Hutchinson-Gilford progeria syndrome and Werner syndrome are rare genetic diseases that cause premature aging in children and adolescents who suffer from them. Those affected have a physical appearance similar to that of an elderly person, but they also experience symptoms and pathologies that are associated with the natural aging process such as cardiovascular diseases, cataracts, type 2 diabetes, osteoporosis and cancer.
Although there are still no effective treatments against these and other progeroid syndromes, the Spanish scientist Juan Carlos Izpisua Belmonte and his team have been researching for a long time to find a way to reverse aging and improve the quality and life expectancy of these patients. Now, these researchers have identified a type of RNA that accumulates in the cell nucleus of people with progeria or premature aging and have found that blocking this RNA reverses the symptoms of the disease and prolongs life in mice.
The results of the study that have given rise to this finding have been published in Science Translational Medicine and come from one of the projects developed by Dr. Izpisua, which have been promoted and financed by the UCAM and focus on the study of a fragment of RNA known as LINE-1.
“These findings provide a new insight into progeroid syndromes and how to treat them, while highlighting the importance of RNA LINE-1 in the normal aging process,” says Dr. Izpisua, Professor of Developmental Biology at UCAM, professor at the Salk Institute Gene Expression Laboratory and director of the Altos Labs Science Institute in San Diego, California.
DNA alteration in the normal or pathological aging process
The researchers knew that one of the molecular hallmarks of both normal aging and progeroid syndromes is altered DNA organization in the cell nucleus. When DNA is packaged differently, the genes that are accessible for the cell to read change, and therefore cellular behavior and function are drastically altered. They also knew that the human genome contains hundreds of pieces of DNA that move around the genome, in addition to encoding RNA LINE-1.
“Targeting RNA LINE-1 may be an effective way to treat progeroid syndromes, as well as other age-related diseases, including neuropsychiatric, ocular, metabolic disorders, or cancer”
The function of these elements is little known, but they change and multiply as we age, or when health problems such as cancer and cardiovascular disease appear. The researchers wanted to find out if these elements also changed and accumulated in progeroid syndromes.
“Repeated sequences in DNA, as is the case with LINE-1, constitute a large percentage of our genome, however, until now not much attention has been paid to the effects that the accumulation of this RNA LINE-1 may have. 1 synthesized in the cell nucleus, which increases with age”, said Pradeep Reddy, a scientist at the Salk Institute and Altos Labs.
These scientists studied cells from patients with progeroid syndromes and found that they had between four and seven times more RNA LINE-1 than cells from healthy people, and also showed that the accumulation of this RNA LINE-1 occurred before the major structural changes in DNA associated with progeria.
“So we developed a series of molecules that could specifically bind to LINE-1 RNA, blocking it and preventing it from accumulating and affecting cell function. This type of treatment reversed the molecular signs of progeria in isolated cells and prolonged the life of mice with genetic mutations that cause premature aging”, explains Estrella Núñez, Vice-Rector for Research at UCAM and co-author of the work. In both cases, the expression of genes associated with cell proliferation and DNA structure increased after treatment, while the expression of genes associated with aging, inflammation, and DNA damage decreased.
“Targeting LINE-1 RNA may be an effective way to treat progeroid syndromes, as well as other age-related diseases that have been linked to LINE-1, including neuropsychiatric, ocular, metabolic disorders, or cancer,” says Izpisua Belmonte. “Over time, we believe this approach may lead to treatments that help prolong human health during aging.”
.
