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We determined the site-specific relations of hormone replacement therapy (HRT) and habitual exercise status with intima-media thickness (IMT) in both elastic (carotid) and muscular (femoral) arteries in 77 healthy postmenopausal women: 43 women were sedentary (20 no-HRT and 23 HRT users) and 34 women were endurance trained (14 no-HRT and 20 HRT users). Femoral IMT was not different among the sedentary HRT and endurance-trained no-HRT and HRT groups, but was lower ( P < 0.005) in these three groups than in the sedentary no-HRT women. There were no significant group differences in carotid IMT. However, in older women (≥65 yrs) carotid IMT was smaller ( P < 0.05) in HRT compared with no-HRT women. We conclude that both endurance training and HRT status are independently associated with a smaller IMT and these effects are evident primarily in muscular arteries. These results suggest that HRT and habitual exercise may protect postmenopausal women against cardiovascular disease through influences on IMT. The site-specific relations may be due to a greater number of smooth muscle cells and plasticity of muscular arteries compared with elastic arteries and/or differences in heterogeneous influences such as metabolic requirements and hydrostatic pressures.

Carotid artery intima-media thickness (IMT), an independent risk factor for stroke, increases with age. Habitual exercise is associated with a lower prevalence of stroke, but it is unclear whether this protective effect could be mediated through a favorable influence on carotid IMT. We examined this possibility using both cross-sectional and intervention approaches. First, 137 healthy men (age 18–77 yr) who were either sedentary or endurance trained were studied. In both groups, carotid IMT and IMT-to-lumen ratio were progressively higher with age ( P < 0.05). There were no significant differences in measures of carotid IMT between sedentary and endurance-trained men at any age. Carotid systolic blood pressure increased progressively with age and was related to carotid IMT ( r = 0.63, P < 0.01). Second, 18 healthy sedentary subjects (54 ± 2 yr) were studied before and after 3 mo of endurance training. Carotid IMT, IMT/lumen ratio, and carotid systolic blood pressure did not change with exercise intervention. Our results do not support the hypothesis that regular aerobic exercise exerts its protective effect against stroke by attenuating the age-related increase in carotid IMT. This lack of effect on carotid IMT may be due to the apparent inability of habitual exercise to prevent or reduce the age-associated elevation in carotid distending pressure.

The influence of ageing on the sympathetic nervous system and adrenal medulla was studied neurochemically in humans, using isotopic dilution measurement of regional and whole body catecholamine release to plasma in humans. With ageing, sympathetic activation was evident in the heart, and the gut and liver at rest. The mechanism appeared to be by activation of sympathoexcitatory noradrenergic suprabulbar projections from the brainstem. Sympathetic nervous responses with stressors were augmented. Conversely, adrenal medullary release of epinephrine was subnormal in the elderly, at rest and during stress.

The gut microbiome, an emerging mediator of host physiological function, is adversely altered by aging and many diseases, termed “gut dysbiosis.” One consequence of gut dysbiosis is elevated circulating levels of the gut-derived metabolite trimethylamine N-oxide (TMAO), which has been directly linked to cardiovascular (CV) risk, including the development of atherosclerosis. However, it is unknown whether TMAO mediates arterial dysfunction that precedes the onset of clinical disease, and if so, the underlying mechanisms. Purpose: To determine whether TMAO independently induces large elastic artery stiffening and endothelial dysfunction via increased superoxide-related oxidative stress. Method: Twenty young (6 mo) male C57BL/6 mice were fed a chemically-defined choline (0.08–0.09%) diet supplemented without (Control; N = 9) or with (N = 11) 0.12% TMAO for 6 months. Arterial stiffness was assessed as aortic pulse wave velocity (aPWV). Endothelial function was evaluated ex vivo as carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine (10−9 to 10−4M) in the absence or presence of the superoxide dismutase mimetic TEMPOL. Results: TMAO increased aPWV (Control: 392 ± 20 vs. TMAO: 483 ± 32 cm/sec, p = 0.04) and impaired EDD (peak dilation, Control: 93.7 ± 3.2 vs. TMAO: 79.9 ± 3.4%, p = 0.01). Suppression of oxidative stress with TEMPOL restored EDD in TMAO-treated animals (peak dilation: 92.1 ± 4.7%, p = 0.46 vs. Control). Conclusions: TMAO independently induces large elastic artery stiffening and endothelial dysfunction in mice. Dysfunction appears to occur through increases in oxidative stress. These data may explain, at least in part, why TMAO increases CV risk and provide a potential target for prevention/treatment of arterial dysfunction. Supported by R01 HL134887 & T32 HL007822.

Despite dedicated efforts to identify interventions to delay aging, most promising interventions yielding dramatic life-span extension in animal models of aging are often ineffective when translated to clinical trials. This may be due to differences in primary outcomes between species and difficulties in determining the optimal clinical trial paradigms for translation. Measures of physical function, including brief standardized testing batteries, are currently being proposed as biomarkers of aging in humans, are predictive of adverse health events, disability, and mortality, and are commonly used as functional outcomes for clinical trials. Motor outcomes are now being incorporated into preclinical testing, a positive step toward enhancing our ability to translate aging interventions to clinical trials. To further these efforts, we begin a discussion of physical function and disability assessment across species, with special emphasis on mice, rats, monkeys, and man. By understanding how physical function is assessed in humans, we can tailor measurements in animals to better model those outcomes to establish effective, standardized translational functional assessments with aging.

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-1β [IL-1β] 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-1β 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 ( R2 = 0.822, P < 0.001, IL-1β, INF-γ, group), open field distance ( R2 = 0.574, P < 0.01, IL-1β, group) and endurance run time ( R2 = 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.

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.

