Senotherapeutics: An emerging approach to the treatment of viral infectious diseases in the elderly

Abstract

In the context of the global COVID-19 pandemic, the phenomenon that the elderly have higher morbidity and mortality is of great concern. Existing evidence suggests that senescence and viral infection interact with each other. Viral infection can lead to the aggravation of senescence through multiple pathways, while virus-induced senescence combined with existing senescence in the elderly aggravates the severity of viral infections and promotes excessive age-related inflammation and multiple organ damage or dysfunction, ultimately resulting in higher mortality. The underlying mechanisms may involve mitochondrial dysfunction, abnormal activation of the cGAS-STING pathway and NLRP3 inflammasome, the role of pre-activated macrophages and over-recruited immune cells, and accumulation of immune cells with trained immunity. Thus, senescence-targeted drugs were shown to have positive effects on the treatment of viral infectious diseases in the elderly, which has received great attention and extensive research. Therefore, this review focused on the relationship between senescence and viral infection, as well as the significance of senotherapeutics for the treatment of viral infectious diseases.

Loss of CFTR Reverses Senescence Hallmarks in SARS-CoV-2 Infected Bronchial Epithelial Cells

“…Viral infections can trigger premature cellular senescence, known as virus-induced senescence (VIS). It was reported that some viruses, such as human immunodeficiency virus, measles virus, respiratory syncytial virus, and influenza virus, can take advantage of senescence as a mechanism of spread in infected organisms [ 66 ], triggering senescence to increase their replication rate [ 67 ]. Recently, it was demonstrated that SARS-CoV-2 also evokes cellular senescence as a primary stress response in infected cells, activating the DNA damage response and exacerbating SASP-related paracrine senescence [ 8 , 9 , 13 , 15 ].…”

“…Thus, senotherapeutics, drugs targeting senescent cells [ 73 ], seem to play an important role in fighting viral infection. In particular, senolytics (such as quercetin, fisetin, navitoclax, and dasatinib), acting by removing senescent cells, and senomorphic agents (such as rapamycin, metformin, anakinra, and tocilizumab), inhibiting some component of the SASP, mitigate age-related viral infection [ 66 ]. The CFTR phenotype appears to have a senotherapeutic impact on SARS-CoV-2 infection, mimicking the effect of the previously mentioned compounds and contributing to explaining the significantly different response of non-CF and CF cells to SARS-CoV-2 infection.…”

DNA damage response(DDR): a link between cellular senescence and human cytomegalovirus

“…According to recent researches, virus infections, such as measles virus, human respiratory syncytial virus and COVID-19, can prematurely stimulate cellular senescence, known as virus-induced senescence (VIS) [ 23 , 113 , 114 ]. Measles virus (MV) infection has been proven to induce p53 and p16-pRb pathway-dependent cellular senescence via cell [ 115 ].…”

“…In addition, it has been proved that cellular senescence was induced in host cells upon HCMV infection [ 81 ], which was recognized as an antiviral immune response [ 113 , 119 , 183 ]. Mechanistically, this induction of cellular senescence was mainly due to activation of the cGAS-STING pathway triggered by HCMV dsDNA as well as the subsequent SASP secretion [ 85 , 184 ].…”