Researchers Discover Key Protein for Human Aging


Judy Lau
Staff Writer

Researchers at the Salk Institute and the Chinese Academy of Science discovered a protein that plays a key role in stabilizing heterochromatin, a tightly packaged form of DNA. These findings suggest that heterochromatin disorganization may be a key driver of aging.

The discovery used cutting-edge stem cell and gene-editing technologies and found that genetic mutations underlying Werner syndrome, a disorder that leads to premature aging and death, resulted from deterioration of bundles of DNA known as heterochromatin. This research could lead to ways of countering age-related physiological declines by preventing or reversing heterochromatin damage.

Werner syndrome is a genetic disorder that causes people to age rapidly, and it affects around one in every 200,000 people in the United States. People with this disorder also suffer age-related diseases earlier in life, including diabetes, hardening of arteries, cancer, and cataracts. Most die in their late 40s and early 50s.

“Our findings show that the gene mutation that causes Werner syndrome results in the disorganization of heterochromatin, and that this disruption of normal DNA packaging is a key driver of aging,” says Juan Carlos Izpisua Belmonte, a senior author on the paper. “This has implications beyond Werner syndrome, as it identifies a central mechanism of aging—heterochromatin disorganization—which has been shown to be reversible.”

The disease is caused by a mutation to the RecQ helicase-like gene, which play an important role in catalyzing ATP to unwind DNA and help genome maintenance, known as the WRN gene for short, which generates the WRN protein. The normal form of the protein is an enzyme that maintains the integrity and structure of a person’s DNA. In Werner syndrome, the protein is mutated and disrupts the replication and repair of DNA, thus altering the expression of genes, which was originally thought to cause premature aging. However, it is unclear as to how the WRN protein disrupts these processes.

“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,” says Belmonte.

Salk researchers sought to determine how the mutated WRN protein caused all these cellular problems. They created a cellular model of Werner syndrome by using gene-editing technology to delete WRN gene in human stem cells. This stem cell model gave scientists the ability to study rapidly aging cells in the laboratory.

They discovered that deletion of the WRN gene leads to heterochromatin disorganization, pointing to an important role for the WRN protein in maintaining heterochromatin. Further experiments showed that the protein interacts with molecular structures known to stabilize heterochromatin, showing that heterochromatin destabilization directly links to a mutated WRN protein.

The bundling of DNA switches between controlling genes’ activity and directing a cell’s complex molecular machinery. Heterochromatin bundles are chemical markers, known as epigenetic tags, which control the structure of the heterochromatin. Alterations of these chemical switches can cause genes to be expressed or silence.

“More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging,” says Belmonte. “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.”

Belmonte added that more studies will be needed to fully understand the role of heterochromatin disorganization in aging, including how it interacts with other cellular processes that come with aging, such as shortening of telomeres, which are the ends of chromosomes. The Belmonte team is also developing epigenetic editing technologies to reverse such alterations, with a primary focus on human aging and disease.