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Werner Syndrome: DNA and Human Aging

Author: Thomas C. Weiss : Contact:

Published: 2015-05-20 : (Rev. 2018-06-15)

Synopsis and Key Points:

Information regarding Werner syndrome, a genetic disorder that causes those affected to age more quickly than usual.

Main Digest

A study that ties the aging process to the deterioration of tightly packed bundles of cellular DNA might lead to methods of treating and preventing age-related diseases such as diabetes, cancer and Alzheimer's disease.

Werner syndrome (WS), also known as "adult progeria", is a rare, autosomal recessive progeroid syndrome (PS), which is characterized by the appearance of premature aging. Individuals with this disorder typically grow and develop normally until they reach puberty. Affected teenagers usually do not have a growth spurt, resulting in short stature. Werner syndrome is inherited in an autosomal recessive pattern, which means both copies of the WRN gene in each cell have mutations. The parents of an individual with Werner syndrome each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

In the study, scientists at the Salk Institute and the Chinese Academy of Science discovered that the genetic mutations underlying Werner syndrome, a disorder that leads to premature aging and death, resulted in the deterioration of bundles of DNA known as, 'heterochromatin.' The discovery was made possible through a combination of stem cell and gene-editing technologies. The discovery might lead to ways of countering age-related physiological declines by reversing or preventing damage to heterochromatin.

The findings show that the gene mutation that causes Werner syndrome results in the disorganization of heterochromatin and that this disruption of usual DNA packaging is a main driver of aging, according to Juan Carlos Izpisua Belmonte, a Senior Author of the paper. Mr. Belmonte stated, "This has implications beyond Werner syndrome, as it identifies a central mechanism of aging-heterochromatin disorganization - which has been shown to be reversible.

Werner syndrome is a genetic disorder that causes those affected to age more quickly than usual. The syndrome affects approximately 1 in every 200,000 people in the United States of America, and a global incidence rate of less than 1 in 100,000 live births (although incidence in Japan and Sardinia is higher, affecting 1 in 20,000 - 40,000 and 1 in 50,000, respectively). 1,300 cases had been reported as of 2006.. People with the disorder experience age-related diseases early in their lives to include:

The majority of those affected by the syndrome die in their late 40's to early 50's. The disease is caused by a mutation to the Werner syndrome RecQ helicase-like gene, which is known as the WRN gene for short and generates the WRN protein. Prior studies revealed that the usual form of the protein is an enzyme that maintains the structure and integrity of a person's DNA. When the protein is mutated by Werner syndrome, it disrupts the replication and repair of DNA and the expression of genes, which was thought to cause premature aging. How the mutated WRN protein disrupted critical cellular processes; however, was unclear.

Salk scientists, in their study, sought to determine exactly how the mutated WRN protein causes such a degree of cellular mayhem. To achieve this, the scientists created a cellular model of Werner syndrome by using a cutting-edge gene-editing technology to delete WRN gene in human stem cells. The stem cell model of the disease gave the scientists the unprecedented ability to study quickly aging cells in a laboratory. The resulting cells mimicked the genetic mutation seen in actual people with Werner syndrome whose cells started to age more quickly than usual. Upon closer examination, the scientists discovered that the deletion of the WRN gene also led to disruptions to the structure of heterochromatin, the tightly packed DNA found in a cell's nucleus.

The bundling of DNA acts as a form of, 'switchboard,' for controlling genes' activity and directs a cell's complex molecular machinery. On the outside of the heterochromatin bundles are chemical markers known as, 'epigenetic tags,' which control the structure of the heterochromatin. For example; alterations to these chemical switches may change the architecture of the heterochromatin and cause genes to be silenced or expressed.

The Salk researchers found that deletion of the WRN gene leads to heterochromatin disorganization, pointing to an important role for the WRN protein in maintaining heterochromatin. In additional experiments, the researchers showed that the protein interacts directly with molecular structures known to stabilize heterochromatin, revealing a type of, 'smoking gun,' that for the first time directly links mutated WRN protein to heterochromatin destabilization.

The researchers stated, "Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation. 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."

Mr. Belmonte added that more extensive studies are needed to completely understand the role of heterochromatin disorganization in aging, to include how it interacts with additional cellular processes implicated in aging such as shortening of the end of chromosomes known as, 'telomeres.' The researchers are developing apigenetic editing technologies to reverse epigenetic alterations with a role in human disease and aging.

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