Pamela Parker Jones

Limb Blood Flow and Vascular Conductance Are Reduced With Age in Healthy Humans Relation to Elevations in Sympathetic Nerve Activity and Declines in Oxygen Demand

BACKGROUND We tested the hypothesis that basal (resting) limb blood flow and vascular conductance are reduced with age in adult humans and that these changes are related to elevations in sympathetic vasoconstrictor nerve activity and reductions in limb oxygen demand. METHODS AND RESULTS Sixteen young (28+/-1 years; mean+/-SEM) and 15 older (63+/-1 years) healthy normotensive adult men were studied. Diastolic blood pressure and body fat were higher (P<0.005) in the older men, but there were no other age-related differences in subject characteristics. Femoral artery blood flow (Doppler ultrasound) was 26% lower in the older men (P<0.005), despite similar levels of cardiac output (systemic arterial blood flow) in the 2 groups. Femoral artery vascular conductance was 32% lower and femoral vascular resistance was 45% higher in the older men (P<0. 005). Muscle sympathetic nerve activity (peroneal microneurography) was 74% higher in the older men (P<0.001) and correlated with femoral artery blood flow (r=-0.55, P<0.005), vascular conductance (r=-0.65, P<0.001), and vascular resistance (r=0.61, P<0.001). The age-related differences in femoral hemodynamics were no longer significant after correction for the influence of muscle sympathetic nerve activity. There were no significant age-group differences in leg tissue mass (by dual-energy x-ray absorptiometry), but estimated leg oxygen consumption was 15% lower in the older men (P<0.001). Femoral artery blood flow was directly related to estimated leg oxygen consumption (r=0.78, P<0.001). The age-group differences in femoral artery blood flow were no longer significant after correction for estimated leg oxygen consumption by ANCOVA. CONCLUSIONS (1) Basal whole-leg arterial blood flow and vascular conductance are reduced with age in healthy adult men; (2) these changes are associated with elevations in sympathetic vasoconstrictor nerve activity; and (3) the lower whole-limb blood flow is related to a lower oxygen demand that is independent of tissue mass.

Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men

Background—Short-term and tonic regulation of arterial blood pressure (BP) differ in premenopausal women and men of similar age. The autonomic nervous system (ANS) plays a critical role in BP regulation. Methods and Results—To test the hypothesis that women have lower tonic ANS support of BP (reduction in intra-arterial BP during acute ganglionic blockade [GB] with intravenous trimethaphan) and less effective baroreflex buffering (BRB) of BP (potentiation of the systolic BP [SBP] response to bolus phenylephrine during versus before GB) than men, 51 healthy adults, 22 premenopausal women (aged 28±1 years, mean±SE) and 29 men (aged 27±1 years), were studied. Women had lower baseline SBP and plasma catecholamine concentrations than men (P<0.05). Tonic ANS support of BP was ≈50% to 65% lower in the women (P<0.001). The reductions in BP during GB were related to baseline plasma catecholamine concentrations (r=−0.31 to −0.41, P<0.05). Acute BRB of BP was 47% smaller in the women (3.3±0.5 versus 6.3±0.9, P=0.006) and was related to the SBP responses to phenylephrine before GB (R2=0.71, P<0.0001). Systemic &agr;1-adrenergic vascular responsiveness (SBP response to bolus phenylephrine during GB) was not different (women 21.5±2 mm Hg versus men 18.6±2 mm Hg, P=0.3). Conclusions—Premenopausal women have lower tonic sympathoadrenal activity-related ANS support of BP and less effective BRB of BP than men of similar age. The lower tonic ANS support of BP could contribute to the lower chronic BP levels of premenopausal women, whereas attenuated BRB of BP may help explain less effective BP regulation in women in response to vasoactive drugs and acute stress.

