Difficulties of finding the pill of immortality (7)
(Continued. See the beginning of the article here.)
Senolytic drugs
Selective destruction of cells that have entered the phase of physiological aging with the help of recently discovered drugs-senolytics ("solvents of old age", from Lat. senesco – aging and Greek lysis – dissolution, decay), is manifested by softening the manifestations of decrepitude, improving cardiac function and increasing the duration of a healthy life.
The physiological aging of cells consists in the irreversible cessation of cell growth, which can be induced by many stressors, including a series of replanting, telomere shortening, inadequate mitotic stimuli and genotoxic effects. It is believed that physiological aging plays an important role in suppressing tumor growth in mammals. However, cells that have entered the phase of physiological aging develop an altered secretory phenotype (senescence-associated secretory phenotype, SASP), which is characterized by the release of factors such as proteases, growth factors, interleukins, chemokines and extracellular remodeling proteins. As they age, such cells accumulate in different tissues and potentially contribute to the development of pathological conditions, since the factors secreted by them induce the development of chronic inflammation, the extinction of the functions of progenitor cells and disruption of the functions of the extracellular matrix. The functional effect of cells that have entered the phase of physiological aging in vivo has remained a hotly debated issue of aging biology for many years. Recently, genetic approaches have been described to destroy these cells in the body of mice by activating the drug-induced "suicide gene". The destruction of cells that entered the phase of physiological aging in the mouse progeria model significantly delayed the development of many age-related phenotypes, including lordokyphosis (an analogue of sarcopenia), cataracts, adipose tissue atrophy and muscle dysfunction. However, in general, this was not accompanied by a significant increase in the survival rate of these animals, possibly due to the fact that the suicide gene was not expressed in the heart and aorta, and heart failure is considered the main cause of death of animals of this line.
A recent landmark study by Baker et al. It was demonstrated that the destruction of cells that naturally entered the phase of physiological aging in the body of non-progeroid mice prevented the age-related extinction of the functionality of a number of organs, delayed the formation of lethal tumors and increased the median life expectancy of mice with mixed and pure C57BL/6 genotypes by 27% (p<0.001) and 24% (p<0.001), respectively. This study provided very convincing evidence that the age-associated accumulation of cells that have entered the phase of physiological aging contributes to the development of age-related pathologies and reduces the life expectancy of wild-type animals.
Unlike genetic approaches, pharmacological approaches to the destruction of cells that have entered the phase of physiological aging are associated with serious technical and conceptual difficulties. Recent work has shown that these cells exhibit increased expression of survival-promoting factors responsible for their well-known resistance to apoptosis. Interestingly, the silencing of many of these factors (ephrins, PI3K-delta, p21, BCL-xL and others) mediated by small interfering RNAs (miRNAs) selectively destroys cells that have entered the phase of physiological aging without affecting dividing cells and cells in the resting phase. These miRNAs are called senolytic. Small molecules acting on the same factors (senolytic drugs) also selectively destroy such cells. Of the 46 agents tested in this class, dasatinib and quercetin were the most effective. Dasatenib, used in cancer therapy, is an inhibitor of many tyrosine kinases. Quercetin is a natural flavonol that inhibits PI3K, other kinases and serpins. Dasatinib mainly destroyed physiologically aged preadipocytes, whereas quercetin was more effective against human endothelial cells and mesenchymal bone marrow stem cells of mice. The combination of dasatinib and quercetin was effective in selectively destroying human cells of all three listed types that had entered the phase of physiological aging. The combination of drugs also destroyed mouse embryonic fibroblasts that had entered the phase of physiological aging more effectively than each of the drugs separately. Therapy of chronologically aged wild-type mice, wild-type mice exposed to radiation, and progeroid hypomorphic Ercc1 mice with a combination of dasatinib and quercetin reduced the number of target cells. At the end of therapy, old wild–type mice showed an improvement in cardiac function and carotid artery reactivity, irradiated mice showed an improvement in their ability to tolerate physical activity, and progeroid Ercc1 mutants showed a later manifestation of age-related symptoms and pathologies. In a recent study by Chang et al. ABT263 (a navitoclax–specific inhibitor of BCL-2 and BCL-xL antiapoptotic proteins), also a potent senolytic agent, has been identified. Used in the therapy of many types of cancer, ABT263 induced apoptosis and selectively destroyed cells that had entered the phase of physiological aging, regardless of cell type and species. In culture, human lung fibroblasts (IMR90), human renal epithelial cells and mouse embryonic fibroblasts that had entered the phase of physiological aging were more sensitive to ABT263 than their normal counterparts. However, another study showed that ABT263 is not a broad-spectrum senolytic, instead they act on certain types of cells. According to the results of this study, ABT263 has a senolytic effect on human umbilical vein cells (HUVECs), IMR90 cells, mouse embryonic fibroblasts, but not primary human preadipocytes.
Exposure of ABT263 to irradiated or naturally aged mice not only reduced the number of cells that entered the phase of physiological aging, including populations of bone marrow hematopoietic cells and muscle stem cells, but also suppressed the expression of a number of SASP factors, as well as rejuvenated the functions of these cells during their aging. These data, together with earlier impressive results obtained on genetic models, indicate that senolytic drugs can help improve the functions of aging tissues. However, the use of some cenolytic drugs is associated with toxic side effects, such as thrombocytopenia and neutropenia in the case of ABT263, which is the main potential obstacle to their clinical use as anti-aging drugs. These manifestations of toxicity can be somewhat weakened by intermittent use.
The most important results concerning small molecules are shown in Figure 2 in the section "Other potential anti-aging drugs".
Ending: Problems of anti-aging drug screening
Portal "Eternal youth" http://vechnayamolodost.ru
13.09.2016