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Administration of anti‐inflammatory interleukin‐37 ameliorates age‐related vascular, metabolic and physical dysfunction in mice
Author(s) -
Sapinsley Zachary J,
Ballak Dov B,
Brunt Vienna E,
Zigler Melanie C,
GiosciaRyan Rachel A,
Richey James J,
Dinarello Charles A,
Seals Douglas R
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1079.3
Subject(s) - medicine , endocrinology , inflammation , ex vivo , pulse wave velocity , endothelial dysfunction , nitric oxide synthase , vasodilation , nitric oxide , endothelium , saline , common carotid artery , in vivo , blood pressure , carotid arteries , biology , microbiology and biotechnology
Chronic, low‐grade inflammation that occurs with age, termed inflammaging, is a key mechanism in the etiology of age‐related disease and dysfunction, which has been linked to the pathophysiology of cardiovascular diseases, metabolic diseases including type 2 diabetes mellitus, and physical decline. Interleukin‐37 (IL‐37), a member of the interleukin‐1 family of cytokines, broadly inhibits inflammation and therefore carries strong potential as an anti‐aging intervention. PURPOSE We tested the hypothesis that two weeks of recombinant IL‐37 (recIL‐37) administration would improve vascular, metabolic, and motor function in old mice. METHODS Twenty old (27 mo) and fourteen young (9–10 mo) male C57BL/6 mice were treated with recIL‐37 or vehicle (phosphate buffered saline) for two weeks, injected intraperitoneally (IP) (200μL of 5μg/L) daily. Vascular, metabolic, and motor functions were measured at baseline and again post‐intervention using blood pressure and large elastic artery stiffness testing with pulse wave velocity, 2‐hr glucose and insulin tolerance tests, and RotaRod endurance run time, respectively. Vascular function was further evaluated through ex vivo carotid artery endothelium‐dependent dilation to increasing doses of acetylcholine (10 −9 to 10 −4 M) without and with nitric oxide (NO) synthase inhibition via 10 −4 M L‐N G ‐nitroarginine methyl ester (L‐NAME). RESULTS Two weeks of recIL‐37 administration in old mice: (1) improved ex vivo endothelium‐dependent dilation of carotid arteries (p < 0.05 for 10 −7 to 10 −5 M ACh, n=7–9 per group; 10 −5 M ACh: recIL‐37: 86.2±2.7%max vs. vehicle: 64.6±3.0%max, p=0.01) seemingly by improving NO‐dependent dilation (difference between dilation to max ACh dose without and with L‐NAME: recIL‐37: 67.4±7%max vs. vehicle 50.5±5.3%max, p=0.08, n=6 per group); (2) improved insulin sensitivity (2‐hr glucose AUC following IP insulin injection [0.75U/kg body weight], recIL‐37: 232±23 mM · min vs. vehicle: 293±17 mM · min, p=0.05) and tended to improve glucose tolerance in a subset of mice (20‐min peak blood glucose following IP glucose injection [2μg/g body weight], recIL‐37: 10.4±0.8mM vs. vehicle: 13.3±1.2mM, p=0.08), and (3) completely restored RotaRod endurance run time (recIL‐37: 36±7 m vs. vehicle: 17±7, p=0.03) to levels comparable to young vehicle‐treated mice (34±8m, P=0.86 vs. old recIL‐37). No changes were observed in blood pressure or pulse wave velocity or in any variables in young mice. CONCLUSIONS Two‐week administration of anti‐inflammatory recIL‐37 improves selective vascular, metabolic, and motor functions in old mice. Anti‐inflammatory treatments such as recIL‐37 present a novel strategy for preserving physiological function with advancing age and preventing age‐related diseases. Support or Funding Information Supported by NIA grant #RAG053804A.