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1Department of Kinesiology, 2Intercollege Graduate Degree Program in Physiology, and 3Penn State College of Medicine, The Pennsylvania State University, University Park, Pennsylvania
Submitted 26 October 2007 ; accepted in final form 21 December 2007
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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estrogen; muscle blood flow; femoral artery dilation
With respect to the latter premise, the use of upright two-legged cycling exercise in the aforementioned studies prohibits the ability to conclusively determine whether these sex-specific effects of aging are the result of central(cardiac) or peripheral (local) factors. For example, whereas leg vascular conductance was attenuated at all exercise intensities in older women, at the highest work rates utilized during submaximal cycling exercise, older women were also exercising at 85% of their peak cardiac output (33). Thus, given that two-legged cycling utilizes a large muscle mass, it is possible that there was a sex-specific central limitation (i.e., supply limitation) to leg blood flow that confounded interpretation of responses even during submaximal cycling exercise. Utilizing small muscle mass dynamic leg exercise, a model not limited by the pumping capacity of the heart and consequently eliciting less excitation of the sympathetic nervous system than two-legged exercise (7, 40, 42, 46, 47), minimizes these central limitations on exercising leg hemodynamics in older men and women.
Thus the major purpose of the present study was to determine whether the blunted leg vasodilatory response in women persisted during graded single knee extensor exercise, when the confounding influence of central cardiac limitations on leg hyperemia is minimized. Using a design statistically powered to detect age x sex interactions in healthy, normally active men and women, we hypothesized that there would be a significant age x sex interaction in the leg hemodynamic responses to graded exercise, with older women exhibiting a significantly greater age-related reduction in leg blood flow and vascular conductance relative to young controls than older men.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Fifteen young men, 16 young women (ages 20–30 yr), 13 older men, and 18 older women (ages 60–79 yr) completed the study. All subjects were nonobese (body mass index 
30 kg/m2), were nonsmokers, had clinically normal blood chemistry (i.e., hemoglobin concentrations ranged from 11.1–16.2 g/dl, total cholesterol 240 mg/dl, LDL cholesterol 150 mg/dl), and had resting supine ankle-brachial index ratings between 0.90 and 1.30 (VP2000, Colin Medical). All subjects were normotensive (resting blood pressure 140/90 mmHg) and free of overt chronic diseases as evaluated by medical history questionnaire, a physical examination, and resting ECG. Additionally, no subjects were taking medications having significant hemodynamic effects (including oral contraceptives and hormone therapy) for at least the last 12 mo. Young female subjects were studied in days 1–7 of their menstrual cycle to standardize the influence of female hormones. On study day, subjects were asked to refrain from alcohol, exercise, caffeine, aspirin, ibuprofen, or herbal supplements for at least 12 h before testing. All subjects gave their written, informed consent to participate. This study was approved by the Office for Research Protections and the Institutional Review Board at The Pennsylvania State University in agreement with the guidelines set forth by the Declaration of Helsinki. Subject characteristics are presented in Table 1.
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Total and regional body composition was estimated using dual-energy X-ray absorptiometery (model QDR 4500W, Hologic, Waltham, MA) with subjects in the supine position as described previously (34). In addition, thigh volume was estimated by the anthropometric method described by Jones and Pearson (18) from thigh patellar-pubic length, skinfold thicknesses, and circumference. Quadriceps femoris muscle mass was then estimated from thigh volume as originally described by Andersen and Saltin (2).
Study Procedures
Exercise modality.