Most nations of the world are undergoing rapid and dramatic population ageing, which presents great socio‐economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population ageing has been ‘compression of morbidity’ and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological ageing research, ‘geroscience’, is focused on healthspan extension. Superimposed on this background are new attitudes and demand for ‘optimal longevity’ – living long, but with good health and quality of life. A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with ageing, which causes functional limitations (e.g. reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan centre on slowing the fundamental biological processes of ageing such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global ageing. Effective strategies should delay, reduce in magnitude or abolish reductions in function with ageing (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention). Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first‐line function‐preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel ‘nutraceutical’ compounds, serving as potential complementary approaches. Future research efforts should focus on defining the temporal patterns of functional declines with ageing, identifying the underlying mechanisms and modulatory factors involved, and establishing the most effective lifestyle practices and pharmacological options for maintaining function. Continuing development of effective behavioural approaches for enhancing adherence to healthy ageing practices in diverse populations, and ongoing analysis of the socio‐economic costs and benefits of healthspan extension will be important supporting goals. To meet the demands created by rapid population ageing, a new emphasis in physiological geroscience is needed, which will require the collaborative, interdisciplinary efforts of investigators working throughout the translational research continuum from basic science to public health.

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 (P0.05). 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, P0.05). 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 (P0.05). 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 (P0.05). 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.

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMDBA, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMDBA, aPWV, and vascular endothelial cell protein expression.

Vascular endothelial dysfunction develops with aging as a result of insufficient nitric oxide (NO) bioavailability. Supplementation with nitrite, a precursor to NO, may improve NO bioavailability. We tested the safety, dose (80 vs. 160 mg/d), duration (4 and 10 weeks), and efficacy of oral sodium nitrite for improving endothelial dysfunction in middle-aged and older (MA/O) adults (n=28, 61±1 yr) in a randomized, placebo-controlled, double-blind pilot intervention study. Both doses of nitrite acutely increased plasma nitrite (10 to 20-fold, p

The accumulation of damaged proteins can perturb cellular homeostasis and provoke aging, pathological states and cell death. Quality control systems, such as the unfolded protein response (UPR), in...

Declines in exercise capacity with aging are associated with increased risk of disability and mortality. Dietary interventions that increase circulating nitrite may improve exercise capacity. We pe...

Using only indirect, static markers of the dynamic cellular quality control system, autophagy, we have reported impaired autophagy in biopsied vascular endothelial cells (EC) of humans with aging t...

Reduced bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 (SIRT1), may contribute to age-related vascular dysfunction via oxidative stress and red...

Aging causes physiological dysfunction, some of which can be prevented or reduced by habitual aerobic exercise (AE). However, the molecular mechanisms underlying these effects remain largely unknown, particularly in humans. We used a novel high-throughput molecular assay (SOMAscan v3.0, SomaLogic Inc., Boulder, CO) to characterize the effects of age and regular AE on the plasma proteome of healthy adult humans. From 1129 analytes, the expression of 48 proteins was greater and 37 lower in older (O; 64±6 yr; n=16) vs. young (Y; 24±4 yr; n=16) healthy men (false discovery rate [FDR] < 15%, p

Reduced nitric oxide (NO) bioavailability contributes to physiological dysfunction with aging. Oral sodium nitrite supplementation (SN) increases circulating nitrite, a precursor of NO, and improve...

Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD.

Aging is the major risk factor for cardiovascular diseases (CVD). This is attributable primarily to adverse changes in arteries, notably, increases in large elastic artery stiffness and endothelial dysfunction mediated by inadequate concentrations of the vascular-protective molecule, nitric oxide (NO), and higher levels of oxidative stress and inflammation. Inorganic nitrite is a promising precursor molecule for augmenting circulating and tissue NO bioavailability because it requires only a one-step reduction to NO. Nitrite also acts as an independent signaling molecule, exerting many of the effects previously attributed to NO. Results of recent studies indicate that nitrite may be effective in the treatment of vascular aging. In old mice, short-term oral sodium nitrite supplementation reduces aortic pulse wave velocity, the gold-standard measure of large elastic artery stiffness, and ameliorates endothelial dysfunction, as indicated by normalization of NO-mediated endothelium-dependent dilation. These improvements in age-related vascular dysfunction with nitrite are mediated by reductions in oxidative stress and inflammation, and may be linked to increases in mitochondrial biogenesis and health. Increasing nitrite levels via dietary intake of nitrate appears to have similarly beneficial effects in many of the same physiological and clinical settings. Several clinical trials are being performed to determine the broad therapeutic potential of increasing nitrite bioavailability on human health and disease, including studies related to vascular aging. In summary, inorganic nitrite, as well as dietary nitrate supplementation, represents a promising therapy for treatment of arterial aging and prevention of age-associated CVD in humans.

By 2050, the number of people over the age of 80 will triple globally. These demographics could come at great cost to individuals and economies. Two groups describe how research in animals and humans should be refocused to find ways to delay the onset of frailty.

Background Cardiovagal baroreflex sensitivity (BRS) declines with age but is favorably modulated by habitual aerobic exercise. We tested the hypothesis that compliance (transducing capacity) of an elastic artery in which baroreceptors are located is associated with these age-exercise interactions. Methods and Results Nine young (28±1 years old) and 9 older (65±1) sedentary and 10 young (27±1) and 9 older (63±2) endurance-trained healthy men were studied. Cardiovagal BRS was assessed conventionally (R-R interval–systolic blood pressure [SBP] relation) by the Oxford technique. Because of age-associated increases in central arterial stiffness, cardiovagal BRS was expressed with both peripheral (Finapres) and central (applanation tonometry) SBP values. The change in carotid artery end-systolic lumen diameter (ultrasonography) per unit increase in SBP and the slope of the R-R interval–carotid artery diameter relation also were determined. Cardiovagal BRS declined with age in both sedentary (≈65%) and endurance-trained (≈40%) men but was higher in endurance-trained than sedentary older men regardless of the SBP values used (all P P P >0.70). Conclusions These results demonstrate that age- and habitual exercise–related differences in cardiovagal BRS are associated with corresponding differences in carotid artery compliance among healthy men.

