There Will be Many More Approaches to the Destruction of Senescent Cells

Targeted removal of senescent cells is a narrow form of rejuvenation, reversing one of the causes of degenerative aging. A variety of different approaches are in clinical development: targeting standard cell destruction techniques based on gene expression inside cells, as illustrated by the Oisin Biotechnologies method; various antibodies that bind to surface characteristics of senescent cells to induce immune cells to destroy them; and numerous small molecule drug candidates to target portions of the cellular mechanisms that either encourage or prevent cell self-destruction.

Senescent cells are primed for the programmed cell death process of apoptosis, and the overwhelming majority follow that path. The few that linger are the problem, but there are many points in the mechanisms of apoptosis that might be targeted to push them over the edge. A few have been discovered and demonstrated, such as the Bcl-2 family, the interaction between FOXO4 and p53, and HSP90, but the research community has only started in earnest on this line of work in the past couple of years. Initial successes to date will encourage greater efforts in the years ahead. The research here is an example of the type, in that it is a more detailed consideration of how cells choose between continued senescence and self-destruction that points out a new potential target by which that choice can be swayed in either direction.

DNA damage is a threat to genome integrity and its protection relies on the tumor protein, p53, signaling pathway response to the threat. The activity of the p53 pathway involves several feedback loops that control phosphorylated p53 concentration levels and can influence in different ways the expression of gene sets that lead to specific cell fates. In general, positive feedback loops are associated with cell fate stabilization and negative feedback loops with reversible cell fates. Under DNA damage the cell cycle is arrested at checkpoints activating the p53 pathway dynamics, in the case of light DNA damage an oscillatory dynamics is observed while for heavy damage, senescence (permanently cell cycle arrested cells) or apoptosis pathways are triggered.

Experimental and theoretical attempts to describe the oscillatory and apoptotic phenotypes are in progress, but in the case of senescence more investigations are required. Recently, an experiment confirmed a correlation between the DNA damage level induced by the anti-cancer drug etoposide with a switch in the p53 pathway behavior. For low concentrations of the drug culture cells present an oscillatory phenotype and few cell deaths, while for high concentrations there are arrested cells, no oscillations, and many cell deaths.

The onset of senescence is associated mainly with the upregulation of the cell cycle inhibitors pRB, p21, and/or the senescence DNA locus CDKN2A. MicroRNAs (miRNAs) can also regulate the cell cycle. For example, microRNAs can form feedback loops with p53. MiRNAs are small noncoding regulatory RNA molecules that target specific messenger RNAs (mRNAs) to repress their translation. A recent experimental study confirmed that miR-16, whose expression is regulated by p53, mediates the fate between senescence or apoptosis through p21. By changing miR-16 expression level the authors observed a phenotype change from senescence to apoptosis in cells. These experimental observations provide a basis for understanding how the p53 pathway dynamics is determined by repairable or irreparable DNA damage, and how perturbations of miR-16 can allow the control of cell fate.

Link: https://doi.org/10.1371/journal.pone.0185794

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