Single leg knee extensor exercise, designed to isolate the quadriceps muscle group, was performed as described previously (2, 43). Briefly, subjects were reclined in a seat in the supine position [to minimize cardiopulmonary baroreceptor-mediated decreases in muscle sympathetic nerve activity during knee extensor exercise (42) as well as age- and sex-related differences in stroke volume responses to exercise (13)] with knees flexed at an angle of 90°. The subject's torso and both legs were fixed by straps attached to the chair to reduce extraneous movement and straining, and the left foot was placed in a boot attached to a rod containing a strain gauge for force measurements and connected to the pedal arm of a cycle ergometer (Monark) placed behind the subject. The right leg was allowed to hang free, although subjects were instructed not to swing or move this leg. One extension of the quadriceps muscle moved the subject's lower leg 90–170°, and the ensuing flexion was a passive return pulled by the flywheel of the ergometer. Subjects kicked at a constant cadence of 40 kicks/min (0.67 Hz), because this cadence facilitated both young and older subjects' maintenance of cadence with minimum motion artifact and consistent duty cycles. Resistance was increased by increasing the weight attached to a belt surrounding the flywheel such that friction on the flywheel increased proportionately. Subjects participated in two familiarization visits totaling 
1 h of kicking such that they could learn to minimize accessory muscle recruitment (i.e., of the hamstring, inactive leg, and upper body) and maintain cadence. The first familiarization visit consisted of constant-load knee extension exercise, while the second visit involved instrumentation and data acquisition identical to that described below for the actual study visit with the exception that work rate increases were halved.
Exercise protocol. On the study day, the subjects began the protocol with 3 min of quiet rest, followed by 3 min of unloaded passive exercise (a research technician moved the subject's leg at 40 kicks/min). The purpose of the passive bout was to investigate the increase in flow due to mechanical influences and tachycardia separate from metabolic stimuli (53). The subject was then instructed to begin kicking against no resistance (0 W) for 3 min, after which resistance increased incrementally every 3 min until the subject could no longer maintain cadence. The work rate increases used were 8 W in young and older men and 4.8 W in young and older women [increases were designed to produce similar time to exhaustion in all groups, taking into account the reduced quadriceps muscle mass of women and the observation that maximal knee extension work rate does not decline with age (22)].
Data Acquisition and Measurements
All variables were collected online at a sampling frequency of 400 Hz and stored using a Powerlab system (AD Instruments, Castle Hill, Australia). Heart rate and beat-to-beat systolic and diastolic blood pressure (continuous assessment of arterial waveforms by piezoelectric pressure transducers through radial tonometry of the right hand; Colin CBM-7000, Medical Instruments) were measured continuously throughout the study. In addition, manual auscultation was used every 3 min throughout the study to check the accuracy of the Colin during exercise. EMG signals of the active (left) biceps femoris and inactive (right) rectus femoris (to ensure that contraction was limited to the active quadriceps of the active leg, respectively) were collected with bipolar silver chloride surface electrodes (Bio-Tac, Tyco Healthcare Group, Mansfield, MA) fixed lengthwise over the middle of the muscle belly placed 10–20 cm apart. Reference electrodes were placed on the knee of each leg. Electrode signals were amplified (Gould Universal Amplifier model 13 4615 55, Cleveland, OH; and Powerlab bioamplifier) with a bandwidth frequency ranging from 1.5 Hz to 2 kHz and simultaneously digitized using Powerlab. Knee extensor cadence was captured using a Cateye Astrale 8 (Cateye, Boulder, CO) cycle computer attached to the flywheel. Knee extensor force tracings were obtained using a load cell attached to the boot arm of the knee extensor ergometer.
A Doppler ultrasound machine (HDI 5000, Philips, Bothell, WA) equipped with a high resolution 4- to 7-MHz linear-array transducer was used to measure mean blood velocity and vessel diameter of the left common femoral artery, distal to the inguinal ligament but above the bifurcation into the superficial and profunda femoral branch. For velocity measurements, the artery was insonated at a constant angle of 60° with the sample volume adjusted to cover the width of the artery, while diameter measurements were obtained with the artery insonated perpendicularly. Velocity measurements were taken continuously during minutes 1 and 3 of rest, passive exercise, and each work rate, while high-resolution diameter measurements (taken in 2-dimensional mode to optimize imaging) were taken during minute 2 of every work rate (except the peak work rate, during which diameter measurements were not taken). A custom interface unit processed the high-resolution angle-corrected, intensity-weighted Doppler audio information (i.e., mean blood velocity) from the ultrasound system into a lower frequency velocity signal (frequency range 0–20 Hz) that could be sampled in real time by Powerlab. That is, whereas the ultrasound system strips off the probe carrier frequency to get the audio signal, the converter processes the low-frequency variations in the audio signal that carry information about the velocity of the blood flow. Postprocessing using PowerLab's Chart application package yielded mean blood velocities.
