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.

Keywords: COVID-19; NLRP3 inflammasome; cGAS-STING; senescence; senotherapeutics; virus.

Figure 1

Inducing factors and characteristics of senescence. In addition to replicative senescence induced by telomere shortening, numerous factors such as irradiation, chemotherapeutic drugs, and pathogenic infections can evoke senescence by impacting oncogene activation, DNA damage, mitochondrial dysfunction, etc. DNA damage response (DDR) is an essential mechanism in triggering senescence. Cellular senescence features altered cell morphology and structure, arrest of the cell cycle (upregulation of p16/p21), and enhanced resistance to apoptosis (upregulation of Bcl-xL and Bcl-w), along with detectable nuclear senescence-associated heterochromatin foci (SAHFs), increased senescence-associated β-galactosidase (SA-β-gal) activity, and secretion of senescence-associated secretory phenotype (SASP). ROS, reactive oxygen species; MMP, membrane potential; CCFs, cytoplasmic chromatin fragments; mtDNA, mitochondrial DNA.

Figure 2

Virus-induced senescence (VIS) combined with an existing senescence in the elderly intensifies the severity of viral infections. Senescence can promote the development of viral infectious diseases via abnormal activation of the mtDNA/CCFs-cGAS-STING pathway and NLRP3 inflammasome, pre-activated macrophages, over-recruited immune cells, and accumulation of innate immune cells with “trained immunity” characteristics. These alterations can trigger excessive SASP production and secondary paracrine senescence, resulting in hyperinflammation, tissue damage, coagulation disorders, and even multiple organ dysfunction, thus leading to a higher mortality risk. SASP, senescence-associated secretory phenotype; cGAMP, cyclic GMP–AMP; CCFs, cytoplasmic chromatin fragments; DDR, DNA damage response; eNOS, endothelial NO synthase; PAI-1, plasminogen activator inhibitor-1; TXA2, thromboxane A2; TM, thrombomodulin; ROS, reactive oxygen species.

Figure 3

Dual role of senescence in antiviral immune responses.