Anti Aging

A Popular Science View of Recent Thinking on DNA Damage as a Cause of Aging – Fight Aging!

There are presently two views of the way in which stochastic DNA damage can contribute to aging. Most DNA damage occurs in inactive genes in cells that will not replicate many more times, and thus cannot possibly produce systemic consequences throughout large regions of the body. The first argument for a way in which random DNA damage can produce a broader effect is via somatic mosaicismin which mutational damage occurs in stem cellsallowing those mutations to spread throughout tissue over time. It is unclear as to how to measure the contribution of this process to age-related loss of function, however, and its contribution to aspects of aging other than cancer risk remains debated.

The second view focuses on changes in gene expression that can result from the complex processes of DNA damage and DNA repair. The actions of DNA repair in particular can alter the balance of various factors in the cell nucleus, leading to altered epigenetic marks on the genomealtered nuclear genome structure, and consequently altered transcription of DNA to RNA. This can link DNA damage even in inactive genes to broad consequences for cell behavior. Today’s popular science article provides a readable overview of one such issue noted in older animals, dysfunction in the RNA polymerase II that moves along the genome to read DNA and assemble molecules to form RNA. With age, this production of RNA becomes slower and more prone to failure, changing the landscape of gene expression and thus also changing cell behavior.

Why Do We Age? DNA Damage A Likely Cause

Researchers discovered that, in older mice, RNA polymerase II often begins to stall while transcribing DNA into RNA. By analyzing the liver of two-year-old mice – ancient, by mice standards – they noticed that up to 40% of all RNA polymerase II complexes had stalled. To add to this, each stalled complex is likely to block the next three complexes behind it, quickly leading to queuing and gunking up the DNA strand until the obstruction can be cleared. The researchers found that larger genes are especially prone to these issues, leading to a bias towards expression of small genes.

With transcription interrupted, gene expression is also interrupted. As a result, many cellular pathways begin to go haywire; they are deprived of the proteins they need for problem-free functioning. These include all of the same pathways that begin to malfunction as we age. In other words, the genetic fingerprint produced by interrupted transcription is the same as that produced by aging, suggesting that the two are intimately connected. Affected pathways include those involved in nutrient sensingclearing of cellular debris, energy metabolism, immune functionand the ability of cells to handle damage. All of these play vital roles in shaping life span.

The researchers next set out to understand what caused the RNA polymerase II to stall in older mice. Their suspicions fell on spontaneous, internal DNA damage. Gene expression patterns in cells that have been exposed to DNA-damaging agents are very similar to those seen during normal aging. Premature aging disorders, such as Cockayne syndromeare also characterized by DNA damage; the usual DNA repair mechanisms malfunction, leading to stalled RNA polymerases at sites of damage, known as lesions. Given these similarities, the scientists speculated that DNA damage could also be involved in normal aging.

To test their hunch, the researchers monitored genetically altered mice that lacked the usual DNA repair machinery, leaving them prone to accumulated DNA damage. These mice exhibit many features of premature aging, including a significantly shortened lifespan. As expected, the rate of transcription was noticeably lower in these mice compared to healthy controls.

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