Aging-US: Senescence-associated hyper-activation to inflammatory stimuli in vitro09-21-2021
Aging-US published "Senescence-associated hyper-activation to inflammatory stimuli in vitro" which reported that aging is associated with an increased susceptibility to adverse inflammatory conditions such as sepsis and cytokine storm.
To test this hypothesis, the authors 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, interleukin-1β, and tumor necrosis factor stimulation. This senescence-associated hyper-activation is likely mediated in part via the p38MAPK and NFB pathways because LPS stimulation elicited significantly higher levels of p38 phosphorylation and NFB p65 nuclear translation in SnCs when compared to their non-senescent counterparts and inhibition of these pathways with losmapimod and BMS-345541 attenuated LPS-induced expression of IL6, TNF, CCL5, and IL1β mRNA in SnCs.
Figure 6. Regulation of senescence-associated hyper-activation via NF-κB pathway. (A–C) IR HUVEC exhibit higher baseline expression and activation of NF-κB when compared to NC HUVEC. Representative western-blot images (A) (the middle line is the molecular weight markers), densitometry based quantitative analysis of nuclear fraction (B) and cytoplasmic fraction (C) of NF-κB p65 in NC HUVEC and IR HUVEC stimulated with LPS (30 ng/ml) for 0-90 min (n = 3; mean ± SEM; * p<0.05, # p <0.01, + p<0.001 vs. NC HUVEC). Histone H3 and GAPDH were used as the loading control for nuclear and cytoplasmic proteins, respectively. (D–G) NF-κB inhibition attenuates the expression of IL6 (D), TNFα (E), CCL5 (F), and IL1β (G) mRNA in IR HUVEC. NC HUVEC and IR HUVEC were treated with LPS (30 ng/ml) or the NF-κB inhibitor BMS-345541 (10 μM) or their combination for three hours followed by mRNA analysis. Gene expression in unstimulated NC HUVEC was used as baseline and GAPDH was used as endogenous control. (n = 3; mean ± SEM; * p<0.05, ** p<0.01, *** p<0.001).
Dr. Daohong Zhou from The University of Florida said, "Advancing age is associated with a multitude of physical and physiological deteriorations that leave the elderly susceptible to a wide variety of pathological conditions."
Consequently, there is a steep decline in the health-related quality of life for the elderly. Amongst a wide variety of conditions, increased susceptibility to severe infections and inflammatory conditions is one such age-related phenomenon. Despite representing under 25% of the population, people older than 60 account for more than 75% of sepsis related deaths. With respect to COVID-19, people over 60 are three times more likely to die from a severe infection than people under 60. The severity of disease progression in these population upon infection is partially attributed to the higher prevalence of severe cytokine storm in the elderly. Though there are many theories as to what makes the elderly susceptible to severe cytokine storm, there is no commonly accepted explanation to this phenomenon.
Cellular senescence is a phenomenon by virtue of which stressed or damaged cells undergo a permanent cell cycle arrest. The detrimental effects of SnCs are partly a consequence of their expression of the senescence-associated secretory phenotype. The SASP includes an extensive list of factors such as inflammatory cytokines, chemokines, and matrix metalloproteases, which are detrimental to the normal functioning of neighboring cells. Hence, the authors hypothesized that SnCs contribute to the increased severity of infectious diseases and infection-mediated cytokine storm in the elderly through the expression of the SASP. To test this hypothesis, they examined whether SnCs exhibit hyper-activation to LPS, IL1β and TNF stimulation.
The Zhou Research Team concluded in their Aging-US Research Output, "we discovered that SnCs exhibit hyper-activation upon an inflammatory insult, which we termed senescence-associated hyper-activation. Our results suggest that SnCs could contribute to the age-related predisposition of the body to develop stronger cytokine storm upon infections. This calls for a paradigm shifting study from considering SnCs as indirect participants in inflammatory pathologies to being recognized as central players in these processes. Discovering the senescence-associated hyper-activation phenomenon also highlights an opportunity and the urgent need for testing the possibilities that the newly developed senotherapeutics may have the potential to mitigate the incidence of life-threatening inflammatory conditions in the elderly and potentially lengthen their health-span."
Full Text - https://www.aging-us.com/article/203396/text
Correspondence to: Daohong Zhou email: email@example.com
Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.