Diameter measurements were stored on VHS tape and digitized at 4 frames/s using Brachial Imager software (Medical Imaging Applications, Iowa City, IA). Posttest analysis of diameters was performed using edge-detection software (Brachial Analyzer Software, Medical Imaging Applications); briefly, the technician (always the same and blind to any subject information) selected a region of interest along the arterial wall and the edge of the wall was detected by pixel density and represented by a line of best fit. Each sequence of images was reviewed by the technician and adjusted to ensure that diameter measurements were always calculated from the intima-lumen interface at both the distal and proximal vessel wall. Images affected by motion artifact were excluded based on visual inspection by the technician as well as a calculation by the software program that the confidence limit for the best-fit line was <80%. Diameter measurements for each work rate comprised an average of 80 frames.
Data Analysis and Computations
For all study variables, values were calculated as the average over the last minute of rest, passive exercise, and each work rate [to allow hemodynamic variables to reach steady-state conditions (16, 24)], with the exception of peak measurements, which were calculated with first- and/or second-minute data if the subject did not complete the peak work rate. Mean arterial pressure (in mmHg) was calculated as (
systolic pressure) + (
diastolic pressure). The EMG signals were full-wave rectified, squared, and median filtered, from which the root-mean-square value was derived. A spike-triggered average of EMG over the last minute was then derived from the cadence and calculated as a percentage of the RMS value garnered from maximal isometric contraction (EMG averaged from three, 5-s isometric contractions performed at the beginning of the study). Femoral artery blood flow for each condition or work rate was calculated by multiplying the cross-sectional area of the femoral (the diameter taken in minute 2 of each condition or work rate) with mean blood velocity (cm/s), according to the formula:
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where the femoral blood flow is in milliliters per minute, the blood velocity is in centimeters per second, the femoral diameter (averaged across the cardiac cycle) is in centimeters, and 60 is used to convert from milliliters per second to milliliters per minute (18). To validate the assumption that the diameter taken in minute 2 was representative of the diameter underlying the blood flow measured in minute 3 of each condition or work rate, four subjects performed knee extensor exercise at various 3-min work rates with high-resolution diameter imaged constantly in two-dimensional mode. The within-subject correlation between minute 2 and minute 3 diameters was 0.99. In addition, because peak diameter measurements were not obtained, peak leg blood flow measurements were calculated with the diameter from the previous work rate. Femoral vascular conductance was calculated as femoral blood flow divided by mean arterial pressure.
Statistical Analysis
Statistical analyses were performed using SAS (SAS 9.1, Cary, NC) software. All data are reported as means ± SE with significance set at P < 0.05. A two-way ANOVA (Proc GLM) and Tukey post hoc analysis were used to compare baseline and peak differences between groups. For graded responses, data beyond 32 W in men and 19.2 W in women were excluded from analysis and graphic representation due to artifact of significant subject dropouts. For within-sex comparisons of responses to graded knee extensor exercise, a repeated-measures ANOVA (Proc Mixed) model with work rate as the within-individual factor and age and sex as the between-individual factors and an autoregressive variance-covariance structure was used to determine differences between young and older subjects in outcome variables. A Bonferroni post hoc adjustment was performed when significant age x work rate differences were detected. Slopes of each individual's linear regression line were determined mathematically (change in outcome variable/change in work rate), excluding rest and passive exercise and compared within sexes using a one-way ANOVA. To test for age x sex interactions (i.e., whether the effect of age on leg hemodynamic responses to exercise differed by sex), relative responses to graded knee extensor exercise were examined with a random-coefficients model (Proc Mixed), using a continuous predictor (work rate as a percentage of maximal work rate attained) and fitting a random intercept and slope with work rate as the within-individual factor and age, sex, and age x sex as the between-individual factors. An autoregressive variance-covariance structure was used to determine differences between subject groups in outcome variables (23).
