The processes of aging and the development of various age-related diseases have long been of interest to scientists around the world, because by understanding their course, we can not only correct, but possibly completely reverse them. However, until recently, it remained unclear what triggers the aging process.
Science has published a study linking the aging process to the deterioration of densely packed bundles of cellular DNA, which may lead to the development of methods for the prevention and treatment of age-related diseases such as cancer, diabetes and Alzheimer's disease in the future.
During their joint study, scientists from the Salk Institute and the Chinese Academy of Sciences discovered that the genetic mutations that underlie Werner's syndrome, a disorder that leads to premature aging and death, are caused by a deterioration of DNA bundles known as heterochromatin.
The discovery, made through the combination of stem cells and gene editing technology, could be the basis for developing methods to counteract age-related changes by preventing or repairing damage to heterochromatin.
"Our findings show that mutations in the gene that causes Werner's syndrome cause disorganization of heterochromatin, and that this disruption of the DNA structure is a key factor in triggering the aging process," says Juan Carlos Ispisua Belmonte, head of research. — "This discovery not only made it possible to determine the main cause of aging - the destruction of heterochromatin, but also showed that this process is reversible."
Werner Syndrome is a genetic disorder that causes people to age faster than usual. It occurs once in 200,000 people. People with this disorder suffer early in life from age-related diseases (cataracts, type 2 diabetes, hardening of the arteries, osteoporosis, and cancer), and their life expectancy is reduced to 40-50 years.
The disease is caused by a mutation in the Werner syndrome helicase gene RecQ, or WRN gene for short, which generates the WRN protein. Previous research has shown that the normal form of a protein is an enzyme that maintains the structure and integrity of human DNA. Mutation of this protein disrupts DNA replication and repair and gene expression, which was thought to be the cause of premature aging. However, it remained a mystery how exactly the mutated WRN protein disrupts these important cellular processes.
During their study, the Salk Institute scientists tried to determine how exactly the mutated WRN protein causes such massive cellular chaos. To do this, they created a cellular model of Werner syndrome using gene editing technologies to remove the WRN gene from human stem cells. This stem cell model of the disease has provided scientists with an unprecedented opportunity to study rapidly aging cells in the laboratory. The resulting cells mimicked a genetic mutation that occurs in patients with Werner's syndrome, so they began to age faster than usual. Upon closer examination, the scientists found that the extraction of the WRN gene also disrupted the structure of heterochromatin - sections of chromatin that are in a condensed (compact) state during the cell cycle.
The structure of DNA acts as a switch to control the activity of genes and governs complex cellular machinery. On the outside of heterochromatin bundles are chemical markers known as epigenetic endings that control the structure of heterochromatin. For example, changes to these chemical switches can alter the structure of heterochromatin, causing gene expression or silencing.
Researchers have found that deletion of the WRN gene leads to disorganization of heterochromatin, proving an important role for the WRN protein in maintaining heterochromatin structure. in further experiments, it was found that the protein interacts directly with molecular structures known to stabilize heterochromatin, which is indisputable evidence of a direct connection of the mutated WRN protein with heterochromatin destabilization.
"Our study has shown a link between Werner's syndrome and heterochromatin disorganization, demonstrating the molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by interfering with epigenetic regulation of gene expression," Belmonte says. “In other words, he suggests that accumulated changes in the structure of heterochromatin may be the main cause of cellular aging. The question arises whether it is possible to reverse these changes in order to prevent or even cure age-related disorders.”
Further studies will be required to definitively determine the role of heterochromatin disorganization in triggering the aging process. They will allow scientists to understand how this disorganization interacts with other cellular processes involved in aging, such as the shortening of the ends of chromosomes, known as telomeres. In addition, a team of researchers is working on epigenetic editing technology to reverse epigenetic changes that play an important role in the process of human disease evolution and development.
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