DNA Damage Theory of Aging and DNA Repair.

How Our Damaged DNA Kills Us

Summary:  Without DNA repair, the damage in our genome builds up, which in turn causes disease and aging. Scientists have made headway in understanding our DNA repair mechanisms and have found potential ways to mitigate some of its effects. 

For those us wanting to live in good health to the age of 120, the damaged DNA in our bodies is keeping us from reaching our goal.

Research has shown that our DNA repair mechanisms decline as we get older. Unless we are lucky to be among the tiny percentage of centenarians who are blessed with superb DNA repair mechanisms, the odds are that unrepaired DNA damage will strike us down with chronic diseases before we reach our goal.

DNA damage is a fact of life. Permanent DNA damage leads to loss of function, inflammation, chronic illness and participates significantly in our eventual demise. While the best option is to minimize DNA damage in the first place, efficient and reliable DNA repair is the goal.

Although a research report published this month shows that geroscientists have made significant progress, we still lack treatments that repair damaged DNA in healthy older adults.

Repairing DNA damage won’t stop aging and disease altogether. However, treatments that repair DNA will substantially slow down the aging process and could be a key weapon in our anti-aging arsenal.

The Holy Grail of DNA Repair

Effective DNA repair is one of the holy grails of anti-aging medicine.

Our body has its DNA repair mechanisms, but this, like many other things in our body, falters with age. If we could somehow keep our body’s DNA repair mechanisms in good working order, we would be well on our way to reaching the age of 120.

Researchers are piecing together the DNA repair puzzle.
Researchers are piecing together the DNA repair puzzle. Credit: Arek Socha/Qimono

DNA Repair Enthusiasts Have Their Own Magazine

DNA repair elsevier
DNA Repair Journal. © 2017 Elsevier B.V.

In the not too distant past, the concept of a physician repairing DNA was thought impossible. However, DNA repair is no longer far-fetched, rather, it is an emerging area of research and development. So popular in fact, that there is a scientific journal targeted to those dedicated to the field. While the DNA Repair journal is not available on newsstands, it shows that reputable scientific organizations have given their endorsement to the once-thought-impossible task of DNA Repair.

Don’t expect revolutionary treatments to come out of this field anytime soon. Scientists must first understand the pathways, to develop drugs that stimulate them. For years,  researchers have continued to identify DNA repair pathways, and the activity seems to have increased in the summer of 2017, leading to many published articles on the subject. So many, in fact, that a group of researchers led by Pan-Pan Jia at the Chinese Academy of Sciences,  felt it necessary to publish a review that summarizes the role of an important DNA repair molecule called DNA2.   According to the authors of the review,

DNA nuclease/helicase 2 (DNA2), a multi-functional protein protecting the high fidelity of genomic transmission, plays critical roles in DNA replication and repair processes.

The authors highlighted the recent findings around DNA2 and its importance in maintaining the length of telomeres. The researchers highlighted the potential role of DNA2 in the treatment of cancer and other diseases, adding

DNA2 is also involved in the stability of mitochondrial DNA and the maintenance of telomeres. Moreover, DNA2 potentially participates in controlling the cell cycle by repairing the DNA replication faults at main checkpoints.

Failing DNA Repair Mechanisms

Our real source of trouble isn’t the DNA damage in and of itself, as DNA damage happens all the time. Most of the time, our body’s DNA repair mechanisms fix the damage, but errors slip through and accumulate as we age. The deterioration of our DNA repair machinery is a primary cause of aging, as our failing repair mechanisms allow temporary errors to become permanent. As we grow older, decades of cumulative DNA damage take their toll, causing the gradual decline, disease and eventually death.

DNA Damage Theory of Aging. Aging is due to faulty DNA Repair.
DNA Damage Theory of Aging says that aging is mainly due to faulty DNA Repair. Photo Credit: Lisichik.

DNA Damage Theory of Aging

According to the DNA Damage Theory of Aging, the process of aging is caused by the accumulation of unrepaired DNA damage.

There is little disagreement among scientists that this accumulation of DNA damage is a significant cause of aging. Although there is a minority of researchers who disagree with the theory, the DNA Damage Theory of Aging is backed up by a great deal of experimental evidence over the past several decades.

As our DNA replicates, the cellular machinery involved in the process makes mistakes, leading to changes in the DNA sequence. Toxins such as free radicals, also called reactive oxygen species (ROS) or radiation can also damage DNA.  And since our body is made up cells, as our cells die, they bring the whole organism down to it.

While scientists know that excessive DNA damage causes illness and aging, they don’t have all the answers, yet. A noted authority on the genetics of aging, Jan Vijg is a researcher with the Albert Einstein College of Medicine. In a 2015 interview with The Scientist, Vijg said,

“We have beautiful next-generation sequencing methods, and we can sequence the DNA that we isolate from a tissue. But that will not help us a lot because mutations are random, and they will be different from cell to cell.”