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RESULTS |
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In addition to peak work rate data reported in Table 1, there were no significant age or sex differences (P > 0.13 for all comparisons) in the number of work rates taken to reach peak power output (young men: 5.8 ± 0.2 work rates; older men: 5.5 ± 0.2 work rates; young women: 6.2 ± 0.3 work rates; older women: 5.6 ± 0.2 work rates) such that the exercise protocols were of similar duration. There were also no age or sex differences (P > 0.80 for all comparisons) in the time spent in the contraction (contraction time in young men: 0.83 ± 0.01 s; older men: 0.84 ± 0.01 s; young women: 0.83 ± 0.02 s; older women: 0.82 ± 0.01 s) and relaxation (relaxation time in young men: 0.69 ± 0.01 s; older men: 0.68 ± 0.01 s; young women: 0.69 ± 0.02 s; older women: 0.69 ± 0.01 s) portions of the duty cycle.
Peak Leg Blood Flow and Vascular Conductance
Because of significant subject dropouts at higher work rates, data are not represented or included in analysis beyond 32 W in men and 19.2 W in women. However, peak leg blood flow and vascular conductance responses also demonstrated significant age x sex interactions (P < 0.01 for both), with no age differences in peak leg blood flow (young: 1,886 ± 63 ml/min vs. older: 2,032 ± 152 ml/min; P = 0.30) and peak leg vascular conductance (young: 17.9 ± 0.7 ml·min–1·mmHg–1 vs. older: 19.0 ± 2.1 ml·min–1·mmHg–1; P = 0.55) in men, and significantly attenuated peak leg blood flow (young: 1,913 ± 72 ml/min vs. older: 1,349 ± 92 ml/min; P < 0.01) and leg vascular conductance in older women relative to young women (young: 22.6 ± 1.4 ml·min–1·mmHg–1 vs. older: 13.6 ± 1.0 ml·min–1·mmHg–1; P < 0.01). The age x sex interactions were still significant (P < 0.01 for both) when peak leg blood flow and vascular conductance were normalized to quadriceps muscle mass; that is, peak leg blood flow and leg vascular conductance normalized to quadriceps muscle were lower in older women relative to young women (P = 0.02 and P < 0.01, respectively), whereas peak leg blood flow normalized to quadriceps muscle was marginally higher in older men (P = 0.05) and peak leg vascular conductance was similar in young vs. older men (P = 0.24).
Within-Sex Age Group Differences in Leg Hemodynamic Responses to Graded Knee Extensor Exercise (Fig. 1)
Age-group differences in blood pressure, femoral blood flow, and femoral vascular conductance responses at rest, passive exercise, and absolute work rates during incremental knee extensor exercise to exhaustion are shown in Fig. 1. For men, calculations of slopes of responses were conducted from 0 to 24 W in men, when the responses exhibited a linear relation to work rate and a curvilinear function was not significant; both a linear and a curvilinear relation fit responses from 0 to 32 W and therefore confounded interpretation of slopes. From 0 to 24 W, older men had a significantly greater hyperemic (slope of femoral blood flow vs. absolute work rate in young: 35 ± 2 ml·min–1·W–1 vs. older: 49 ± 3 ml·min–1·W–1; P < 0.01) and vasodilatory response (slope of femoral vascular conductance vs. absolute work rate in young: 0.30 ± 0.03 ml·min–1·mmHg–1·W–1 vs. older: 0.44 ± 0.04 ml min–1 mmHg–1·W–1; P < 0.01) to graded exercise than younger men. By contrast, comparisons of responses from 0 to 19.2 W in women demonstrated that older women had a blunted hyperemic (slope of femoral blood flow vs. absolute work rate in young: 52 ± 3 ml·min–1·W–1 vs. older: 40 ± 4 ml·min–1·W–1; P = 0.02) and vasodilatory response (slope of femoral vascular conductance vs. absolute work rate in young: 0.56 ± 0.06 ml·min–1·mmHg–1·W–1 vs. older: 0.37 ± 0.04 ml·min–1·mmHg–1·W–1; P < 0.01) to graded exercise compared with younger women. There were no age differences in the pressor response (slope of mean arterial pressure vs. absolute work rate) calculated across the same range of work rates in men (P = 0.62) or women (P = 0.93).