We recently demonstrated in young adult humans that the sympathetic nervous system contributes to the control of resting metabolic rate via tonic β-adrenergic receptor stimulation. In the present follow-up study we determined the respective effects of age, habitual exercise status, and sex on this regulatory mechanism. Resting metabolic rate (ventilated hood, indirect calorimetry) was determined in 55 healthy sedentary or endurance exercise-trained adults, aged 18–35 or 60–75 yr (29 men and 26 women), before (baseline) and during the infusion of either a nonselective β-adrenergic receptor antagonist (propranolol) or saline (control). Relative to baseline values, during β-adrenergic receptor antagonism resting metabolic rate adjusted for fat-free mass was reduced to a lesser extent in older (mean ± se,− 130 ± 46 kJ/d) compared with young (−297 ± 46) adults, sedentary (−151 ± 50) compared with endurance exercise-trained (−268 ± 46) adults, and women (−105 ± 33) compared with men (−318 ± 50; all P < 0.01). Reductions in resting metabolic rate during β-adrenergic receptor antagonism were positively related to higher baseline resting metabolic rate and plasma catecholamine concentrations and negatively related to adiposity (all P < 0.05). Resting metabolic rate was unchanged in response to saline control in all groups. These results provide experimental support for the hypothesis that aging, sedentary living, and female sex are associated with attenuated sympathetic nervous system support of resting metabolic rate in healthy adult humans.

1. In experimental animals chronic elevations in arterial blood flow increase the lumen diameter and reduce the intima-media thickness (IMT) of the arterial segment involved. We determined whether intermittent elevations in active muscle blood flow associated with regular aerobic leg exercise induced such expansive arterial remodelling in the common femoral artery of humans. 2. In the cross-sectional study 53 sedentary (47 +/- 2 years) and 55 endurance exercise-trained (47 +/- 2 years) men were studied. Common femoral artery lumen diameter (B-mode ultrasound) was 7 % greater (9.62 +/- 0.12 vs. 9.03 +/- 0.13 mm), and femoral IMT (0.46 +/- 0.02 vs. 0.55 +/- 0.02 mm) and IMT/lumen ratio were 16-21 % smaller in the endurance-trained men (all P < 0.001). Basal femoral artery blood flow (duplex ultrasound) was not different, shear stress tended to be lower (P = 0.08), and mean femoral tangential wall stress was 30 % higher in the endurance-trained men (P < 0.001). 3. In the intervention study 22 men (51 +/- 2 years) were studied before and after 3 months of regular aerobic leg exercise (primarily walking). After training, the femoral diameter increased by 9 % (8.82 +/- 0.18 vs. 9.60 +/- 0.20 mm), and IMT (0.65 +/- 0.05 vs. 0.56 +/- 0.05 mm) and the IMT/lumen ratio were approximately 15-20 % smaller (all P < 0.001). Basal femoral blood flow and shear stress were not different after training, whereas the mean femoral tangential wall stress increased by 31 %. The changes in arterial structure were not related to changes in risk factors for atherosclerosis. 4. Our results are consistent with the concept that regular aerobic leg exercise induces expansive arterial remodelling in the femoral artery of healthy men. This adaptive process is produced by even a moderate training stimulus, is not obviously dependent on corresponding improvements in risk factors for atherosclerosis, and is robust, occurring in healthy men of different ages.

The sympathetic nervous system (SNS) plays an important role in the regulation of energy expenditure. However, whether tonic SNS activity contributes to resting metabolic rate (RMR) in healthy adult humans is controversial, with the majority of studies showing no effect. We hypothesized that an intravenous propranolol infusion designed to achieve complete β-adrenergic blockade would result in a significant acute decrease in RMR in healthy adults. RMR (ventilated hood, indirect calorimetry) was measured in 29 healthy adults (15 males, 14 females) before and during complete β-adrenergic blockade documented by plasma propranolol concentrations ≥100 ng/ml, lack of heart rate response to isoproterenol, and a plateau in RMR with increased doses of propranolol. Propranolol infusion evoked an acute decrease in RMR (−71 ± 11 kcal/day; −5 ± 0.7%, P < 0.0001), whereas RMR was unchanged from baseline levels during a saline control infusion ( P > 0.05). The response to propranolol differed from the response to saline control ( P < 0.01). The absolute and percent decreases in RMR with propranolol were modestly related to baseline plasma concentration of norepinephrine ( r = 0.38, P = 0.05; r= 0.44, P = 0.02, respectively). These findings provide direct evidence for the concept of tonic sympathetic β-adrenergic support of RMR in healthy nonobese adults.

