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ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design.

ABSTRACT: To test two interventions to reduce interleukin (IL)-6 levels, an indicator of low-grade chronic inflammation and an independent risk factor for impaired mobility and slow walking speed in older adults.The ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot Study was a multicenter, double-blind, placebo-controlled randomized pilot trial of two interventions to reduce IL-6 levels.Five university-based research centers.Target enrollment was 300 men and women aged 70 and older with an average plasma IL-6 level between 2.5 and 30 pg/mL measured twice at least 1 week apart. Participants had low to moderate physical function, defined as self-reported difficulty walking one-quarter of a mile or climbing a flight of stairs and usual walk speed of less than 1 m/s on a 4-m usual-pace walk.Participants were randomized to losartan, omega-3 fish oil (?-3), combined losartan and ?-3, or placebo. Randomization was stratified depending on eligibility for each group. A titration schedule was implemented to reach a dose that was safe and effective for IL-6 reduction. Maximal doses were 100 mg/d for losartan and 2.8 g/d for ?-3.IL-6, walking speed over 400 m, physical function (Short Physical Performance Battery), other inflammatory markers, safety, tolerability, frailty domains, and maximal leg strength were measured.Results from the ENRGISE Pilot Study will provide recruitment yields, feasibility, medication tolerance and adherence, and preliminary data to help justify a sample size for a more definitive randomized trial.The ENRGISE Pilot Study will inform a larger subsequent trial that is expected to have important clinical and public health implications for the growing population of older adults with low-grade chronic inflammation and mobility limitations.

SUBMITTER: Manini TM

PROVIDER: S-EPMC5642998 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design.

Manini Todd M TM Anton Stephen D SD Beavers Daniel P DP Cauley Jane A JA Espeland Mark A MA Fielding Roger A RA Kritchevsky Stephen B SB Leeuwenburgh Christiaan C Lewis Kristina H KH Liu Christine C McDermott Mary M MM Miller Michael E ME Tracy Russell P RP Walston Jeremy D JD Radziszewska Barbara B Lu Jane J Stowe Cindy C Wu Samuel S Newman Anne B AB Ambrosius Walter T WT Pahor Marco M

Journal of the American Geriatrics Society 20170722 9

<h4>Objectives</h4>To test two interventions to reduce interleukin (IL)-6 levels, an indicator of low-grade chronic inflammation and an independent risk factor for impaired mobility and slow walking speed in older adults.<h4>Design</h4>The ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot Study was a multicenter, double-blind, placebo-controlled randomized pilot trial of two interventions to reduce IL-6 levels.<h4>Setting</h4>Five university-based research centers.<h4>Parti ...[more]

PMID: 28734043

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Project description:BackgroundRadiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors.MethodsWe biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection.Findings942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration.InterpretationOur results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors.FundingThis study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow's foundation (MA and VP).

Dataset Information

ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design.

Publications

ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design.

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