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To investigate age x sex interactions in responses to graded exercise, data are represented as each subject's work rates normalized to his or her peak work rate (percentage of maximal work rate) to account for the different work rate increases used in men vs. women. Heart rate, mean arterial pressure, femoral blood flow, and femoral vascular conductance responses at rest, passive exercise, and incremental knee extensor exercise to exhaustion are shown in Fig. 2.
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Femoral blood flow was normalized to estimated quadriceps muscle (kg) in men and women (Fig. 3). In men, normalizing to kilogram muscle did not influence interpretation of data significantly (age difference in hyperemic and vasodilatory slope was P < 0.01 and P = 0.01, respectively), although the age difference in normalized resting femoral blood flow was marginally significant (P = 0.08) rather than significant and normalized femoral vascular conductance at 0 W was not different with age. In women, normalizing to kg muscle altered the significance of slopes such that the slope of the hyperemic response was not significantly different with age (P = 0.41); the slope of the vasodilatory response was marginally lower in older women (P < 0.09). In addition, in eight young and eight older women matched for anthropometrically estimated quadriceps muscle (1.79 ± 0.08 vs. 1.79 ± 0.09 kg, respectively), femoral blood flow, and femoral vascular conductance were attenuated (P < 0.05) at all absolute work rates from rest to maximal exertion. There was no age difference (P = 0.55) in the slope of the hyperemic response, but the slope of the vasodilatory response was greater in young women (P < 0.01).
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In women, there was a significant agexwork rate interaction (P = 0.03) such that femoral diameter changes relative to rest were greater (P < 0.05) in young women compared with older women at all exercise work rates >0 W. For example, from rest to 19.2 W, diameter increased from 7.2 ± 0.2 to 7.7 ± 0.1 mm in young women and from 7.3 ± 0.2 to 7.4 ± 0.2 mm in older women. In men, the age x work rate interaction was not significant (P = 0.94); nor were there age-related differences in diameter changes at any work rate (P > 0.50 for all work rates). Diameter did not increase >0.1 mm relative to rest in young or older men at any work rate.
Ipsilateral Hamstring and Contralateral Quadriceps Muscle Recruitment (Fig. 4)
Older women exhibited significantly greater hamstring recruitment in the active leg (expressed as a percentage of maximal isometric contraction) at work rates 
14.4 W relative to young women; by contrast, there were no age differences in quadriceps recruitment in the inactive leg (P > 0.10 at all work rates) in women (ranges of quadriceps EMG from 0 to 19.2 W in young women: 2.7 ± 0.5 to 5.1 ± 0.7%, and older women: 2.6 ± 0.5 to 7.2 ± 1.3%). To investigate the influence of the hamstring recruitment in women, we compared femoral blood flow between young women and seven older women with minimal hamstring recruitment (i.e., recruitment was similar to young women; Fig. 4B). There were no age differences in active hamstring recruitment (ranges of hamstring EMG from 0 to 32 W in young men: 2.8 ± 0.6 to 10.0 ± 1.9%, vs. older men: 3.4 ± 0.5 to 10.6 ± 1.7%) or inactive quadriceps recruitment (ranges of quadriceps EMG from 0 to 32 W in young men: 2.2 ± 0.5 to 5.4 ± 0.6%, vs. older men: 1.6 ± 0.4 to 3.4 ± 1.2%; P > 0.22 for all work rates).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Interactive Effects of Age and Sex on Leg Vasodilation
To the best of our knowledge, the present study is the first with a design statistically powered to detect interactive effects of age and sex on the rise in active muscle blood flow and vascular conductance during dynamic exercise in humans. Using this approach and comparing men and women at relative work rates to take into account differences in peak power output (Fig. 2), we observed significant age x sex x work rate interactions for leg blood flow and vascular conductance such that vasodilator responses to graded exercise were attenuated with age in women. Thus, despite similar age-associated reductions in resting leg vascular conductance in men and women, older women demonstrated blunted vasodilator responsiveness with graded contractions relative to young women that was not observed in older men (relative to young men). It is important to note that hemoglobin was marginally lower in young women relative to older women (young: 12.8 ± 0.2 vs. older: 