Scientists have corrected the defect underlying premature aging
Scientists from several French research institutions, working under the leadership of Miria Ricchetti from the Pasteur Institute, identified the role of the HTRA3 protease enzyme in the functioning of cells of patients with Coccain syndrome, and restored the normal activity of these cells.
Accelerated premature aging of a person is caused by several rare genetic diseases. To date, there are no methods of treating these diseases, and understanding the causes of premature aging in these pathologies can not only find adequate methods of their therapy, but also help in studying the mechanisms of normal aging.
The frequency of occurrence of one of these diseases – Coccain syndrome – is approximately one case per 2.5 million newborns. In the most severe cases, patients do not even live up to 7 years. Already at an early age, they develop symptoms of premature aging such as weight loss, hair loss, decreased visual and hearing acuity, as well as facial deformity and neurodegeneration.
Coccain syndrome is caused by mutations in one of two genes involved in the mechanisms of repairing DNA damage caused by ultraviolet radiation. Patients with this disease are very sensitive to sunlight, and their skin quickly burns in the sun. For several decades, it was believed that the process of premature aging in this case is mainly due to the lack of mechanisms for repairing DNA damage.
When comparing the cells of patients with Coccain syndrome with the cells of patients with another genetic syndrome, accompanied only by increased sensitivity to ultraviolet light, the authors found that cell defects in Coccain syndrome are caused by excessive production of HTRA3 protease and are induced by oxidative stress. In such cells, HTRA3 protease destroys a key component of the mechanism responsible for mitochondrial DNA replication, which disrupts the activity of these organelles.
Three-dimensional reconstruction of the primary fibroblast of the skin of a patient with Coccain syndrome:
mitochondria are colored green, and the nucleus is blue.
Until now, the main cause of neurodegeneration and aging was considered to be cell damage caused by free radicals, which are by-products of mitochondrial activity. The new data suggest that free radicals also activate the expression of the HTRA3 enzyme, whose activity is particularly dangerous for mitochondria. Such an attack on mitochondria is a key factor in the process of cell degeneration in patients suffering from premature aging.
With the help of two new approaches, consisting in the use of an HTRA3 inhibitor or a broad–spectrum antioxidant neutralizing free radicals, the researchers managed (so far only "in vitro") to suppress the activity of HTRA3 in the cells of patients with Coccain syndrome to a normal level, which in turn restored mitochondrial activity.
The authors believe that the data obtained can form the basis for the development of treatment methods for patients with Coccain syndrome and hope to start conducting clinical trials in the near future. Moreover, they note that the described mechanisms can develop, albeit more slowly, in healthy cells, leading to their physiological aging. From this point of view, the development of approaches to the treatment of premature aging can become a starting point for new methods of prevention of diseases accompanying normal aging.
Article by Laurent Chatre et al. Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome is published in the journal Proceedings of the National Academy of Sciences.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Institut Pasteur:
Premature aging: scientists identify and correct defects in diseased cells.
22.05.2015