Inflammation and cell-to-cell communication, two related aspects in frailty

Abstract

Background: Frailty is a complex, multi-dimensional age-related syndrome that increases the susceptibility to adverse health outcomes and poor quality of life. A growing consensus supports the contribution of chronic inflammation and immune system alterations to frailty, however a clear role of such alterations remains to be elucidated. Furthermore, pro- and anti-inflammatory cytokines together with other signaling molecules might spread from activated cells to the adjacent ones through extracellular vesicles (EVs), which have also a role in cellular aging. The aim of the present research was to investigate if EVs play a role in the immune function in frailty. Results: In 219 older adults aged 76–78 years, selected from the InveCe.Ab study (Abbiategrasso, Italy), we investigated inflammation and EVs-mediated intercellular communication. C-reactive protein (CRP) and pro- (IL-1β, IL-2, IL-6, IL-8, IL-12 p70, TNFα and IFNγ) and anti- (IL-4, IL-10, IL-13) inflammatory cytokines were evaluated on plasma of Frail and non-Frail subjects. We reported a significant increase in CRP, interleukin-1β and -6 (IL-1β, IL-6) and tumor necrosis factor alpha (TNFα) plasma levels in frailty. In female Fr subjects, we also reported an increase in interferon‐gamma (IFN‐γ) and, surprisingly, in IL-13, an anti-inflammatory cytokine, whose increase seems to oppose the inflammaging theory. An inflammatory panel (toll-like receptors 2 and 4 (TLR2 and TLR4), tumor necrosis factor receptors TNFRec5/CD 40 and TNFRec1B/CD120B) and a panel including receptors involved in cellular senescence (insulin-like growth factor 1 receptor (CD221) and interleukin 6 receptor (IL-6R)) were indeed analysed in plasma isolated large EVs (lEVs) from Frail (n = 20) and non-Frail (n = 20) subjects. In lEVs isolated from plasma of Frail subjects we reported an increase in TLR2 and TLR4, TNFRec5/CD 40 and TNFRec1B/CD120B, suggesting a chronic state of inflammation. In addition, CD221 and IL-6R increases in lEVs of Frail individuals. Conclusions: To conclude, the pro-inflammatory status, notably the increase in circulating cytokines is pivotal to understand the potential mechanisms underlying the frailty syndrome. Moreover, cytokines release from EVs, mainly the large ones, into the extracellular space suggest their contribution to the formation of a pro-inflammatory and pro-senescent microenvironment that, in turn, can contribute to frailty.