Abstract
Aging is associated with an increased susceptibility to adverse inflammatory conditions such as sepsis and cytokine storm. We hypothesized that senescent cells (SnCs) play a central role in this age-associated pathology in part due to their expression of the senescence-associated secretory phenotype (SASP), which may prime SnCs to inflammatory stimulation. To test this hypothesis, we examined the expression of various inflammatory cytokines and chemokines at the levels of gene transcription and protein production in various SnCs in vitro in response to lipopolysaccharide (LPS), interleukin-1β (IL1β), and tumor necrosis factor α (TNFα) stimulation. We found that SnCs not only expressed higher basal levels of various inflammatory cytokines and chemokines as a manifestation of the SASP, but more importantly exhibited hyper-activation of the induction of a variety of inflammatory mediators in response to LPS, IL1β and TNFα stimulation as compared with non-SnCs. This senescence-associated hyper-activation is likely mediated in part via the p38MAPK (p38) and NFκB pathways because LPS stimulation elicited significantly higher levels of p38 phosphorylation and NFκB p65 nuclear translation in SnCs when compared to their non-senescent counterparts and inhibition of these pathways with losmapimod (a p38 specific inhibitor) and BMS-345541 (a selective NFκB inhibitor) attenuated LPS-induced expression of IL6, TNFα, CCL5, and IL1β mRNA in SnCs. These findings suggest that SnCs may play an important role in the age-related increases in the susceptibility to developing an exacerbated inflammatory response and highlight the potential to use senotherapeutics to ameliorate the severity of various devastating inflammatory conditions in the elderly.
Highlights
Advancing age is associated with a multitude of physical and physiological deteriorations that leave the elderly susceptible to a wide variety of pathological conditions [1]
To determine if an inflammatory stimulus could significantly exacerbate the pro-inflammatory phenotype of senescent human umbilical vein endothelial cells (HUVEC) compared to their normal counterparts, we examined the transcriptional response of non-senescent (NC HUVEC) and ionizing radiation (IR)-induced senescent HUVEC (IR HUVEC) to lipopolysaccharide (LPS)
Our analysis revealed that the upregulation of IL6, tumor necrosis factor α (TNFα), CCL5 and IL1β mRNA expressions in IR HUVEC with or without LPS stimulation were abrogated or significantly reduced by the pretreatment with BMS-345541 (Figure 6C–6F), confirming that the NF-κB pathway plays an important role in the induction of both senescence-associated secretory phenotype (SASP) and senescence-associated hyperactivation in IR HUVEC
Summary
Advancing age is associated with a multitude of physical and physiological deteriorations that leave the elderly susceptible to a wide variety of pathological conditions [1]. There is a steep decline in the healthrelated quality of life for the elderly [2]. Amongst a wide variety of conditions, increased susceptibility to severe infections (such as COVID-19) and inflammatory conditions (such as sepsis) is one such age-related phenomenon [3,4,5,6]. Despite representing under 25% of the population, people older than 60 account for more than 75% of sepsis related deaths [7]. With respect to COVID-19, people over 60 are three times more likely to die from a severe infection than people under 60 [8]. Santesmasses et al, estimated that the risk of dying from www.aging-us.com
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