Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor κB.

Habitual aerobic exercise prevents age-related impairments in endothelium-dependent dilation (EDD). We have hypothesized that the pro-inflammatory transcription factor nuclear factor κB (NF-κB) impairs EDD with sedentary aging, and habitual aerobic exercise prevents this age-related suppression of EDD by NF-κB. To test this hypothesis, we have inhibited NF-κB signalling via oral salsalate administration in healthy older aerobic exercise-trained adults (OT, n=14, 58 ± 2 years), older non-exercising adults (ON, n=16, 61 ± 1 years) and young non-exercising controls (YN, n=8, 23 ± 1 years). Salsalate reduced endothelial cell expression of NF-κB p65 by ~25% in ON (P<0.05) but did not significantly change expression in OT or YN (P>0.05). EDD, assessed by brachial artery flow-mediated dilation (FMD), was improved by salsalate in ON (4.0 ± 0.7% compared with 6.8 ± 0.7%, placebo compared with salsalate, P<0.001) but did not change with salsalate in OT or YN (OT: 7.2 ± 0.7% compared with 7.7 ± 0.6%; YN: 7.6 ± 0.9% compared with 8.1 ± 0.8%; placebo compared with salsalate, P>0.05). Endothelium-independent dilation was not affected by salsalate in any group (P>0.05). In ON, vitamin C infusion improved FMD by ~30% during placebo (P<0.001) but had no affect during salsalate (P>0.05). In OT and YN, vitamin C infusion did not affect FMD during either placebo or salsalate (P>0.05). Salsalate reduced endothelial cell nitrotyrosine content by ~25% and NADPH oxidase p47phox expression by ~30% in ON (P<0.05) but had no effect in OT or YN (P>0.05). Our results suggest that endothelial NF-κB signalling is associated with oxidative stress-related impairment of EDD in healthy non-exercising but not aerobically exercising older adults. This may be a key mechanism by which regular aerobic exercise preserves endothelial function and reduces cardiovascular risk with aging.

Oral trehalose supplementation improves resistance artery endothelial function in healthy middle-aged and older adults.

We hypothesized that supplementation with trehalose, a disaccharide that reverses arterial aging in mice, would improve vascular function in middle-aged and older (MA/O) men and women. Thirty-two healthy adults aged 50-77 years consumed 100 g/day of trehalose (n=15) or maltose (n=17, isocaloric control) for 12 weeks (randomized, double-blind). In subjects with Δbody mass less than 2.3kg (5 lb.), resistance artery endothelial function, assessed by forearm blood flow to brachial artery infusion of acetylcholine (FBFACh), increased ~30% with trehalose (13.3±1.0 vs. 10.5±1.1 AUC, P=0.02), but not maltose (P=0.40). This improvement in FBFACh was abolished when endothelial nitric oxide (NO) production was inhibited. Endothelium-independent dilation, assessed by FBF to sodium nitroprusside (FBFSNP), also increased ~30% with trehalose (155±13 vs. 116±12 AUC, P=0.03) but not maltose (P=0.92). Changes in FBFACh and FBFSNP with trehalose were not significant when subjects with Δbody mass ≥ 2.3kg were included. Trehalose supplementation had no effect on conduit artery endothelial function, large elastic artery stiffness or circulating markers of oxidative stress or inflammation (all P>0.1) independent of changes in body weight. Our findings demonstrate that oral trehalose improves resistance artery (microvascular) function, a major risk factor for cardiovascular diseases, in MA/O adults, possibly through increasing NO bioavailability and smooth muscle sensitivity to NO.

Reduced large elastic artery stiffness with regular aerobic exercise in middle-aged and older adults: potential role of suppressed nuclear factor κ B signalling.

