The team, from Houston Methodist Research Institute in Texas, describes the breakthrough in a research letter published in the Journal of the American College of Cardiology.
Lead investigator Dr. John Cooke, department chair of cardiovascular sciences, and colleagues were studying cells from children with progeria in order to find out more about the aging process.
They believe that their findings could lead to a way to reverse other aging-related problems.
Progeria is a very rare disease caused by mutations in the LMNA gene. The mutation almost always arises spontaneously rather than being inherited from a parent. It is thought that at any one time, there are fewer than 250 children worldwide living with the disease.
Children with progeria may appear normal at birth but within a year they start to show distinctive physical signs, such as a much slower rate of growth, loss of hair, a pinched nose, and a face and jaw that are small in proportion to the rest of the body.
Progeria, telomeres, and rapid aging
Children with progeria also experience symptoms normally associated with much older people, including progressive severe heart and circulation problems, stiffness in the joints, and hip dislocations. Most patients die from heart attack or stroke and few live past their mid-teens.
“These kids are dying of heart attack and stroke at 13, 14, 15 years old,” explains Dr. Cooke. “We wanted to do something that would improve the children’s quality of life and potentially allow them to live longer, so we set about studying their cells and seeing if we could improve the cell function.”
The usual starting point for investigating a disease caused by a faulty gene is to try and correct the gene or alter the protein that it codes for. However, Dr. Cooke and colleagues decided to approach the problem from a different angle: they focused on telomeres.
Telomeres shorten with age; with each cell division, a small piece of telomere is lost. When telomeres reach a critical length, cells come to the end of their lives and stop dividing, or go through an organized process of cell death called apoptosis.
Shorter telomeres have been linked to higher rates of disease and shorter lifespans. For this reason, telomere length is similar to a “biological clock” that can predict how long a cell or organism will live.
‘Dramatic effect’ from telomere lengthening
The team noticed that the cells from children with progeria had much shorter telomeres. They decided to see if they could improve the function of these cells, their response to stress, and ability to divide by finding a way to lengthen their telomeres.
Dr. Cooke explains that many of the things that happen to children with progeria happen to all of us eventually as our telomeres erode, except that in their case, the pace is vastly accelerated.
The team used a new technology called RNA therapeutics, which delivers small molecules into cells to alter their gene expression. In this way, they were able to get the cells from progeria patients to produce telomerase, a protein that lengthens telomeres.
Within a few days of treatment, cells were showing substantial changes that affected their lifespan and function. Dr. Cooke says that they were very surprised that just one treatment could have such an effect.
“We were not expecting to see such a dramatic effect on the ability of the cells to proliferate,” he explains. “They could function and divide more normally, and we gave them extra lifespan, as well as better function.”
‘Reversed many markers of cell aging’
The team also compared the cellular effects of the novel RNA therapeutic approach to therapies currently in use and found some dramatic contrasts.“Our approach had a much greater effect on all the markers of cellular aging. We markedly improved the ability of cells to multiply and reversed the production of inflammatory proteins. Those markers of cell aging we looked at were all reversed with the treatment in our study.”Dr. John Cooke
Dr. Cooke explains that as a physician, many of the diseases he comes across are a result of aging. For example, it is a major risk factor for cardiovascular disease, which is the primary cause of the strokes and heart attacks that around a third of people in the United States succumb to.
He suggests that because their research shows how RNA therapeutics can reverse the shortening of telomeres and lengthen them in cells from children with progeria, then it may be possible to “reverse a lot of the problems associated with aging.”
He and his colleagues believe that they can make something useful out of these results reasonably quickly, within a few years.
“Our next steps are to start moving this therapy toward clinical use,” says Dr. Cooke. He adds, “We plan to do so by improving existing cell therapies. I want to develop a therapy for these children. It’s an unmet need.”