Arterial aging, characterized by stiffening of large elastic arteries and the development of arterial endothelial dysfunction, increases cardiovascular disease (CVD) risk. We tested the hypothesis that spermidine, a nutrient associated with the anti-aging process autophagy, would improve arterial aging. Aortic pulse wave velocity (aPWV), a measure of arterial stiffness, was ~20% greater in old (O, 28 months) compared with young C57BL6 mice (Y, 4 months, P < 0.05). Arterial endothelium-dependent dilation (EDD), a measure of endothelial function, was ~25% lower in O (P < 0.05 vs. Y) due to reduced nitric oxide (NO) bioavailability. These impairments were associated with greater arterial oxidative stress (nitrotyrosine), superoxide production, and protein cross-linking (advanced glycation end-products, AGEs) in O (all P < 0.05). Spermidine supplementation normalized aPWV, restored NO-mediated EDD and reduced nitrotyrosine, superoxide, AGEs and collagen in O. These effects of spermidine were associated with enhanced arterial expression of autophagy markers, and in vitro experiments demonstrated that vascular protection by spermidine was autophagy-dependent. Our results indicate that spermidine exerts a potent anti-aging influence on arteries by increasing NO bioavailability, reducing oxidative stress, modifying structural factors and enhancing autophagy. Spermidine may be a promising nutraceutical treatment for arterial aging and prevention of age-associated CVD.

Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator SRT1720 improves endothelial function [endothelium-dependent dilation (EDD)] in old mice. Young (4-9 mo) and old (29-32 mo) male B6D2F1 mice treated with SRT1720 (100 mg/kg body wt) or vehicle for 4 wk were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced (P < 0.05) and EDD was impaired (83 ± 2 vs. 96 ± 1%; P < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice and restored EDD (95 ± 1%) by enhancing cyclooxygenase (COX)-2-mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NADPH oxidase 4 (NOX4) were increased in old vehicle mice (P < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4 and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor-κB (NF-κB) activity and tumor necrosis factor-α (TNF-α) were increased in old vehicle mice (P < 0.05), whereas SRT1720 normalized NF-κB activation and reduced TNF-α in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans.

Central arterial stiffness increases with sedentary ageing. While near-daily, vigorous lifelong (>25 years) endurance exercise training prevents arterial stiffening with ageing, this rigorous routine of exercise training over a lifetime is impractical for most individuals. The aim was to examine whether a less frequent 'dose' of lifelong exercise training (four to five sessions per week for > 30 min) that is consistent with current physical activity recommendations elicits similar benefits on central arterial stiffening with ageing. A cross-sectional examination of 102 seniors (>60 years old) who had a consistent lifelong exercise history was performed. Subjects were stratified into four groups based on exercise frequency as an index of exercise 'dose': sedentary: fewer than two sessions per week; casual exercisers: two to three sessions per week; committed exercisers: four to five sessions per week; and Masters athletes: six to seven sessions per week plus regular competitions. Detailed measurements of arterial stiffness and left ventricular afterload were collected. Biological aortic age and central pulse wave velocity were younger in committed exercisers and Masters athletes compared to sedentary seniors. Total arterial compliance index (TACi) was lower, while carotid β-stiffness index and effective arterial elastance were higher in sedentary seniors compared to the other groups. There appeared to be a dose-response threshold for carotid β-stiffness index and TACi. Peripheral arterial stiffness was not significantly different among the groups. These data suggest that four to five weekly exercise sessions over a lifetime is associated with reduced central arterial stiffness in the elderly. A less frequent dose of lifelong exercise (two to three sessions per week) is associated with decreased ventricular afterload and peripheral resistance, while peripheral arterial stiffness is unaffected by any dose of exercise.

There is heterogeneity in the observed O2peak response to similar exercise training, and different exercise approaches produce variable degrees of exercise response (trainability). The aim of this study was to combine data from different laboratories to compare O2peak trainability between various volumes of interval training and Moderate Intensity Continuous Training (MICT). For interval training, volumes were classified by the duration of total interval time. High-volume High Intensity Interval Training (HIIT) included studies that had participants complete more than 15 min of high intensity efforts per session. Low-volume HIIT/Sprint Interval Training (SIT) included studies using less than 15 min of high intensity efforts per session. In total, 677 participants across 18 aerobic exercise training interventions from eight different universities in five countries were included in the analysis. Participants had completed 3 weeks or more of either high-volume HIIT (n = 299), low-volume HIIT/SIT (n = 116), or MICT (n = 262) and were predominately men (n = 495) with a mix of healthy, elderly and clinical populations. Each training intervention improved mean O2peak at the group level (P < 0.001). After adjusting for covariates, high-volume HIIT had a significantly greater (P < 0.05) absolute O2peak increase (0.29 L/min) compared to MICT (0.20 L/min) and low-volume HIIT/SIT (0.18 L/min). Adjusted relative O2peak increase was also significantly greater (P < 0.01) in high-volume HIIT (3.3 ml/kg/min) than MICT (2.4 ml/kg/min) and insignificantly greater (P = 0.09) than low-volume HIIT/SIT (2.5 mL/kg/min). Based on a high threshold for a likely response (technical error of measurement plus the minimal clinically important difference), high-volume HIIT had significantly more (P < 0.01) likely responders (31%) compared to low-volume HIIT/SIT (16%) and MICT (21%). Covariates such as age, sex, the individual study, population group, sessions per week, study duration and the average between pre and post O2peak explained only 17.3% of the variance in O2peak trainability. In conclusion, high-volume HIIT had more likely responders to improvements in O2peak compared to low-volume HIIT/SIT and MICT.