13.4 ± 0.2 g/dl; P = 0.05) and significantly higher in young men relative to older men (young: 15.0 ± 0.2 vs. older: 14.4 ± 0.2 g/dl; P = 0.02). However, evaluating the influence of hemoglobin on the leg blood flow responses by estimating leg oxygen delivery {multiplying the estimated arterial oxygen content [1.34·Hb·arterial oxygen saturation (assuming arterial oxygen saturation of 97%) ml O2/dl blood] by femoral blood flow} did not at all change the effect of age on absolute blood flow responses or the slope of the hyperemic responsiveness in women or men. Thus the present observations do not appear to be attributable to sex-specific age differences in hemoglobin, and they are in line with previous observations of reduced smooth muscle responsiveness (28a, 31) and peak vascular conductance (27a, 34, 44) in the legs of older women but not older men. These results suggest a dramatic loss of leg vasodilatory responsiveness with healthy aging in women, the mechanisms of which could involve the menopause-induced loss of estrogen (8, 12, 28, 51). In addition, some of the sex difference in vasodilator responsiveness among older adults could further be explained by the modulatory influence of chronic aerobic fitness in men, but not women (Fig. 5), a finding consistent with longitudinal training data (27) suggesting that the influence of fitness on age group differences in leg vasodilatory capacity in humans is sex specific.
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At rest, and during the initial stages of the knee extensor protocol (3 min of passive movement of the limb followed by 3 min of active unloaded kicking), older men exhibited lower vascular conductance than their younger counterparts (Fig. 1). The attenuated rise in leg conductance among the older men during the early stages of this protocol could reflect the persistent effects of heightened baseline (tonic) vasoconstriction in the legs of older (vs. young) men (9), in the absence of significant contraction-induced metabolic stimuli. Alternatively, the delayed rise in leg conductance exhibited by our older men during the early stages of this protocol could be explained by slower contraction-induced vasodilatory kinetics in the microcirculation of the leg, as recently observed in aged male rats (4). Regardless, reducing the increases in work rate by 50% (4 W; data collected on second familiarization visit) did not alter this pattern; i.e., conductance and blood flow during the initial stages of the protocol (<4 W) were attenuated in these older men (Fig. 6). This latter finding suggests that the metabolic stimulus needed to counter the influence of heightened baseline vasoconstriction and/or slowed vasomotor kinetics in the legs of older men is minimal.
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Our present results of preserved leg hemodynamic responses to exercise are similar to what our laboratory previously reported in normally active older men during two-legged cycling exercise (35) and are again at odds with other published studies showing reduced leg blood flow and/or leg vascular conductance during one- or two-legged exercise (22, 25, 32, 36). Our laboratory has previously hypothesized that these differences may be attributable to the chronic fitness levels of the subjects studied such that reduced leg blood flow may be maladaptive in sedentary older men but adaptive in older trained men when variables such as oxygen extraction and leg oxygen uptake are considered (19). Accordingly, when we investigated the most fit older men (those with the highest maximal oxygen uptake at or above the 60th percentile for age-group norms) vs. the least fit older men (those with the lowest maximal oxygen uptake, at or below the 30th percentile for age-group norms) in the study population, we found that fitness significantly influenced leg vascular conductance in men, offering a possible explanation for the discrepancy within the literature (Fig. 5). However, with respect to this topic, it should also be noted that 1) leg blood flow may increase (5) or remain unchanged (21) in older men following a training protocol, and 2) Donato et al. (11) also published results of reduced leg blood flow in normally active older men relative to young men during low-intensity knee extensor exercise (although aerobic fitness of the men was not reported and older men had a 50% reduction in maximal knee extensor work rate relative to young men, unlike the present study); therefore, a more comprehensive investigation of the relation between chronic aerobic fitness, training, and leg hemodynamic responses to exercise in older men is merited.
