Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities

Abstract

Whereas aging is a whole-organism process, senescence is a cell mechanism that can be triggered by several stimuli. There is increasing evidence that critical conditions activate cell senescence programs irrespective of patient's age. In this review, we briefly describe the basic senescence pathways and the consequences of their activation in critically ill patients. The available evidence suggests a paradigm in which activation of senescence can be beneficial in the short term by rendering cells resistant to apoptosis, but also detrimental in a late phase by inducing a pro-inflammatory and pro-fibrotic state. Senescence can be a therapeutic target. The use of drugs that eliminate senescent cells (senolytics) or the senescence-associated phenotype (senomorphics) will require monitoring of these cell responses and identification of therapeutic windows to improve the outcome of critically ill patients.

Keywords: Apoptosis; DNA damage response; Post-ICU syndrome; Senescence; Senotherapeutics.

Fig. 1

Activation of senescence and its consequences. Critically ill patients are exposed to a variety of injurious stimuli that may activate senescence mechanisms, in which P53, P21 and P16 play a key role. Senescent cells show several specific features including cell cycle arrest, changes in cell structure and release of a number of factors (known as Senescence associated secretory phenotype -SASP-) that result in systemic spread of the response and modulate inflammation and tissue remodeling. Although these mechanisms are aimed at tissue repair and clearance of damaged and senescent cells, their persistence leads to chronic inflammation and fibrosis. Created with BioRender.com

Fig. 2

Mechanisms of immunosenescence. Triggers of senescence induce several changes in immune cell populations, favoring the shift towards a state of impaired immune response (both innate and adaptative). This “inflammaging” includes a low intensity pro-inflammatory response, in part due to the release of immune mediators from senescent cells. All these mechanisms lead to dysregulation of the immune response and establish a positive feedback loop that perpetuates this state. Created with BioRender.com