Targeted Deletion of Interleukin-6 in a Mouse Model of Chronic Inflammation Demonstrates Opposing Roles in Aging: Benefit and Harm

Abstract

Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty.

The physical frailty syndrome as a transition from homeostatic symphony to cacophony

“…There is no direct evidence of efficacy of pharmacological interventions on physical frailty beyond phenotypic components such as muscle strength, body weight and fatigue 103 . Interventions designed to target the phenotypic components of frailty or a single-system-focused one deficit/one therapy model in the case of hormonal therapy will likely be ineffective in alleviating the root cause(s) of frailty 104,105 . Rather, pharmacology to improve multiple systems simultaneously and/or individually tailored pharmacology via precision medicine to personalize how equilibrium is restored may be required.…”

Valsartan nano‐filaments alter mitochondrial energetics and promote faster healing in diabetic rat wounds

“…Metabolomics assessment was performed at the Johns Hopkins Medical Institution's Metabolomics Facility. Wound tissues from rats treated with val‐filament hydrogel and the placebo were processed according to the previously published protocol 18,19 . In brief, samples were extracted in methanol, and the resultant supernatant containing the metabolite fraction was measured using mass spectroscopy.…”

“…Wound tissues from rats treated with val-filament hydrogel and the placebo were processed according to the previously published protocol. 18,19 In brief, samples were extracted in methanol, and the resultant supernatant containing the metabolite fraction was measured using mass spectroscopy. The protein fraction was used to standardise metabolite intensities by protein concentration.…”

Neuro-Inflammaging and Psychopathological Distress

“…IL-6 is provided by endothelial cells, fibroblasts, monocytes, and macrophages in response to diverse triggers such as IL-1, IL-17, and TNF-a during the inflammatory response [ 16 ]. Higher plasma concentrations of inflammatory factors such as IL-6 and TNF-α have been identified as predictors of mortality in the elderly, demonstrating the interconnection between their immune and functional status [ 17 ]. IL-6 has been shown to be associated, for example, with a dysregulation of lipid metabolism and worse cardiac mitochondrial oxygen uptake and therefore an increase in the incidence of cardiovascular diseases [ 18 ].…”