Background: Indirect measures of body composition suggest that Hispanic women have an excess prevalence of overweight and obesity compared with white women. Socioeconomic status (SES) is a potentially confounding factor in such studies. Objective: Our aim was to determine whether Hispanic ethnicity is associated with higher total and regional adiposity and lower fat-free mass (FFM) in healthy women across the adult age range. Design: We used a prospective cross-sectional design to examine total and regional body composition in 54 Hispanic women (primarily of Mexican descent) and 56 white women of similar SES. Results: The groups were not significantly different in mean age, body mass, or SES, although the Hispanic women were shorter (P < 0.05). Body mass index (in kg/m 2 ; 25.2 ± 0.5 compared with 23.9 ± 0.5; P < 0.05), percentage body fat (38.4 ± 0.8% compared with 34.9 ± 1.3%: P < 0.05), and total fat mass (25.0 ± I.0 compared with 23.0 ± 1.2 kg; P = 0.10) were or tended to be higher in the Hispanic women. The greater total adiposity of the Hispanic women was primarily the result of higher percentage fat and fat mass in the trunk (P < 0.05); within the trunk region, abdominal and subscapular skinfold thicknesses were 30-40% greater in the Hispanic women (P

Hispanic women may undergo greater age-related reductions in physical functional capacity compared with Caucasian women. If so, a greater rate of decline in muscle strength with age could contribute. We tested this hypothesis in 82 healthy sedentary Caucasian (n = 37) and Hispanic (n = 45) adult women aged 21-78 years of similar socioeconomic status. Absolute one-repetition maximum (1-RM) strength of the knee extensors (KE) declined with advancing age in the Caucasian (r = -.55, p < .01) and Hispanic (r = -.45, p < .01) women; the rates of decline were similar in the two groups (-7% to 8% x decade(-1), p = .60). KE strength normalized for thigh fat-free mass (FFM) also declined with age in the Caucasian (r = .52, p < .01) and Hispanic (r = -.41, p < .01) women, the rates of decline being similar (-6% to 7% x decade(-1), p = .66). For all functional performance tasks (10-m walk, stair ascent, stair descent, and chair stand), performance time increased with advancing age (mean of four tasks vs age: Caucasian, r = .64, p < .01; Hispanic, r = .56, p < .01). Absolute and normalized KE 1-RM were inversely related to the mean time for the four performance tasks (r = -.34 to -.58, all p < .01). Normalized KE 1-RM was the best independent predictor of the age-related decline in task performance in both groups. These cross-sectional findings do not support the hypothesis that Hispanic ethnicity per se is associated with a greater decline in KE strength and performance tasks associated with KE strength in healthy women.

1. Cardiovagal baroreflex sensitivity (BRS), the arterial baroreflex-mediated change in the R-R interval per unit change in systolic blood pressure, decreases with advancing age in sedentary adult humans. We determined the effects of regular aerobic exercise on the age-related decline in cardiovagal BRS. 2. In the cross-sectional study, 133 healthy men 18-79 years of age who were either sedentary, performing moderate aerobic exercise, or endurance exercise trained were studied. Among the sedentary men, cardiovagal BRS (phase IV of Valsalva's manoeuvre) was progressively lower (P < 0.05) in the middle-aged ( approximately 33 %) and older ( approximately 60 %) groups compared with the young group. In contrast, cardiovagal BRS was similar in the young and middle-aged men in the moderate exercise and endurance-trained groups. Cardiovagal BRS was lower (P < 0.05) in the older exercising men, but the magnitude of decline across age ( approximately 30 %) was only half as great as that in sedentary men. Cardiovagal BRS was 40-75 % greater (P < 0.05) in middle-aged and older men who exercised regularly compared with their sedentary peers. 3. In the intervention study, a 3 month aerobic exercise intervention (primarily walking) increased cardiovagal BRS by an average of 25 % (P < 0.05) in 13 previously sedentary middle-aged and older (56 +/- 1 years) healthy men. 4. Our results demonstrate for the first time that regular aerobic exercise: (1) attenuates the age-associated decline in cardiovagal BRS; and (2) partially restores the loss of cardiovagal BRS in previously sedentary middle-aged and older healthy men.

Background —In sedentary humans endothelium-dependent vasodilation is impaired with advancing age contributing to their increased cardiovascular risk, whereas endurance-trained adults demonstrate lower age-related risk. We determined the influence of regular aerobic exercise on the age-related decline in endothelium-dependent vasodilation. Methods and Results —In a cross-sectional study, 68 healthy men 22 to 35 or 50 to 76 years of age who were either sedentary or endurance exercise–trained were studied. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine and sodium nitroprusside were measured by strain-gauge plethysmography. Among the sedentary men, the maximum FBF response to acetylcholine was 25% lower in the middle aged and older compared with the young group ( P P Conclusions —Our results indicate that regular aerobic exercise can prevent the age-associated loss in endothelium-dependent vasodilation and restore levels in previously sedentary middle aged and older healthy men. This may represent an important mechanism by which regular aerobic exercise lowers the risk of cardiovascular disease in this population.

Background —A reduction in compliance of the large-sized cardiothoracic (central) arteries is an independent risk factor for the development of cardiovascular disease with advancing age. Methods and Results —We determined the role of habitual exercise on the age-related decrease in central arterial compliance by using both cross-sectional and interventional approaches. First, we studied 151 healthy men aged 18 to 77 years: 54 were sedentary, 45 were recreationally active, and 53 were endurance exercise–trained. Central arterial compliance (simultaneous B-mode ultrasound and arterial applanation tonometry on the common carotid artery) was lower ( P P P Conclusions —Regular aerobic-endurance exercise attenuates age-related reductions in central arterial compliance and restores levels in previously sedentary healthy middle-aged and older men. This may be one mechanism by which habitual exercise lowers the risk of cardiovascular disease in this population.

The ability to contribute consistent, fundamentally sound critiques is an essential element of the scientific peer review process and an important professional skill for investigators. Despite its importance, many students and junior scientists do not have an adequate working knowledge of how to effectively critique research manuscripts. Part of the problem, in our view, is that novice referees often lack a comprehensive understanding of the basic issues that should be considered in evaluating scientific articles. Specifically, they tend to overemphasize certain limitations (usually methodological), while missing other key points related to the scientific method that should be weighed much more heavily. In our journal club and graduate courses we have been using a "checklist" to help graduate students and postdoctoral fellows critically analyze original research papers. In this article we present these guidelines in the hope that they will serve as a helpful resource for students and other novice reviewers when critiquing scientific manuscripts.

