Short-term interleukin-37 treatment improves vascular endothelial function, endurance exercise capacity, and whole-body glucose metabolism in old mice.

Aging is associated with vascular endothelial dysfunction, reduced exercise tolerance, and impaired whole-body glucose metabolism. Interleukin-37 (IL-37), an anti-inflammatory cytokine of the interleukin-1 family, exerts salutary physiological effects in young mice independent of its inflammation-suppressing properties. Here, we assess the efficacy of IL-37 treatment for improving physiological function in older age. Old mice (26-28 months) received daily intraperitoneal injections of recombinant human IL-37 (recIL-37; 1 µg/200 ml PBS) or vehicle (200 ml PBS) for 10-14 days. Vascular endothelial function (ex vivo carotid artery dilation to increasing doses of acetylcholine, ACh) was enhanced in recIL-37 vs. vehicle-treated mice via increased nitric oxide (NO) bioavailability (all p < .05); this effect was accompanied by enhanced ACh-stimulated NO production and reduced levels of reactive oxygen species in endothelial cells cultured with plasma from IL-37-treated animals (p < .05 vs. vehicle plasma). RecIL-37 treatment increased endurance exercise capacity by 2.4-fold, which was accompanied by a 2.9-fold increase in the phosphorylated AMP-activated kinase (AMPK) to AMPK ratio (i.e., AMPK activation) in quadriceps muscle. RecIL-37 treatment also improved whole-body insulin sensitivity and glucose tolerance (p < .05 vs. vehicle). Improvements in physiological function occurred without significant changes in plasma, aortic, and skeletal muscle pro-inflammatory proteins (under resting conditions), whereas pro-/anti-inflammatory IL-6 was greater in recIL-37-treated animals. Plasma metabolomics analysis revealed that recIL-37 treatment altered metabolites related to pathways involved in NO synthesis (e.g., increased L-arginine and citrulline/arginine ratio) and fatty acid metabolism (e.g., increased pantothenol and free fatty acids). Our findings provide experimental support for IL-37 therapy as a novel strategy to improve diverse physiological functions in old age.

Improved motor and cognitive performance with sodium nitrite supplementation is related to small metabolite signatures: a pilot trial in middle-aged and older adults.

Advancing age is associated with reductions in nitric oxide bioavailability and changes in metabolic activity, which are implicated in declines in motor and cognitive function. In preclinical models, sodium nitrite supplementation (SN) increases plasma nitrite and improves motor function, whereas other nitric oxide-boosting agents improve cognitive function. This pilot study was designed to translate these findings to middle-aged and older (MA/O) humans to provide proof-of-concept support for larger trials. SN (10 weeks, 80 to 160 mg/day capsules, TheraVasc, Inc.) acutely and chronically increased plasma nitrite and improved performance on measures of motor and cognitive outcomes (all p<0.05 or better) in healthy MA/O adults (62 ± 7 years). Untargeted metabolomics analysis revealed that SN significantly altered 33 (160 mg/day) to 45 (80 mg/day) different metabolites, 13 of which were related to changes in functional outcomes; baseline concentrations of 99 different metabolites predicted functional improvements with SN. This pilot study provides the first evidence that SN improves aspects of motor and cognitive function in healthy MA/O adults, and that these improvements are associated with, and predicted by, the plasma metabolome. Our findings provide the necessary support for larger clinical trials on this promising pharmacological strategy for preserving physiological function with aging.

Sodium nitrite supplementation improves motor function and skeletal muscle inflammatory profile in old male mice.

Aging is associated with motor declines that lead to functional limitations and disability, necessitating the development of therapies to slow or reverse these events. We tested the hypothesis that sodium nitrite supplementation attenuates declines in motor function in older C57BL/6 mice. Motor function was assessed using a battery of tests (grip strength, open-field distance, rota-rod endurance) in old animals (age 20-24 mo) at baseline and after 8 wk of sodium nitrite (old nitrite, n = 22, 50 mg/liter) or no treatment (old control, n = 40), and in young reference animals (3 mo, n = 87). Eight weeks of sodium nitrite supplementation improved grip strength (old nitrite, +12.0 ± 14.9% vs. old control, +1.5 ± 15.2%, P < 0.05) and open field distance (old nitrite, +9.5 ± 7.7%, P < 0.01 vs. old control, -28.1 ± 2.0%) and completely restored rota-rod endurance-run time (old nitrite, +3.2 ± 7.1%, P < 0.01 vs. old control, -21.5 ± 7.2%; old nitrite after treatment P > 0.05 vs. young reference). Inflammatory cytokines were markedly increased in quadriceps of old compared with young reference animals (by ELISA, interleukin-1ß [IL-1ß] 3.86 ± 2.34 vs. 1.11 ± 0.74, P < 0.05; interferon-gamma [INF-γ] 8.31 ± 1.59 vs. 3.99 ± 2.59, P < 0.01; tumor necrosis factor-alpha [TNF-α] 1.69 ± 0.44 vs. 0.76 ± 0.30 pg/ml, P < 0.01), but were reduced to young reference levels after treatment (old nitrite, IL-1ß 0.67 ± 0.95; INF-γ 5.22 ± 2.01, TNF-α 1.21 ± 0.39 pg/ml, P < 0.05 vs. old control, P > 0.05 vs. young reference). Cytokine expression and treatment (old nitrite vs. old control) predicted strength (R(2) = 0.822, P < 0.001, IL-1ß, INF-γ, group), open field distance (R(2) = 0.574, P < 0.01, IL-1ß, group) and endurance run time (R(2) = 0.477, P < 0.05, INF-γ). Our results suggest that sodium nitrite improves motor function in old mice, in part by reducing low-grade inflammation in muscle.