By studying a premature aging disorder called Werner syndrome, researchers may have uncovered a key driver of normal human aging: loose, disorganized bundles of DNA. The findings were published in Science this week.
People with Werner syndrome (also called adult progeria) suffer age-related diseases early in life -- from cataracts and graying hair to osteoporosis, type 2 diabetes, arthrosclerosis, and cancer. Most patients die in their late 40s or early 50s. The disorder is caused by mutations on the WRN gene and the deficiency of the WRN protein that results. Previous work revealed that the protein helps maintain the structure and integrity of DNA, but exactly how the mutated protein wreaks cellular havoc remained unclear.
To create a cellular model of Werner syndrome, Weiqi Zhang from the Chinese Academy of Sciences and colleagues knocked out a portion of the WRN gene from human embryonic stem cells. As they matured, the WRN-deficient cells began to mimic the genetic mutation seen in the cells of Werner syndrome patients, displaying tell-tale signs of premature aging. These include losing the ability to divide and having shorter telomeres (the caps at the ends of chromosomes), Science reports. Importantly, their heterochromatin -- the tightly packed DNA in the cells’ nuclei -- became disorganized. This is the same thing that happens in cells that have aged normally.
The WRN protein, the researchers conclude, safeguards cells against aging by stabilizing their heterochromatin. This important bundle of DNA acts like a switchboard for controlling the activity of genes and directing various molecular components. On the other hand, deleting the WRN gene alters the architecture of the cell’s heterochromatin, aging the cells rapidly.
These changes could be a potential driving force of natural human aging, and by understanding how neatly packaged DNA deteriorates, researchers hope to prevent or treat Werner syndrome as well as various age-related diseases. "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," study author Juan Carlos Izpisua Belmonte of the Salk Institute says in a news release. "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."