While scientists are unsure about the nitty-gritty details, the big picture view is that unrepaired DNA damage promotes aging both directly, by increasing cell dysfunction as well as indirectly, by increasing cancer, cell death, and cellular senescence. The outcome in all of these paths is that the damaged DNA in our body slowly brings us down.

Four Fates of a DNA Damaged Cell

The future is not bright for a cell with DNA damage. Usually, the DNA that is damaged is in an unused portion of the genome. However, damage a vital part of the genome, and the outlook turns grim, because this DNA damage leads to one of four fates for the stricken cell: 1) suicide (cell death), 2) dysfunction, 3) inflammation-causing cellular senescence and 4) cancer.

Suicide is Painless

When its DNA has become too damaged, the healthiest thing for the cell to do is to kill itself. If a cell’s DNA is sufficiently damaged, it can eventually lead to mutations which in turn cause cancer. To combat this, a cell’s DNA damage response mechanisms go into action. These mechanisms can trigger protective measures to prevent the cell from becoming cancerous.

Even though the loss of cells leads to tissue atrophy and dysfunction, it is better for our health than the other fates. Our damaged cells are programmed to die, in a program called cell death. By dying, a damaged cell, ‘takes one for the team’ rather than bring his comrades down with him.

Even with an honorable suicide, we are not off the hook. Cells can sometimes die in the wrong way, and this can lead to a host of problems.

DNA Damage Causes Dysfunction

Most of who have owned a computer for any length of time notice that it slows down as the operating system becomes damaged by viruses or glitches. Damaged DNA declines in a similar way. As our genetic material becomes damaged, our cells become dysfunctional.

To keep our bodies running smoothly, our cells are constantly churning out proteins using the blueprints found in DNA. These proteins are the very fabric of life and, among other things, make up the enzymes that digest our food, create energy and other life-sustaining processes. Damage a crucial piece of DNA, and the cell produces misshapen proteins or simply stops functioning altogether. These misshapen proteins can be useless clutter or downright harmful, for example, when the brain cells of patients with Alzheimer’s disease churn out buckets of the toxic protein amyloid beta.

A few dysfunctional cells here and there don’t make much of a difference. However, as more and more of these cells accumulate, the organ itself can become dysfunctional causing many of the chronic diseases we associate with aging such as Alzheimer’s, frailty, and reduced capacity.

DNA Damage Causes Senescence

Sometimes our DNA-damaged cells don’t do the honorable act of committing hari-kari. Failing to kill themselves, these renegade cells enter a nonreplicating mode, called cellular senescence. Senescent cells refuse to do regular work. Unfortunately, they don’t sit idly by and just take up space. Instead, senescent cells are troublemakers. They speed up the aging process by secreting inflammatory molecules that contribute to age-related diseases. What’s more, they recruit healthy cells around them to become senescent as well.

A Way To Clear Out Senescent Cells

Fortunately, scientists have found new drugs called senolytics that rid our bodies of these troublemakers. While they have been only tested on mice thus far, their effects are nothing but astounding. Middle-aged mice were seemingly brought back to youth and displayed the bounciness, lustrous fur and vitality of a young mouse.

Senolytic drugs hold great promise as a way to rejuvenate our bodies. Two companies are planning to test the compounds in human patients later this year.

Related Article: Learn more about senolytic drugs in this report.

DNA Damage and Cancer

Cumulative DNA damage can also lead to tumors. As bad as cellular senescence is, it’s far preferable fate to cancer.  Becoming cancerous is the third and most health-ruining fate of a DNA-damaged cell.

There is no doubt that age is a risk factor for cancer, as epidemiological studies show that cancer rates rise as we age.  During the same 2015 interview with The Scientist, the geneticist Jan Vijg also said,

“There is this exponential increase in cancer risk during aging, so it’s not at all unlikely . . . that accumulation of damage to the genome is really a major factor here.”

And it’s not just leading scientists such as Vijg who feel that way. A prevailing view is that DNA damage and mutations contribute to cancer.

DNA damage is best fixed by DNA Repair.
Credit: Darwin Laganzon/TypographyImages

Deficient DNA Repair is Bad News

There is little doubt among researchers that DNA damage leads to aging, and our repair mechanisms decline with age. Therefore, scientists have reason to suspect DNA repair and stabilization mechanisms as culprits in the aging process. Researchers have linked the deterioration of DNA repair machinery to aging, showing that DNA errors become more common as organisms age.  One source of DNA damage is that our DNA scaffolding proteins that help stabilize our genome also change with age.

