Scientists have discovered that the deteorioration of the tightly-packed bundles of DNA that are responsible for our normal cell functioning is actually reversible, and figuring out how this process works could enable new treatments for age-related diseases like Alzheimer’s.
Researchers from the Salk Institute in the US and the Chinese Academy of Science made the discovery while studying the underlying causes of Werner syndrome – a genetic disorder that causes affected individuals to age more rapidly than normal.
People with this condition suffer age-related diseases early in life, such as cataracts, type-2 diabetes, osteoporosis, and cancer, and often die prematurely in their 40s or 50s.
The team found that the genetic mutations responsible for this syndrome caused densely packed DNA – known as heterochromatin – to become destabilised, which serves to disrupt normal cellular functions and caused the cells to age prematurely.
“This disruption of normal DNA packaging is a key driver of ageing,” senior researcher Juan Carlos Izpisua Belmonte, from the Salk Institute, said in a press release.
“This has implications beyond Werner syndrome, as it identifies a central mechanism of aging – heterochromatin disorganisation – which has been shown to be reversible.”
The mutant WRN gene that causes Werner syndrome produces a protein, which helps maintain the structure and integrity of a person’s DNA. But dysfunctional forms of this protein, like those that exist in people with Werner syndrome, can disrupt the replication and repair of DNA, and the expression of genes.
Researchers have previously thought that this might be a factor in ageing, but exactly how the dysfunctional protein hinders critical cell processes was unclear.
In this latest study, the team used a gene-editing technology to remove the WRN gene from embryonic stem cells, which can go on to become any type of cell in the body. These cells mimicked the genetic mutation seen in Werner syndrome patients, and they aged much faster than healthy cells.
The team also observed that the deletion of this gene led to the structural breakdown of heterochromatin. This bundling of DNA, which is found inside the cell’s nucleus, controls the activity of genes and helps the molecular machinery inside cells to function normally.
Chemical switches on the outside of these bundles of DNA can change the structure of the heterochromatin, causing genes to be expressed or silenced, the press release says.
In further experiments, the team was able to show that the mutated protein interacts directly with these chemical switches, serving to destabilise the structure of the heterochromatin DNA.
As part of their study, the researchers also tested stem cells from the dental pulp of healthy people across a wide age range. They found that older individuals, aged between 58 and 72, had fewer genetic markers for the DNA instability than people between the ages of seven and 25.
“What this study means is that this protein does not only work in a particular genetic disease, it works in all humans,” Belmonte told Alice Park at TIME. “This mechanism is general for aging process.”
The team’s findings were reported in Science.
“Our study connects the dots between Werner syndrome and heterochromatin disorganisation, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation,” said Belmonte.
“More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations – like remodeling an old house or car – to prevent, or even reverse, age-related declines and diseases.”
The team says more extensive studies will be needed to fully understand the role that this DNA breakdown plays in ageing, particularly, how it works in conjunction with other cellular processes implicated in aging, such as the shortening of telomeres, which are fragments of DNA on the ends of our chromosomes.
Importantly, before it becomes anything close to heralding the fountain of youth we all crave, researchers will need to develop ways to specifically target, and safely edit, these genes in humans, rather than in petri dishes.
Credits: Science Alert.
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