Impaired JAK-STAT pathway signaling in leukocytes of the frail elderly

Leonard Daniël Samson,José A Ferreira,Anne-Marie Buisman,H Susan J Picavet,Mary-Lène De Zeeuw-Brouwer,W M Monique Verschuren,A Mieke H Boots,Peter Engelfriet

doi:10.1186/s12979-021-00261-w

Abstract

BackgroundElderly often show reduced immune functioning and can develop chronic low-grade inflammation. Why some elderly are more prone to become frail is unknown. We investigated whether frailty is associated with altered cytokine signaling through the JAK-STAT pathway in leukocytes of 34 individuals aged 65–74 years. In addition, we investigated how this relation is affected by chronic low-grade inflammation during the previous 20 years. Cytokine signaling was quantified by measuring intracellular STAT1, STAT3, and STAT5 phosphorylation in monocytes, B cells, CD4+ T cells and CD8+ T cells upon stimulation with IL-2, IL-6, IL-10, IFNα and IFNγ, using phospho-flow cytometry. Presence of chronic low-grade inflammation was investigated by evaluating 18 different plasma inflammatory markers that had been measured repeatedly in the same individuals over the previous 20 years. Frailty was assessed as a score on a frailty index.ResultsWe found that lower cytokine-induced pSTAT responsiveness in the various cell subsets was seen with higher frailty scores in both men and women, indicative of dysfunctional pSTAT responses in frailer individuals. Associations differed between men and women, with frailer women showing lower pSTAT1 responses in monocytes and frailer men showing lower pSTAT5 responses in CD4+ and CD8+ T cells. Notably, lower IL-10-induced pSTAT3 responses in men were related to both higher frailty scores and higher CRP levels over the past 20 years. This might indicate poor resolution of low-grade inflammation due to defective regulatory pSTAT signaling in older men.ConclusionsOur results emphasize the importance of preserved JAK-STAT pathway signaling in healthy aging and reveal cellular pSTAT levels as a candidate biomarker of frailty.

Highlights

Adequate functioning of the immune system is thought to be a pivotal factor in the healthy aging process [1]
Cytokine-induced pSTAT responsiveness within different immune cell lineages We used a broad panel of experimental conditions to quantify immune cell cytokine responses by separately stimulating Peripheral blood mononuclear cells (PBMCs) with IL-10, IFNγ, IL-6, IL-2, or IFNα, and subsequently measuring phosphorylated STAT1, STAT3, and STAT5 in monocytes, B cells, and CD4+ and CD8+ T cells (Fig. 1), using phosho-flow cytometry (Fig. S2)
When testing for sex-specific differences, we did not observe differences in baseline pSTAT levels between men and women, but we did find that women had higher pSTAT3 responses to IL-10 stimulation in CD4+ T cells and to some extent in CD8+ T cells, the differences were small (Table S4, Fig. 2)

Summary

Introduction

Adequate functioning of the immune system is thought to be a pivotal factor in the healthy aging process [1]. An important sign of immune dysregulation is the presence of a ‘sterile’ low-grade chronic inflammation, more often seen in older individuals [6–8]. Senescent cells could directly contribute to chronic low-grade inflammation since they produce multiple inflammatory cytokines (known as the Senescence Associated Secretory Profile, SASP), and these cells are more abundant in older people [10]. Often show reduced immune functioning and can develop chronic low-grade inflammation. We investigated whether frailty is associated with altered cytokine signaling through the JAK-STAT pathway in leukocytes of 34 individuals aged 65–74 years. Presence of chronic low-grade inflammation was investigated by evaluating 18 different plasma inflammatory markers that had been measured repeatedly in the same individuals over the previous 20 years.

Methods

Results

Conclusion