A new class of senolytics
Cardiac stimulants rid mice of old cells
Polina Loseva, N+1
An international team of scientists has discovered another group of substances that can work as senolytics, that is, kill old cells in tissues. These are cardiac glycosides – drugs that in small doses stimulate the contraction of the heart muscle, and in large doses become poison. The advantage of newly discovered senolytics is that they act on different types of old cells, and can also prevent the occurrence of tumors. The work was published in the journal Nature Metabolism (Guerrero et al., Cardiac glycosides are broad-spectrum senolytics).
Aging is accompanied by the accumulation of senescent, or old (although a more accurate translation would be "decrepit") cells in the tissues. They do not multiply, but they do not die, and they also secrete pro-inflammatory substances that attract immune cells into the tissue. All this has a detrimental effect on the work of individual organs. Therefore, recently several scientific groups have been searching for senolytics – drugs that could cleanse the tissue from these cells.
It is convenient to look for senolytics among ready-made medicines, about which it is already known in what doses and for which tissues they are safe or toxic. Therefore, for example, many of the already known senolytics are antitumor drugs, for example, dasatinib. Or, for example, substances of plant origin that have long been studied in other contexts – quercetin, curcumin, fisetin.
However, the problem with many senolytics is that they selectively act only on certain types of tissues. Therefore, they can be used to treat specific diseases caused by the accumulation of old cells in individual organs (for example, joint inflammation), but they may be useless for prolonging life in general.
Ana Guerrero and colleagues from England and Germany tested 1,280 pharmacological drugs for the ability to destroy senescent cells. Among the most effective drugs was ouabain (aka strofantin) – an alkaloid from African plants.
To test the versatility of ouabain, the researchers treated the cells with etoposide, a substance that prevents the cell from repairing its DNA, as a result of which it accumulates damage and ages. In this situation, ouabain proved to be effective – only about 25 percent of the old cells remained alive.
How exactly the ouabain performs its action is not completely clear. It is known that, like all cardiac glycosides, it blocks the work of Na/K-ATPase, an enzyme with which the cell maintains the necessary concentrations of ions inside and outside of the membrane. Scientists have found that ion concentrations in senescent cells initially differ from healthy cells, therefore, probably, the former are less resistant to enzyme blockade.
It is known that the removal of senescent cells from tissues has a beneficial effect on the health of the animal as a whole. Therefore, the researchers tested what happens to the body of elderly (2 years old) mice if they are regularly injected with ouabain in small doses. Compared with control mice, some signs of aging disappeared in experimental animals: the concentration of albumin and phosphates increased in the blood, muscle grip increased and they began to stay on the rotating bar longer – an indicator of motor activity and coordination. In their kidneys, liver and heart, the number of senescent cells, as well as immune cells decreased – that is, the senolytic coped not only with the number of cells, but also with the consequences of their activity.
Senescent cells and tumor cells are connected by a complex network of interactions. On the one hand, senescent cells cause inflammation, destruction and restructuring of tissue, which is convenient for tumor cells to multiply. On the other hand, tumor cells create uncomfortable living conditions for their neighbors in the tissue, as a result of which they age. When we try to fight a tumor with the help of radio or chemotherapy, the "peaceful" inhabitants of the tissue also experience stress and age - which helps cancer cells survive.
Therefore, the authors of the work proposed their own two-stage model of fighting cancer: first, a course of chemotherapy, which causes aging of cells, including tumor cells, and then a "blow" with uabain, which cleanses the senescent cells from the tissue. They tested their method on the culture of bowel cancer, breast cancer and melanoma cells – about 10 percent of the cells remained alive.
Thus, senolytics turn out to be potentially multifunctional drugs. On the one hand, they can cope with the disruption of individual tissues, on the other – improve the condition of the body as a whole, on the third – help not only fight cancer, but also prevent it – because they act on cells that have become senescent due to overexpression of oncogenes.
Despite the complex and not completely clear mechanisms of action, senolytics move very quickly from the laboratory to the clinic. In 2016, there were serious reasons to believe that they can improve the health and prolong the life of laboratory animals, and just three years later we see the results of clinical trials, according to which they destroy senescent cells in the body of patients suffering from various age-related diseases.
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