Baroreflex Buffering Is Reduced With Age in Healthy Men

Background—Baroreflex buffering is an important mechanism in arterial blood pressure control. The effect of healthy (physiological) aging on tonic baroreflex buffering in humans is unknown. Methods and Results—Baroreflex buffering was determined in 27 young (aged 25±1 years) and 16 older (aged 65±1 years) healthy normotensive men by measuring the potentiation of the systolic blood pressure (SBP) responses to a phenylephrine bolus (BRBbolus) and incremental infusion (BRBslope) during compared with before ganglionic blockade with trimethaphan. The SBP responses to phenylephrine either were not different or greater in the older men before ganglionic blockade, but smaller during ganglionic blockade. BRBbolus (2.1±0.4 versus 5.1±0.7, P <0.001) and BRBslope (1.6±0.2 versus 3.5±0.4, P <0.0001) were ≈115% smaller in the older men. Baroreflex buffering was not consistently related to mean levels or variability of blood pressure or heart rate, or to cardiovagal baroreflex sensitivity, but correlated with muscle sympathetic nerve activity (BRBbolus:r =−0.55, BRBslope:r =−0.69, P <0.005) and the SBP responses to phenylephrine during ganglionic blockade (BRBbolus:r =0.53; BRBslope:r =0.98, P <0.0001). BRBbolus was also inversely related to the SBP response to phenylephrine before ganglionic blockade (r =−0.78, P <0.0001). Conclusions—Physiological aging in men is associated with a marked reduction in baroreflex buffering. The decrease in baroreflex buffering with aging is related to increases in basal sympathetic nerve activity and reductions in systemic &agr;1–adrenergic vascular responsiveness. These findings are helpful for interpreting changes in baroreflex buffering in older patients with cardiovascular disease, as well as changes in responsiveness to vasoactive drugs with aging.

Physical Activity Status and Adverse Age-Related Differences in Coagulation and Fibrinolytic Factors in Women

Adverse changes in coagulation and fibrinolytic factors are thought to contribute to the increased risk of cardiovascular disease and atherothrombosis with age. We tested the hypothesis that such age-related changes in specific coagulation and fibrinolytic factors are absent in physically active women. Resting levels of plasma fibrinogen, tissue-type plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor-1 (PAI-1) antigen and activity, and fibrin D-dimer were measured in 24 healthy premenopausal women: 11 sedentary (aged 28+/-1 years; Pre-S) and 13 physically active (aged 30+/-1 years; Pre-PA) and in 27 healthy postmenopausal women: 14 sedentary (aged 61+/-1 years; Post-S) and 13 physically active (aged 58+/-1 years; Post-PA). Post-S had higher (P<.05) fibrinogen, t-PA antigen, PAI-1 antigen, PAI-1 activity, and fibrin D-dimer levels and lower t-PA activity than Pre-S. Post-PA demonstrated lower (P<.01) plasma fibrinogen, t-PA antigen, PAI-1 antigen, and PAI-1 activity and higher (P<.01) t-PA activity levels than Post-S. In addition, plasma fibrin D-dimer levels tended (P=.06) to be lower in Post-PA than in Post-S. Although plasma levels of fibrinogen and fibrin D-dimer in Post-PA were lower than in Post-S, they were higher (P<.05) than in Pre-PA. Importantly, however, the fibrinolytic profile of Post-PA did not differ from that of Pre-PA. The results of the present study demonstrate that the adverse age-associated differences in plasma fibrinogen concentrations and the endogenous fibrinolytic system in sedentary healthy women are either attenuated or absent in highly physically active women. The smaller or absent age-related differences in coagulation and fibrinolytic factors in women who habitually exercise may represent an important mechanism contributing to their lower age-related increase in both cardiovascular disease and atherothrombotic events. Future studies need to determine whether women who are moderately active would demonstrate the same favorable hemostatic profile.