The regulation of skeletal muscle blood flow and oxygen delivery to contracting skeletal muscle is complex and involves the mechanical effects of muscle contraction; local metabolic, red blood cell and endothelium‐derived substances; and the sympathetic nervous system (SNS). With advancing age in humans, skeletal muscle blood flow is typically reduced during dynamic exercise and this is due to a lower vascular conductance, which could ultimately contribute to age‐associated reductions in aerobic exercise capacity, a primary predictor of mortality in both healthy and diseased ageing populations. Recent findings have highlighted the contribution of endothelium‐derived substances to blood flow control in contracting muscle of older adults. With advancing age, impaired nitric oxide availability due to scavenging by reactive oxygen species, in conjunction with elevated vasoconstrictor signalling via endothelin‐1, reduces the local vasodilatory response to muscle contraction. Additionally, ageing impairs the ability of contracting skeletal muscle to blunt sympathetic vasoconstriction (i.e. ‘functional sympatholysis’), which is critical for the proper regulation of tissue blood flow distribution and oxygen delivery, and could further reduce skeletal muscle perfusion during high intensity and/or large muscle mass exercise in older adults. We propose that initiation of endothelium‐dependent hyperpolarization is the underlying signalling event necessary to properly modulate sympathetic vasoconstriction in contracting muscle, and that age‐associated impairments in red blood cell adenosine triphosphate release and stimulation of endothelium‐dependent vasodilatation may explain impairments in both local vasodilatation and functional sympatholysis with advancing age in humans.

Stiffening of large elastic arteries with age increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. We investigated the role of mitochondrial quality control (QC, i.e., mitophagy and biogenesis) in arterial stiffening with aging. In C57BL6 mice, aging was associated with impaired aortic expression of mitochondrial QC mediators, greater activation of the mitochondrial redox/stress sensor p66shc, elevated superoxide production and increased arterial stiffness—as indicated by ~20% higher aortic pulse wave velocity (aPWV). In old mice, supplementation with trehalose, a nutraceutical reported to enhance mitophagy, normalized mitochondrial QC markers, p66shc activation and superoxide production, and reduced aPWV and aortic collagen I (a structural protein that confers stiffness). In vitro experiments indicated that mitochondrial QC processes were enhanced in aorta from old trehalose-treated mice, and in aortic rings studied ex vivo, both aging and treatment with the mitochondrial stressor rotenone were associated with increases in p66shc activation and intrinsic mechanical stiffness, whereas co-incubation with trehalose prevented these effects. Taken together, these findings suggest that mitochondrial stress/dysfunction as a result of impaired mitochondrial QC contributes to large elastic artery stiffening with age. Enhancing mitochondrial QC with agents such as trehalose may be a novel strategy for reducing age-associated arterial stiffness and CVD.

-14 ± 5%). We conclude that stimulation of EDH-like vasodilatation can blunt α -adrenergic vasoconstriction in contracting skeletal muscle of humans.

Whole body hyperthermia may produce vasodialation, nausea, and altered cognitive function. Animal research has identified brain regions that have important roles in thermoregulation. However, differences in both the cognitive and sweating abilities of humans and animals implicate the need for human research. Positron emission tomography (PET) was used to identify brain regions with altered activity during systemic hyperthermia. Human subjects were studied under cool (control) conditions and during steady-state hyperthermia induced by means of a liquid-conditioned suit perfused with hot water. PET images were obtained by injecting [(18)F]fluorodeoxyglucose, waiting 20 min for brain uptake, and then scanning for 10 min. Heating was associated with a 23% increase in resting metabolic rate. Significant increases in cerebral metabolic rate occurred in the hypothalamus, thalamus, corpus callosum, cingulate gyrus, and cerebellum. In contrast, significant decreases occurred in the caudate, putamen, insula, and posterior cingulum. These results are important for understanding the mechanisms responsible for altered cognitive and systemic responses during hyperthermia. Novel regions (e.g., lateral cerebellum) with possible thermoregulatory roles were identified.