OBJECTIVE: Whether adrenaline acts as a sympathetic nervous cotransmitter in humans and stimulates beta2-adrenoceptors to augment neuronal noradrenaline release remains a subject of considerable dispute. The aim of this study was to test if adrenaline is released from regional sympathetic nerves (in the heart) in patients with essential hypertension, and to investigate whether locally released adrenaline might enhance cardiac noradrenaline release. METHODS: Using dual isotope dilution methodology, adrenaline and noradrenaline plasma kinetics was measured for the whole body and in the heart in 13 untreated patients with essential hypertension and 27 healthy volunteers. All research participants underwent cardiac catheterization under resting conditions. RESULTS: At rest, there was negligible adrenaline release from the sympathetic nerves of the heart in healthy subjects, 0.27 +/- 1.62 ng/min. In contrast, in patients with essential hypertension, adrenaline was released from the heart at a rate of 1.46 +/- 1.73 ng/min, equivalent on a molar basis to approximately 5% of the associated cardiac noradrenaline spillover value. Cardiac noradrenaline spillover was higher in hypertensive patients, 24.9 +/- 17.0 ng/min compared to 15.4 +/- 11.7 ng/min in healthy volunteers (P< 0.05). Among patients, rates of cardiac adrenaline and noradrenaline spillover correlated directly (r= 0.59, P< 0.05). CONCLUSIONS: This study, in demonstrating release of adrenaline from the heart in patients with essential hypertension, and in disclosing a proportionality between rates of cardiac adrenaline and noradrenaline release, provides perhaps the most direct evidence to date in support of the 'adrenaline hypothesis' of essential hypertension.

Arterial wall hypertrophy occurs with age in humans and is a strong predictor of cardiovascular disease risk. The responsible mechanism is unknown, but data from studies in experimental animals suggest that elevated sympathetic-adrenergic tone may be involved. To test this hypothesis in humans we studied 11 young (29 ± 1 yr; means ± SE) and 13 older (63 ± 1) healthy normotensive men under supine resting conditions. Muscle sympathetic nerve activity (MSNA) burst frequency (peroneal microneurography) was 70% higher in the older men (39 ± 1 vs. 23 ± 2 bursts/min; P < 0.001). Femoral artery intima media thickness (IMT; B-mode ultrasound) and the femoral IMT-to-lumen diameter ratio (IMT/lumen) were ∼75% greater in the older men (both P < 0.001). Femoral IMT ( r = 0.82) and the femoral IMT/lumen ( r = 0.85) were strongly and positively related to MSNA (both P < 0.001). The significant age group differences in femoral IMT and the IMT/lumen were abolished when the influence of MSNA was removed. In contrast, the relationship between MSNA and femoral wall thickness remained significant after removing the influence of age. We conclude that 1) primary aging is associated with femoral artery hypertrophy in humans and 2) this is strongly related to elevations in sympathetic nerve activity to the vasculature. These results support the hypothesis that tonic elevations in sympathetic nerve activity may be an important mechanism in the arterial remodeling that occurs with human aging.

We tested the hypothesis that the elevations in 24-h arterial systolic (SBP) and pulse (PP) pressures with age in sedentary adult females are absent or smaller in women who exercise regularly. Four groups of healthy normotensive women were studied: premenopausal ( n = 12; 29 ± 1 yr, mean ± SE) and postmenopausal ( n = 20; 62 ± 1) sedentary, and premenopausal ( n = 14; 30 ± 1) and postmenopausal ( n= 12; 58 ± 1) endurance-exercise trained (distance runners). In the sedentary group, 24-h SBP and PP (Spacelabs ambulatory monitor 90207) were ∼10 mmHg higher ( P < 0.05) in the postmenopausal women than in the premenopausal controls; this was because of higher daytime and nighttime SBP and PP levels in the postmenopausal women. In contrast, 24-h, daytime and nighttime SBP and PP were not different with age in the endurance-trained women. SBP variability and SBP load (% of all recordings > 140 mmHg) generally were greater with age in the sedentary women (e.g., SBP load = 14 ± 4 vs. 3 ± 1%, P < 0.05) but not in the endurance-trained women. In the pooled population, 24-h SBP and PP were related to waist-to-hip ratio (measure of abdominal adiposity) ( r = 0.48 and 0.49, respectively, P < 0.001) and carotid augmentation index (measure of arterial stiffness) ( r = 0.43 and 0.53, P < 0.005). In the sedentary women, accounting for the influence of either of these factors eliminated the significant age-associated differences in 24-h SBP and PP ( P > 0.3). Our results suggest that the elevations in 24-h SBP and PP with age in sedentary adult females may not occur in women who regularly perform endurance exercise. This appears to be related to the absence of age-associated increases in abdominal adiposity and arterial stiffness in the exercising women.

Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder.Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure.In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese individuals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese individuals (P0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese individuals.The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys; the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese individuals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese individuals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese individuals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.

Leptin, a 16-kDa circulating protein primarily derived from adipocytes, is an important factor in the regulation of appetite and energy expenditure. Using simultaneous arterio-venous blood sampling, several organs were assessed with regard to their individual roles in leptin metabolism in healthy male and female subjects constituting a range of body mass indices. Plasma leptin levels were unchanged after passage through the hepatosplanchnic and forearm circulations. In contrast, concentrations in the renal vein were consistently lower than those in the renal artery (−15%; P < 0.005), indicating net extraction, whereas the brain was observed to be a net leptin releaser. Concentrations in the internal jugular vein were significantly higher than arterial levels in lean females (change, 3.0 ± 1.2 ng/mL; P < 0.02) and in obese males (body mass index, >28 kg/m2), but not lean (change, 2.3 ± 2.3 vs. 0.1 ± 0.1 ng/mL, respectively; P < 0.05), indicating a probable influence of both gender and adiposity on brain leptin release. An attempt to grossly localize the site of brain release by using cerebral venous scans to distinguish between jugular venous drainage from cortical and subcortical brain areas revealed no region-specific secretion. These data raise the possibility that the brain is a nonadipose source of leptin. In addition, the higher level of brain release observed in females may contribute to the well documented gender differences in overall plasma leptin levels.

