Mice were cured and rejuvenated by a new senolytic

Removal of aged cells reversed signs of aging in mice

Oleg Lischuk, N+1

Modified natural protein synthesized by Dutch, Austrian and American scientists eliminated the toxic effects of chemotherapy and physiological signs of aging in mice by targeted removal of aged cells. The results of the work are published in the journal Cell (Baar et al., Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging).

Replicative cell aging, or senescence, is a condition in which cells with accumulated DNA damage and depletion of its repair mechanisms stop dividing. It serves as a natural mechanism of protection against cancer development, but translates cellular metabolism to the synthesis of substances that activate inflammatory reactions and oxidative stress (damage to cellular structures by active oxygen forms). The cell can be in this state for a long time without undergoing apoptosis (programmed death). The accumulation of aged or senescent cells leads to age-related changes in tissues and the whole organism.

In search of cellular mechanisms that protect senescent cells from apoptosis, the staff of Erasmus University, the Medical University of Graz and the Bakovsky Research Institute of Aging analyzed the transcriptome of normal and artificially aged human fibroblasts.

It turned out that the genes responsible for apoptosis were activated in aged cells, but their action was hindered by the transcription factor FOXO4. Suppression of the expression of this factor by synthetic RNA dramatically reduced the viability of such cells. Further experiments showed that FOXO4 accumulates in the region of persistently damaged DNA sites (DNA-SCARS) next to the most important antitumor protein p53, which regulates apoptosis, and can interact with this protein, preventing the death of a senescent cell.

To find out the role of this interaction, the scientists synthesized FOXO4 with a modified binding site with p53. The resulting FOXO4-DRI protein interfered with the interaction of FOXO4 with p53 in vitro. By increasing the lipophilicity of FOXO4-DRI to facilitate its penetration into the cell, the researchers introduced it into the culture of aged fibroblasts and made sure that this substance ensures the release of p53 from the nucleus and stimulates apoptosis.

The action of FOXO4-DRI at the level of molecules, cells, tissues and the body
(here and below are the drawings from the Cell article).

After that, FOXO4-DRI was tested on mice with three models of aging: caused by the chemotherapeutic drug doxorubicin, accelerated by genetic modification and natural. It turned out that this substance selectively acts on senescent cells, causing their apoptosis. This, in turn, led to the restoration of liver functions disrupted by doxorubicin, and also reversed such age-related changes as decreased endurance, impaired kidney function and baldness in animals with all types of aging. There were no pronounced side effects.

The same mouse before and after FOXO4-DRI therapy

"Thus, therapy aimed at aged cells is appropriate when [age–related] deterioration of health has already occurred, and can effectively restore tissue homeostasis," the authors write. Whether FOXO4-DRI therapy will be effective and safe in humans remains to be seen in subsequent experiments.

Previously, scientists extended the life of genetically modified mice by a third, in which senescent cells died under the action of a specially created synthetic drug – this experiment confirmed the role of such cells in the aging of the body. Another scientific team managed to reverse the process of senescence of cells by removing mitochondria from them.

Portal "Eternal youth" http://vechnayamolodost.ru  24.03.2017