Further Evidence for a Diversity of Cellular Senescence and Variable Efficacy of Senolytic Drugs

Cellular senescence is important in aging, as these cells disrupt tissue function and provoke chronic inflammation where they linger in old tissues. The phenomenon is found in cell types throughout the body, but researchers have shown that meaningful differences between cell types exist in the biochemistry of cellular senescence, and possibly between senescent states for the same cell type. A senolytic drug that can efficiently destroy one type of senescent cell may perform poorly for another type. This indicates that a diversity of development of senolytic therapies, and combinations of multiple therapies, will likely prove beneficial. Alternatively, approaches such as the suicide gene therapy developed by Oisin Biotechnologies may win out as p16 expression proves to be a more general characteristic of senescence than others.

There is a heterogeneity in markers expressed by senescent cells depending on both cell type and an insult used to induce senescence. However, there are several common features typical for the most types of senescent cells. The essential characteristic of senescence for any kind of dividing cells is the irreversible proliferation loss. The irreversibility of the cell cycle arrest is controlled by the cyclin-dependent kinase (CDK) inhibitors p16 and p21 and is often regulated by the tumor suppressor protein p53.

The other important features of senescent cells are the activation of a persistent DNA damage response; cell hypertrophy, which often arises as a result of impaired ribosomal biogenesis and protein synthesis; disturbance of lysosomal degradation and dysfunction of the rest degradation systems; increased activity of the specific lysosomal enzyme senescence-associated-β-galactosidase; various mitochondrial alterations; acquisition of the senescence-associated secretory phenotype.

Targeted elimination of senescent cells - senolysis - is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in 'cardiac glycosides-sensitive' A549 cells and '-insensitive' hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis-resistance in senescent hMSCs.

We revealed that apoptosis-resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant compared to their proliferating counterparts.

Link: https://doi.org/10.1101/2020.12.18.423449

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