1. We tested the hypothesis that the ability of the cardiopulmonary baroreflex to produce sympathoinhibition is reduced with age in humans. Eleven young (23 +/- 1 years, mean +/- s.e.m.) and ten older (64 +/- 1) healthy adult males were studied under supine conditions (control) and in response to cardiopulmonary baroreflex stimulation evoked by acute central circulatory hypervolaemia (10 deg head-down tilt). The two groups were normotensive and free of overt cardiovascular disease. 2. Supine baseline (control) levels of efferent muscle sympathetic nerve activity (MSNA) burst frequency were twice as high in the older men (41 +/- 2 vs. 21 +/- 2 bursts min-1, P < 0.05). In both groups in response to head-down tilt arterial blood pressure and heart rate were unchanged, peripheral venous pressure (PVP) increased (P < 0.05), MSNA total activity decreased (P < 0.05), antecubital venous plasma noradrenaline concentrations did not change significantly, and forearm blood flow and vascular conductance increased (vascular resistance decreased) (all P < 0.05). The mean absolute DeltaMSNA/DeltaPVP was similar in the young and older men, although the higher control levels of MSNA in the older men resulted in a smaller percentage DeltaMSNA/DeltaPVP (P < 0.05). Per DeltaPVP, the reduction in forearm vascular resistance was smaller in the older men, but there were no age group differences when expressed as increases in forearm vascular conductance. 3. These results indicate that the ability of the cardiopulmonary baroreflex to inhibit MSNA is well preserved with age in healthy adult humans. As such, these findings are not consistent with the concept that this mechanism plays a role in the age-associated elevation in basal MSNA.

We have shown previously that endurance-trained postmenopausal runners demonstrate more favorable coronary heart disease (CHD) risk factors compared with age-matched sedentary women. However, the runners exhibited higher levels of physical activity and lower levels of body fatness, both of which can influence CHD risk factors. To gain insight into the influence of body fatness per se, we studied 38 postmenopausal healthy women: 10 swimmers, 10 runners, and nine obese and nine leaner sedentary subjects matched for age, hormone replacement use, and years postmenopause. Swimmers and runners were further matched for exercise training volume (4.5+/-0.2 v 4.6+/-0.6 h/wk) and relative competitive performance (79%+/-5% v 77+/-3% of age-adjusted world record). Maximal oxygen consumption (VO2max) on the treadmill was lower (P < .01) in swimmers versus runners. Body mass (65.0+/-2.0 v 59.0+/-1.3 kg), percent body fat (29%+/-2% v 23%+/-2%), and waist circumference (79+/-3 v 71+/-1 cm) were greater (P < .01) in swimmers than in runners. There were no significant differences in total caloric intake or dietary composition between swimmers and runners. Insulin sensitivity (via Bergman's minimal model) and fasting plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), glucose, and plasminogen activator inhibitor-1 (PAI-1) activity were not different between the groups. However, plasma high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL-C/TC, insulin, fibrinogen, fibrin D-dimer, PAI antigen, tissue plasminogen activator (t-PA) activity, and t-PA antigen levels all were less favorable (P < .05) in swimmers versus runners. Daytime, nighttime, and 24-hour systolic blood pressure (SBP) was 6 to 10 mm Hg higher in swimmers compared with runners, but resting blood pressure, 24-hour blood pressure load, and blood pressure variability were not significantly different. Stepwise regression showed that measures of body fatness were the primary independent determinants of most of the metabolic CHD risk factors. When analysis of covariance (ANCOVA) was performed with body fatness as a covariate, differences in CHD risk factors between swimmers and runners were abolished (P=.18 to .90). We conclude that among endurance-trained postmenopausal women matched for training volume and competitive eliteness, higher total and abdominal body fatness is, in general, associated with a less favorable metabolic CHD risk profile. Thus, high levels of habitual aerobic exercise do not appear to negate the deleterious effects of adiposity on the coronary risk profile of healthy middle-aged and older women.

Abstract —Based on observations of smaller increases in limb vascular resistance during acute incremental hypovolemia in older adults, cardiopulmonary and integrative (combined cardiopulmonary and arterial) baroreflex control of sympatho-circulatory function is thought to be impaired with aging in humans. We tested this hypothesis directly by making intraneural measurements of skeletal muscle sympathetic nerve activity (MSNA; peroneal microneurography) in groups of young (23±1 years; n=11) and older (64±1 years; n=12) healthy adult men during progressive hypovolemia produced by graded (−5 to −40 mm Hg) lower body negative pressure (LBNP). Baseline levels of MSNA and arterial blood pressure were higher and heart rate was lower in the older subjects ( P P P P P P