Relation of leptin and insulin to adiposity-associated elevations in sympathetic activity with age in humans

OBJECTIVE: To determine whether plasma leptin and insulin concentrations are related to adiposity-associated elevations in muscle sympathetic nerve activity (MSNA) with age in healthy adult humans.DESIGN: Cross-sectional investigation of young and older adult men.SUBJECTS: Thirty healthy adult men, 16 young (25±1 y, mean±s.e.) and 14 older (61±1 y).MEASUREMENTS/RESULTS: The older men had higher (P<0.05) levels of body mass, BMI, total fat mass and truncal fat mass (dual energy X-ray absorptiometry) than the young men. MSNA burst frequency (microneurography) was ∼75% higher in the older men (P<0.001). Plasma leptin concentrations were ∼150% higher (P<0.01), whereas plasma insulin concentrations were ∼70% higher (P<0.05) in the older subjects. MSNA was related to both total (r=0.51, P<0.01) and truncal (r=0.56, P<0.01) fat mass. Plasma leptin concentrations were related to total and truncal fat mass (both r=0.83, P<0.001), and to MSNA (r=0.49, P<0.01). Plasma insulin concentrations were related to MSNA (r=0.38, P<0.05). We used partial correlation analyses to assess whether leptin and/or insulin are potential contributors to the relation between body fat and MSNA.Adjusting for the effects of plasma leptin, but not insulin, concentrations eliminated the significant relations between MSNA and total and truncal fat mass.CONCLUSION: Our results: (1) demonstrate a positive relation between MSNA and plasma leptin concentrations in young and older healthy men; and (2) support the concept that circulating leptin concentrations may act as a humoral signal contributing to adiposity-associated elevations in MSNA with age in adult humans.

Smaller differences in total and regional adiposity with age in women who regularly perform endurance exercise

Our aim was to determine if women who regularly perform endurance exercise demonstrate age-related elevations in body mass and adiposity. Ninety-five healthy females were studied: premenopausal ( n = 28; mean ± SE age 30 ± 1 yr) and postmenopausal ( n = 31; 56 ± 1 yr) endurance-trained runners and premenopausal ( n = 17; 29 ± 1 yr) and postmenopausal ( n = 19; 61 ± 1 yr) sedentary controls. In the runners, body mass did not differ across age, but percent fat and fat mass were higher ( P < 0.05) in the postmenopausal women. The age-related difference in total body fat, however, was only ∼50% as great ( P < 0.01) as that observed in the sedentary controls due in part to smaller age-related differences in central (truncal) fat. The higher fat mass in the postmenopausal runners was modestly (inversely) related to both exercise volume ( r = -0.44, P < 0.01) and maximal oxygen consumption ( r = -0.41, P < 0.01). The present findings provide experimental support for the hypothesis that women who regularly engage in vigorous endurance exercise may not gain body weight, undergo only a modest increase in total body fat, and do not demonstrate a significant elevation in central adiposity with age.

Influence of body fatness on the coronary risk profile of physically active postmenopausal women

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 Bergmans 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.

Lack of age-associated elevations in 24-h systolic and pulse pressures in women who exercise regularly

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 approximately 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.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.

Role of central circulatory factors in the fat-free mass-maximal aerobic capacity relation across age