OBJECTIVE: Aortic pulse-wave velocity (aPWV) increases with age and is a strong independent predictor of incident cardiovascular diseases (CVDs) in healthy middle-aged and older adults. aPWV is lower in middle-aged and older adults who perform regular aerobic exercise than in their sedentary peers. As exercise is associated with reduced systemic inflammation, we hypothesized that suppression of the pro-inflammatory transcription factor nuclear factor κ B (NFκB) may mediate this process. METHODS: aPWV was measured in young sedentary [n = 10, blood pressure (BP) 108 ±â€Š3/59 ±â€Š2 mmHg; mean ± SEM], middle-aged and older sedentary (n = 9, 124 ±â€Š7/73 ±â€Š5 mmHg) and middle-aged and older aerobic exercise-trained (n = 12, 110 ±â€Š4/67 ±â€Š2 mmHg) healthy, nonhypertensive men and women. RESULTS: Baseline aPWV increased with age [626 ±â€Š14 (young sedentary) vs. 859 ±â€Š49 (middle-aged and older sedentary) cm/s, P < 0.001] but was 20% lower in middle-aged and older trained (686 ±â€Š30 cm/s) than in middle-aged and older sedentary (P < 0.005). Short-term (4 days  x  2500-4500 mg) treatment with the NFκB inhibitor salsalate (randomized, placebo-controlled cross-over design) reduced aPWV (to 783 ±â€Š44 cm/s, P < 0.05) without changing BP (P = 0.40) or heart rate (P = 0.90) in middle-aged and older sedentary, but had no effect in young sedentary (623 ±â€Š19) or middle-aged and older trained (699 ±â€Š30). Following salsalate treatment, aPWV no longer was significantly different in middle-aged and older sedentary vs. middle-aged and older trained (P = 0.29). The reduction in aPWV with salsalate administration was inversely related to baseline (placebo) aPWV (r = -0.60, P < 0.001). CONCLUSION: These results support the hypothesis that suppressed NFκB signalling may partially mediate the lower aortic stiffness in middle-aged and older adults who regularly perform aerobic exercise. Because aPWV predicts incident cardiovascular events in this population, this suggests that tonic suppression of NFκB signalling in middle-aged and older exercising adults may potentially lower cardiovascular risk.

Aging compounds western diet-associated large artery endothelial dysfunction in mice: prevention by voluntary aerobic exercise.

We tested the hypothesis that aging will exacerbate the negative vascular consequences of exposure to a common physiological stressor, i.e., consumption of a "western" (high fat/high sucrose) diet (WD), by inducing superoxide-associated reductions in nitric oxide (NO) bioavailability, and that this would be prevented by voluntary aerobic exercise. Incremental stiffness and endothelium-dependent dilation (EDD) were measured in the carotid arteries of young (5.4±0.3 mo, N=20) and old (30.4±0.2 mo, N=19) male B6D2F1 mice fed normal chow (NC: 17% fat, 0% sucrose) or a western diet (40% fat, 19% sucrose) and housed in either standard cages or cages equipped with running wheels for 10-14 weeks. Incremental stiffness was higher in old NC (P<0.05) and both young (P<0.01) and old (P<0.01) WD fed mice compared with young NC mice, but WD did not further increase stiffness in the old mice. In cage control mice, maximal EDD was 17% lower in both NC fed old mice and young WD fed mice (P<0.05). Consumption of WD by old mice led to a further 20% reduction in maximal EDD (P<0.05). Incremental stiffness was 28% lower and maximal EDD was 38% greater in old WD fed mice with access to running wheels vs. old WD fed control mice (P<0.05) and not different from young NC fed controls. Wheel running also tended to improve maximal EDD (+9%, P=0.11), but not incremental stiffness in young WD fed mice. Ex vivo treatment with the superoxide scavenger TEMPOL and NO inhibitor l-NAME abolished these respective effects of age, WD and voluntary running on EDD. Ingestion of a WD induces similar degrees of endothelial dysfunction in old and young adult B6D2F1 mice, and these effects are mediated by a superoxide-dependent impairment of NO bioavailability. However, the combination of old age and WD, a common occurrence in our aging society, results in a marked, additive reduction in endothelial function. Importantly, regular voluntary aerobic exercise reduces arterial stiffness and protects against the adverse influence of WD on endothelial function in old animals by preventing superoxide suppression of NO. These findings may have important implications for arterial aging and the prevention of age-associated cardiovascular diseases.

Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing endothelial nitric oxide synthase in healthy normolipidemic older adults.

Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation, and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid-lowering agent with potential pleiotropic effects, would improve endothelium-dependent dilation in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was assessed in 22 healthy adults aged 50 to 77 years before and after 7 days of fenofibrate (145 mg/d; n=12) or placebo (n=10). Brachial flow-mediated dilation was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1 ± 0.7 versus 2 days: 6.0 ± 0.7 and 7 days: 6.4 ± 0.6%δ; both P<0.005). The improvements in flow-mediated dilation after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and low-density lipoprotein cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Intravenous infusion of the antioxidant vitamin C improved brachial flow-mediated dilation at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma-oxidized low-density lipoprotein, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54 ± 0.03 versus 2 days: 0.52 ± 0.04 and 7 days: 0.76 ± 0.11 intensity/human umbilical vein endothelial cell control; P<0.05, 7 days). Short-term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged and older adults by reducing oxidative stress and induces an increase in endothelial nitric oxide synthase.