To gain insight into how DNA damage causes aging, scientists have studied premature-aging diseases in humans, such as Hutchinson-Gilford Progeria Syndrome (HGPS).  A rare genetic disorder, the symptoms of HGPS resemble premature aging. From an early age, children with HGPS suffer from an aged appearance, vision deterioration, hair loss, and atherosclerosis. Children afflicted with HGPS have mutations in their gene encoding scaffolding proteins called nuclear lamins.

Researchers have also studied Werner syndrome patients, who develop symptoms of advanced aging in their teens. These patients also have mutations in a gene responsible for DNA repair.

Improved DNA Repair Linked To a Longer Lifespan

Studies show that deficient DNA repair allows greater accumulation of DNA damage and causes premature aging. On the flip side, other studies indicate that increased DNA repair confers extra longevity.

The better your DNA repair mechanisms, the longer you’ll tend to live. And in better health. Researchers have identified lucky people that have single-nucleotide polymorphisms (SNP) in their DNA repair genes. These beneficial genetic changes cause them to have overactive DNA repair systems. Population-wide studies show that people with this particular SNP variant have much longer lifespans than ordinary folk.

Freitas and de Magalhães published a stunning review and appraisal of the DNA damage theory of aging. In their review, the scientific duo found that improved DNA damage repair leads to longer lifespans. Freitas and de Magalhães pointed to a study showing that, when compared to ordinary people 69 to 75 years of age, super agers between 100 and 107 years of age have higher levels of DNA repair enzymes.

Freitas and de Magalhães concluded that defective DNA repair systems accelerate aging. On the flip side, the duo found that enhanced repair mechanisms delay aging. However, the authors admitted that science has yet to grasp the full complexity of how the body responds to DNA damage.

The best way to prevent DNA damage is stop smoking.
The best way to prevent DNA damage is stopping smoking. Credit: Martin Büdenbender

Preventing DNA Damage

“An ounce of prevention is worth a pound of cure.”

– Benjamin Franklin, (One of America’s first scientists)

Heeding the word’s of one of America’s first scientists is the best way to sidestep DNA damage is to keep it from occurring in the first place. The obvious way is to stop smoking. Cigarette smoke is the largest source of preventable DNA damage. As well, some evidence suggests that calorie restriction may mitigate DNA damage. While prolonged calorie restriction is hard, some researchers feel we may get similar benefits from a kindler, gentler form of calorie restriction called the Fasting Mimicking Diet.

A related article tells you more about calorie restriction and the Fasting Mimicking Diet.

We cant repair DNA, but hopefully scientists can reverse some of the ill effects of DNA damage
Illustration: LaCasadeGoethe.

Repairing DNA Damage

Unfortunately, the eager readers of the journal DNA Repair have yet to come up with drugs that will prevent DNA damage in healthy aging adults. However, researchers have made progress in reversing some of its effects. As you’ll recall, the four fates of a cell with DNA Damage are cell death, dysfunction, inflammation-causing cellular senescence, and cancer.  Researchers have tested drugs that reverse cellular senescence in mice and are planning to test them in humans. As well, researchers have come up with a novel way of removing solid tumors in cancer patients. Learn more about these two recent discoveries in the two linked articles.

Related Article: Bacteriobot Holds ‘A Lot Of Promise’ To Treat Cancer, Says Doctor. 

Related Article:  New Age-Reversing Senolytics ‘Can Transform Medicine’ Says Leading Researcher

Bottom Line

Unrepaired DNA damage is one of the leading causes of the diseases of old age. In theory, if we could repair DNA damage effectively, we could slow down aging and illness. The field of DNA repair is an emerging area of research. Until scientists come up with a way to repair DNA damage, the best course of action is to prevent the damage from occurring in the first place.

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“How We Age | The Scientist Magazine®.” The Scientist Magazine. N.p., n.d. Online article. Retrieved 28 Sep. 2017. Link. 

Pan-Pan Jia, Muhammad Junaid, Yan-Bo Ma, Farooq Ahmad, Yong-Fang Jia, Wei-Guo Li, De-Sheng Pei. “Role of human DNA2 (hDNA2) as a potential target for cancer and other diseases: A systematic review,”  DNA Repair, Volume 59, 2017, Pg 9-19, ISSN 1568-7864, http://doi.org/10.1016/j.dnarep.2017.09.001.

Miook Cho, Yousin Suh. “Genome maintenance and human longevity.” Current Opinion in Genetics & Development, Volume 26, Issue null, Pages 105-115. (2014). PMC 4254320. PMID 25151201. doi:10.1016/j.gde.2014.07.002. Link.

Alex A. Freitas, João Pedro de Magalhães. “A review and appraisal of the DNA damage theory of ageing.” Mutation Research. (2011).  728 (1–2): 12–22. doi:10.1016/j.mrrev.2011.05.001. Link.


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