1. Low heart rate variability is associated with an increased risk of cardiac sudden death, coronary heart disease and all-cause mortality. We have previously shown that physically active postmenopausal women demonstrate higher levels of heart rate variability and cardiac baroreflex sensitivity compared to their sedentary peers. The purpose of the present prospective study was to test the hypothesis that heart rate variability and cardiac baroreflex sensitivity would be reduced with age in sedentary but not physically active women. To accomplish this, we measured heart rate variability (both time and frequency domain) and spontaneous cardiac baroreflex sensitivity (SBRS, sequence method) in the sitting posture in 23 sedentary women [11 premenopausal and 12 postmenopausal (age, 28 ± 1 and 61 ± 2 years; Vo2max, 35.3 ± 1.4 and 21.7 ± 1.5 ml · min−1 · kg−1 respectively] and in 22 physically active women [12 premenopausal and 10 postmenopausal (age, 31 ± 1 and 59 ± 2 years; Vo2max, 52.5 ± 1.4 and 39.7 ± 1.8 ml · min−1 · kg−1)]. 2. The S.D. of the R—R interval (time domain) was reduced (P < 0.05) with age in both sedentary (52 ± 6 versus 33 ± 4 ms) and physically active women (72 ± 8 versus 49 ± 9 ms). The high-frequency power (3740 ± 1527 versus 915 ± 188 and 9516 ± 2849 versus 2803 ± 1083 ms2/Hz), total power of heart rate variability and SBRS (11 ± 2 versus 7 ± 2 and 19 ± 3 versus 13 ± 2 ms/mmHg) also demonstrated similar age-related reductions in sedentary and physically active women, respectively (all P < 0.05). The S.D. of the R—R interval, high-frequency and total power of heart rate variability, and SBRS were higher (all P < 0.05) in the physically active compared with the sedentary women at any age. There was no significant influence of age or physical activity status on the low-frequency power of heart rate variability. In addition, no significant differences in any of the time or frequency domain measures of heart rate variability or SBRS were observed in users compared with non-users of hormone replacement therapy. 3. The results of the present study suggest that heart rate variability and cardiac baroreflex sensitivity decline similarly with age in healthy sedentary and physically active women. However, physically active women demonstrate higher levels of heart rate variability and cardiac baroreflex sensitivity compared with their sedentary peers, regardless of age.

Low-frequency arterial pressure oscillations (Mayer waves) have been proposed as an index of vascular sympathetic outflow. However, cross-sectional differences in these pressure oscillations may not reflect different levels of sympathetic nervous outflow in humans. Three groups of healthy subjects with characteristically different sympathetic nervous outflow were studied: young females ( n = 10, 18–28 yr), young males ( n = 11, 18–29 yr), and older males ( n = 13, 60–72 yr). Average R-R interval, arterial pressures, and systolic pressure variability at the Mayer wave frequency (0.05–0.15 Hz) did not differ among the three groups. Diastolic pressure Mayer wave variability was similar in young females vs. young males (39 ± 10 vs. 34 ± 5 mmHg2) and lower in older males vs. young males (14 ± 2 mmHg2; P < 0.05). In contrast, muscle sympathetic activity was lowest in young females (892 ± 249 total activity/min) and highest in older males (3,616 ± 528 total activity/min; both P < 0.05 vs. young males: 2,505 ± 285 total activity/min). Across the three groups, arterial pressure Mayer wave variability did not correlate with any index of sympathetic activity. Our results demonstrate that arterial pressure Mayer wave amplitude is not a surrogate measure of vascular sympathetic outflow.

Abstract —Increased arterial stiffness is thought to contribute to the increased incidence of cardiovascular disease with age. Little, however, is known about the influence of aging on central and peripheral arterial stiffness in females. Moreover, it is unknown whether physical activity status influences age-related increases in arterial stiffness in females. Arterial pulse wave velocity (PWV) and augmentation index (AI, applanation tonometry) were measured in 53 healthy females, including 10 premenopausal (Pre-S) and 18 postmenopausal (Post-S) sedentary women, and 9 premenopausal (Pre-PA) and 16 postmenopausal (Post-PA) physically active women. In the sedentary women, there were no age-related differences in arterial blood pressure, but aortic PWV and carotid AI (measures of central arterial stiffness) were higher ( P P

Tanaka, Hirofumi, Christopher A. DeSouza, Pamela P. Jones, Edith T. Stevenson, Kevin P. Davy, and Douglas R. Seals. Greater rate of decline in maximal aerobic capacity with age in physically active vs. sedentary healthy women. J. Appl. Physiol. 83(6): 1947–1953, 1997.—Using a meta-analytic approach, we recently reported that the rate of decline in maximal oxygen uptake (V˙o 2 max) with age in healthy women is greatest in the most physically active and smallest in the least active when expressed in milliliters per kilogram per minute per decade. We tested this hypothesis prospectively under well-controlled laboratory conditions by studying 156 healthy, nonobese women (age 20–75 yr): 84 endurance-trained runners (ET) and 72 sedentary subjects (S). ET were matched across the age range for age-adjusted 10-km running performance. Body mass was positively related with age in S but not in ET. Fat-free mass was not different with age in ET or S. Maximal respiratory exchange ratio and rating of perceived exertion were similar across age in ET and S, suggesting equivalent voluntary maximal efforts. There was a significant but modest decline in running mileage, frequency, and speed with advancing age in ET.V˙o 2 max(ml ⋅ kg−1 ⋅ min−1) was inversely related to age ( P < 0.001) in ET ( r = −0.82) and S ( r = −0.71) and was higher at any age in ET. Consistent with our meta-analysic findings, the absolute rate of decline inV˙o 2 max was greater in ET (−5.7 ml ⋅ kg−1 ⋅ min−1 ⋅ decade−1) compared with S (−3.2 ml ⋅ kg−1 ⋅ min−1 ⋅ decade−1; P < 0.01), but the relative (%) rate of decline was similar (−9.7 vs −9.1%/decade; not significant). The greater absolute rate of decline inV˙o 2 max in ET compared with S was not associated with a greater rate of decline in maximal heart rate (−5.6 vs. −6.2 beats ⋅ min−1 ⋅ decade−1), nor was it related to training factors. The present cross-sectional findings provide additional evidence that the absolute, but not the relative, rate of decline in maximal aerobic capacity with age may be greater in highly physically active women compared with their sedentary healthy peers. This difference does not appear to be related to age-associated changes in maximal heart rate, body composition, or training factors.

