It’s like something from a nightmare: a disease that ages you at a breakneck pace, so that by age 12, your body more closely resembles someone in their 80’s—inside and out.
Instead of enjoying your childhood and adolescence, you suffer from diseases usually reserved for octogenarians: including heart disease, kidney failure and stroke.
Chances are, you won’t make it past your 13th birthday.
However fantastical this may seem, this condition is real. Called progeria, this rare genetic disorder affects only about 100 people worldwide. But with the help of the latest stem cell technology, a few determined scientists are speeding towards a cure.
In the May 19 issue of the Proceedings of the National Academy of Sciences, University of Maryland researchers have uncovered what may be driving the accelerated aging process. Specifically, the team identified a toxic protein that wreaks havoc on the patient’s arteries from a young age—thereby priming the young patient for disease.
The study’s senior author, Dr. Kan Cao, says in a recent news release that these findings offer hope not just for progeria patients and their families, but also for anyone suffering from or at risk of developing age-related diseases:
“This gives us a very good model for testing drugs to treat progeria. And it may help us understand how cardiovascular disease develops in people aging normally.”
Scientists have long known that progeria was caused by a genetic change, or mutation, that results in the production of a faulty version of a protein called progerin. But until now, they have been unable to pin down precisely how this faulty protein leads to progeria’s deadly symptoms.
Confounding the efforts, progeria has been extremely difficult to study, in large part because of the frailty of the patients. The disease most seriously affects the patient’s internal organs, but obtaining tissue samples is not generally possible, as the procedure is far too invasive. So Dr. Cao and her team tried a different approach.
They took skin samples from progeria patients and, using induced pluripotent stem cell (iPS cell) technology, transformed them into smooth muscle cells. Smooth muscle cells are a type of cell that lines the walls of blood vessels and other tissues. In this case, these smooth muscle cells were genetically identical to the patients’ native muscle cells, effectively allowing the researchers to model the disease in a dish over time, cell by cell. And when they did so, they solved a big part of the riddle.
The faulty version of progerin, the team realized, was interfering with a process essential the health and well being of cells: DNA repair.
As cells grow, age and divide, the DNA housed within them can sometimes break. When this happens, a protein called PARP-1 senses this break and, like a molecular handyman, repairs the damage. But in the case of progeria, the faulty progerin protein builds up within the cells. As it does so, PARP-1 levels drop. Without the expertise of PARP-1, the cells are unable to correctly repair DNA breaks. Sometimes they get it right, but usually they get it wrong. And when the cells try to divide, they can’t. Some end up as one cell with two nuclei, while others end up killing themselves in an act called “mitotic catastrophe.”
Cao and her team reasoned that people with progeria, who are losing smooth muscle cells much faster than is normal, are more vulnerable to stresses, such as blood pressure, which then increases their likelihood of heart disease and stroke.
CIRM-funded researchers at the Salk Institute reported a similar finding in 2011, when they derived muscle cells from iPS cells made from a patient with a different form of progeria. In our 2011 blog post about that work, the Salk team found that lamin A, a protein that accumulates in the normal aging process, also builds up in patients suffering from this form of progeria.
The next step for Cao’s team, she says, will be to find out the nature of the relationship between progerin and PARP-1. She also hopes to use iPS cell technology to test potential treatments for the disease. Since beginning her work on progeria, Cao has become close with progeria patients, and their families. It is these relationships that have spurred Cao and her young research team to understand the disease—and to find a cure:
“[My] students began thinking, ‘My research is so important for the families.’ It’s a lot of motivation for them. And a lot of pressure for all of us to work quickly.”