondrial DNA has fewer protections than the DNA in the nucleus. Antioxidants serve as the first line of defense against ROS, preferentially reacting with them in order to form harmless compounds rather than DNA-damaging byproducts.

Acetaldehyde, which is formed as part of natural metabolism in addition to the consumption of alcohol, binds to DNA and creates cross-links with it. Enzymes metabolize acetaldehyde into acetate before it can harm DNA, and people who are unable to produce these enzymes properly are more susceptible to alcohol-induced cancers.

One of the more interesting sources of damage comes from S-adenosylmethionine (SAM). This chemical is critical for life, as it allows for methylation of DNA; this methylation is responsible for gene expression, which lets our cells differentiate into the familiar cell types, such as muscle cells, neurons, and bone cells. However, when it reacts with DNA without the help of an enzyme, it fails to methylate properly, instead forming a mutagenic methyl adduct.

Ultraviolet radiation is another well-known damage source. In addition to forming specific mutagenic lesions in the DNA, exposure to UV also forms ROS of its own, posing an extra level of threat.

Natural Defenses

There are a few ways in which our bodies attempt to repair genomic damage. Repair enzymes spring into motion, fixing excisions and double-strand breaks along with untangling DNA cross-links. Each enzyme is responsible for repairing a different sort of damage.

However, not everyone is born with fully functional genetic repair mechanisms. People with the same specific defect of a repair source share the same symptoms. A great portion of this review is spent on discussing these conditions, nearly all of which are crippling and significantly reduce lifespan, and many of them also share certain symptoms with aging. The reviewers explain that this suggests that specific types of DNA damage may be responsible for specific symptoms of aging.

Of course, our repair mechanisms, even when fully functional, are imperfect; they cannot repair every error, and accumulated genomic instability leads to downstream effects that cause further damage.

Downstream Effects

Genomic instability leads to one of three outcomes: death, cancer, or senescence.

Cellular death, which cells often undergo in an evolved response to genetic damage, is often considered the safest of these three; dead cells do not grow uncontrollably nor emit the senescence-associated secretory phenotype (SASP). However, rampant genomic instability can kill too many cells, causing degeneration in organs, including the brain, and the researchers name Parkinson’s disease as one of the associated disorders.

Cancer is, of course, the most well-known result of genomic instability, and the researchers do not spend time on explaining it in this review.

Cellular senescence, a downstream hallmark of aging, causes its own damage. While senescent cells promote wound healing and other necessary functions, they also emit the SASP, which causes the chronic inflammation known as inflammaging. The researchers note the effectiveness of senolytics in mouse studies, a topic that we frequently cover.

Potential Therapies

Unfortunately, there are not yet any therapies that directly repair DNA, nor are there any such therapies in development. The researchers discuss senolytics, NAD+, and therapies that affect deregulated nutrient sensing; however, while they have been shown to be beneficial, these therapies deal with the downstream consequences of genomic instability rather than the root cause itself.


As a general rule, as researchers discover more about aging, they often find that it is a panoply of processes, even within individual hallmarks of aging. For example, there is currently no broad senolytic treatment that destroys all senescent cells; instead, different senescent cell types require different senolytics. It should be absolutely no surprise, then, that genomic instability is turning out to be a broad term that refers to multiple types of genetic damage, each of which has its own symptoms and potential therapies.

For rejuvenation researchers and advocates, this should be a call for rejoicing rather than alarm. By discovering the exact causes and consequences of the individual problems that cause crippling diseases, we are better poised to develop therapies that directly counteract them, hopefully leading to cures for the genetic diseases that cause progerias and other “premature aging” disorders along with therapies that directly tackle the multiple varieties of genomic instability itself.

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About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
  1. January 10, 2020

    I am waiting.

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