Genetics of aging revealed by discovery of rare diseases

Small vessel disease (SVD) causes damage to small arteries and capillaries that reduces blood flow to sensitive organs such as the eye, brain, and kidney, and can be caused by aging, high blood pressure, and genetic abnormalities. Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is an SVD caused by an inherited mutation in the TREX1 gene. It is rare, with fewer than 200 known cases worldwide. Symptoms develop between 35 and 55 and affect the liver, kidneys, eyes and brain, leading to organ damage and failure and early death.

Scientists were aware of the link between the TREX1 gene and RVCL, but not how the mutated gene caused damage to the small vessels. Now, a new study led by researchers from the Perelman School of Medicine at the University of Pennsylvania (Penn Medicine) and the Brain Research Institute at Niigata University, Japan, has shed light on the mechanism of action of the mutated gene. And the findings could have ramifications beyond RVCL.

“It appears that accelerated DNA damage in RVCL causes premature aging of certain cells, including cells in the vessel wall,” said Jonathan Miner, an associate professor of rheumatology at the Perelman School of Medicine and corresponding author. of study. “If this is the case, then targeting TREX1 could have far-reaching implications for the treatment of many aging-related human diseases, including cardiovascular disease, autoimmune disorders and cancer.

Many factors contribute to aging, one being DNA damage. The integrity of DNA is essential for the health of cells, tissues and the whole organism. We can detect and repair DNA damage; this so-called “DNA damage response” is commonly seen when our body tries to fight cancer. But if the injury response is prolonged and the DNA damage is not repaired, it is thought to stop cells from growing and dividing and causing them to age prematurely. This is known as the ‘DNA damage theory of aging’.

Examining RCVL patterns in animal and human cells, the researchers found that when both strands of DNA were broken, the TREX1 gene mutation interfered with the repair process, allowing the DNA to be erased and causing cells to stop dividing and premature aging, which led to aging and organ damage.

Surprisingly, they also made a preliminary finding that patients with RVCL had an increased odds ratio of breast cancer. The BRCA1 and BRCA2 genes play a critical role in DNA repair. Mutations of these genes are associated with an increased risk of breast cancer because they compromise this repair and cause the accumulation of DNA damage, increasing genome instability and cancer susceptibility. The finding that RVCL patients were more likely to develop breast cancer supports the hypothesis, the researchers say, that DNA damage caused by TREX1 increases the risk of breast cancer.

The study’s findings have provided insight into how RCVL can be treated, including lowering the levels of the TREX1 protein produced by the gene, correcting the mutation or blocking the gene’s DNA-damaging effects. However, the findings extend beyond RVCL because they contribute to the DNA damage theory of aging.

“One hope is that understanding the role of TREX1 in RVCL may help us uncover mechanisms that may link the TREX1 gene to a wide variety of human conditions that may also include normal aging,” Miner said.

The study was published in the journal Nature Communications.

Source: Penn Medicine