Fat-free mass (FFM) (primarily skeletal muscle mass) is related to maximal aerobic capacity among healthy humans across the adult age range. The basis for this physiological association is assumed to be a direct relation between skeletal muscle mass and its capacity to consume oxygen. We tested the alternative hypothesis that FFM exerts its influence on maximal aerobic capacity in part via an association with central circulatory function. To do so, we analyzed data from 103 healthy sedentary adults aged 18-75 yr. FFM was strongly and positively related to maximal oxygen consumption ( r = 0.80, P < 0.001). FFM was also strongly and positively related to supine resting levels of blood volume ( r = 0.79, P < 0.001) and stroke volume ( r = 0.75, P < 0.001). Statistically controlling for the collective influences of blood volume and stroke volume abolished the tight relation between FFM and maximal oxygen consumption ( r = 0.12, not significant). These results indicate that 1) FFM may be an important physiological determinant of blood volume and stroke volume among healthy sedentary adult humans of varying age; and 2) this relation between FFM and central circulatory function appears to represent the primary physiological basis for the strong association between FFM and maximal aerobic capacity in this population. Our findings suggest that sarcopenia (loss of skeletal muscle mass with aging) may contribute to the age-related decline in maximal aerobic capacity primarily via reductions in blood volume and stroke volume rather than a direct effect on the oxygen-consuming potential of muscle per se.Fat-free mass (FFM) (primarily skeletal muscle mass) is related to maximal aerobic capacity among healthy humans across the adult age range. The basis for this physiological association is assumed to be a direct relation between skeletal muscle mass and its capacity to consume oxygen. We tested the alternative hypothesis that FFM exerts its influence on maximal aerobic capacity in part via an association with central circulatory function. To do so, we analyzed data from 103 healthy sedentary adults aged 18-75 yr. FFM was strongly and positively related to maximal oxygen consumption (r = 0.80, P < 0. 001). FFM was also strongly and positively related to supine resting levels of blood volume (r = 0.79, P < 0.001) and stroke volume (r = 0.75, P < 0.001). Statistically controlling for the collective influences of blood volume and stroke volume abolished the tight relation between FFM and maximal oxygen consumption (r = 0.12, not significant). These results indicate that 1) FFM may be an important physiological determinant of blood volume and stroke volume among healthy sedentary adult humans of varying age; and 2) this relation between FFM and central circulatory function appears to represent the primary physiological basis for the strong association between FFM and maximal aerobic capacity in this population. Our findings suggest that sarcopenia (loss of skeletal muscle mass with aging) may contribute to the age-related decline in maximal aerobic capacity primarily via reductions in blood volume and stroke volume rather than a direct effect on the oxygen-consuming potential of muscle per se.

Relations of total and abdominal adiposity to muscle sympathetic nerve activity in healthy older males

OBJECTIVES: We recently reported that skeletal muscle sympathetic nerve activity (MSNA) is related to total body and abdominal fatness in a pooled population of young and older males. Both MSNA and adiposity increase with age. Thus, it is not clear if the relation between MSNA and adiposity exists among older adults and if the age-related increase in MSNA is explained by increases in adiposity. We therefore tested the hypotheses that: 1) among older men, those with higher total body fatness and abdominal adiposity have higher MSNA and 2) MSNA is not different in healthy young and older men with similar total body and/or abdominal fatness. DESIGN: Older healthy men (63±1 y) were separated into higher and lower groups of body fat (26.9±0.8%, n=9 vs 21.3±1.1, n=10; P<0.0001) and waist circumference (96.4±3.5 cm, n=8 vs 86.2±1.5, n=8; P<0.01). Younger controls (26±1 y) were then matched with those in the older-lower groups for %body fat (21±1.1%, n=10) or waist circumference (86.2±0.8 cm, n=10). MEASUREMENTS: Total body fat was determined by hydrodensitometry, abdominal adiposity by waist circumference and resting MSNA by microneurography. RESULTS: Among the older subjects those in the higher %body fat and waist circumference groups had higher (P<0.02) MSNA (47±3 and 48±4 bursts/min, respectively) than those in the lower groups (37±2 and 38±3 bursts/min). MSNA was directly related to %body fat (r=0.52, P=0.03) and waist circumference (r=0.64, P=0.007) in the older groups. MSNA was greater (P<0.001) in the older-lower groups than in the young controls matched for %body fat (23±2 bursts/min) or waist circumference (24±3 bursts/min). CONCLUSIONS: 1) among healthy older men, higher levels of total body and/or abdominal adiposity are associated with higher levels of MSNA and 2) the age-related elevation in MSNA is reduced but not abolished when differences in adiposity are eliminated.