The results of this study support the hypothesis that women who exercise regularly have less adverse changes in plasma lipids and lipoproteins with age than sedentary women. This may contribute to the smaller age-related increase in the incidence of coronary heart disease observed in physically active women.

A low resting metabolic rate (RMR) is a risk factor for future weight gain. We tested the hypothesis that the age-related decline in RMR in sedentary women is not observed in women who exercise regularly. Sixty-five healthy, weight-stable women, aged 21-35 or 50-72 yr, were studied: 12 premenopausal and 15 postmenopausal sedentary women, 13 premenopausal and 15 postmenopausal distance runners, and 10 endurance-trained postmenopausal swimmers. RMR was measured by indirect calorimetry (ventilated hood system) after an overnight fast, and values were adjusted for fat mass and fat-free mass (RMRadj). The RMRadj was approximately 10% lower in the postmenopausal vs. premenopausal sedentary women (52 +/- 2 vs. 57 +/- 2 Cal/h; P < 0.002). In contrast, RMRadj was not significantly different in the premenopausal (59 +/- 2 Cal/h) and postmenopausal (57 +/- 1 Cal/h) distance runners. The postmenopausal swimmers had a RMRadj (57 +/- 2 Cal/h) identical to that of the postmenopausal runners, suggesting a generalized influence of the endurance exercise-trained state in postmenopausal women. Group differences in RMRadj were not associated with differences in total energy intake or composition or with plasma concentrations of norepinephrine, T3, or T4. However, maximal oxygen consumption (aerobic fitness) accounted for 35% of the individual variance in RMRadj in the overall population (r = 0.59; P < 0.001). Our results are consistent with the concept that the age-related decline in RMR in sedentary women is not observed in women who regularly perform endurance exercise. The elevated level of RMR observed in middle-aged and older exercising women may play a role in their lower levels of body weight and fatness compared to those in sedentary women.

Background Fibrinogen is a major component of the coagulation system and a powerful independent risk factor for cardiovascular disease in postmenopausal women. Regular physical activity has been recommended as an effective clinical approach to lowering plasma fibrinogen levels; currently, however, there are little or no data to support a relationship between habitual exercise status and plasma fibrinogen levels in healthy postmenopausal women who either use or do not use hormone replacement therapy (HRT). Methods Plasma fibrinogen levels were measured in 20 physically active (56 +/- 1 yr) and 31 sedentary (58 +/- 1 yr) healthy postmenopausal women. Nine (45%) physically active and 15 (48%) sedentary women had been using HRT for > 1 year; the others were nonusers of HRT. Results Plasma fibrinogen levels were approximately 15% lower (p = .001) in the physically active women (2.48 +/- .08 g/L) than the sedentary controls (2.92 +/- .06 g/L) and approximately 7% lower (p = .04) in the users (2.65 +/- .08 g/L) versus nonusers (2.84 +/- .08 g/L) of HRT. Moreover, the lower (0.4 g/L) plasma fibrinogen levels associated with regular physical activity were evident in both the users (2.39 +/- .11 vs 2.80 +/- .08 g/L, p = .001) and nonusers (2.56 +/- .11 vs 3.03 +/- .08 g/L, p = .006) of HRT. Stepwise multiple regression analysis revealed that percent body fat was the primary determinant of plasma fibrinogen levels, accounting for 30% of the variability. Conclusions Regular physical activity is associated with lower plasma fibrinogen levels in postmenopausal women; the lower plasma fibrinogen levels associated with regular physical activity are evident in both users and nonusers of HRT; and plasma fibrinogen levels are positively related to percent body fat in postmenopausal women differing in physical activity and HRT status. Lower plasma fibrinogen levels in physically active postmenopausal women may contribute to their lower risk of cardiovascular disease.

We tested the hypothesis that the age-related changes in systemic hemodynamic determinants of arterial blood pressure in healthy women are related to physical activity and hormone replacement status. We studied 66 healthy, normotensive premenopausal (21-35 yr) and postmenopausal (50-72 yr) sedentary and endurance-trained women under supine resting conditions. Mean blood pressure was 7 mmHg higher in sedentary post- compared with premenopausal women, which was associated with an 11-mmHg higher systolic blood pressure, a 25% lower stroke volume and cardiac output, and a 50% higher systemic vascular resistance (all P < 0.05). Absolute (ml) levels of total blood volume did not differ across age, but resting oxygen consumption was approximately 35% lower in the postmenopausal women (P < 0.05). The elevations in mean and systolic blood pressures with age were similar in endurance-trained runners, but, in contrast to the sedentary women, the elevations were not associated with significant age-related differences in cardiac output, stroke volume, or oxygen consumption, and only a modest (15%) increase in systemic vascular resistance (P = 0.06). Postmenopausal swimmers demonstrated the same systemic hemodynamic profile as that of postmenopausal runners, indicating a nonspecific influence of the endurance-trained state. Blood pressure and its systemic hemodynamic determinants did not differ in postmenopausal users compared with those of nonusers of hormone replacement therapy. Resting oxygen consumption was the strongest physiological correlate of cardiac output in the overall population (r = 0.65, P < 0.001). We conclude that 1) the increases in arterial blood pressure at rest with age in healthy normotensive women are not obviously related to habitual physical activity status; 2) the systemic hemodynamic determinants of the age-related elevations in blood pressure are fundamentally different in sedentary vs. active women, possibly due, in part, to an absence of decline in resting oxygen consumption in the latter; and 3) systemic hemodynamics at rest are not different in healthy normotensive postmenopausal users vs. nonusers of estrogen-based hormone replacement.