Age and Exercising Leg Vascular Responses in Women
In comparison to young women, older women exhibited significantly lower femoral blood flow and vascular conductance responses at rest and throughout all stages of the graded knee extensor protocol. Although the attenuated vascular responses observed in older women at the same absolute work rates may have been influenced by their smaller (20% less muscle mass) quadriceps muscles, normalization to estimated quadriceps muscle did not completely abolish age differences (Fig. 3), nor did comparing older vs. young women matched for muscle mass. The slope of the hyperemic response, however, was not significantly different between young vs. older women when muscle mass was taken into account in either analysis, suggesting that hyperemic responsiveness could be influenced by an age-related loss of muscle mass in women. However, normalization to total estimated quadriceps muscle mass is an admittedly limited analysis with respect to graded exercise, given that the actual volume, quality, location, and metabolic activity of recruited quadriceps muscle at each work rate is not known, at least in women (20, 38, 41). In addition, although older women did recruit their hamstring muscles to a slightly greater extent at higher work rates, examining responses in older women for whom hamstring recruitment was similar to young women did not influence the effect of age on the leg blood flow response to exercise (Fig. 4), suggesting that the hamstring did not increase knee extensor economy and lower the flow demand in older women. These findings collectively point to age- and/or estrogen-dependent alterations in leg vasodilator responsiveness with age in women.
One potential mechanism underlying the blunted leg vasodilation in older women is a progressively greater vasoconstriction in the active muscle bed during incremental exercise. Although older women exhibited higher systemic blood pressures compared with young women at every exercise work rate (10–20 mmHg, twice the difference between young and older men), it is unlikely that the observed blunted vasodilatory response is solely attributable to increasingly heightened vasoconstriction given that the slope of the pressor response (Fig. 1) was not different between young and older women and metabolic inhibition of sympathoexcitation increases in proportion to exercise intensity (6). However, greater sympathetic outflow during exercise combined with attenuated functional sympatholysis (12) could certainly contribute to the reductions in leg blood flow and leg vascular conductance observed in older women at every work rate, although large increases in muscle sympathetic nerve activity have not been observed during single-leg exercise, at least in young subjects (42, 47).
Additional explanations for the observed age difference in the vasodilatory response to small muscle mass exercise in women are either an age-associated alteration in the control of leg blood flow by local vasoregulatory mechanisms and/or a structural limitation to vasodilation in the quadriceps vasculature. Several studies, including those from our laboratory, have documented age-related reductions in local vasoregulatory pathways in women (12, 30, 31, 50). In addition, as suggested by our laboratory's previous findings of reduced peak leg vasodilator capacity and leg smooth muscle dilation (31, 44), structural alterations in the quadriceps vasculature (stiffening, less responsive vessels, and reductions in arterial cross-sectional area) are likely factors contributing to the blunted vasodilatory responses observed in the legs of older women.
One final point worthy of discussion is the finding that older women exercised at the same absolute work rates and for the same duration as young women with no difference in peak work rate attained, yet with reduced leg blood flow. There are several implications of this finding, given the expected close matching of muscle perfusion to metabolic demand (39, 43). The first is that if the leg oxygen uptake-to-work rate relationship is preserved with age during knee extensor exercise in women, as has been reported during comparable exercise in sedentary men (22), then older women must be compensating for reduced leg blood flow with augmented oxygen extraction. Following this line of reasoning, an alternative explanation of the present data could even be that the lower leg blood flow observed in older women is resultant from, rather than directive of, an augmented oxygen extraction. Regardless, however, Proctor et al. (33) did not previously observe increased oxygen extraction during submaximal cycling exercise in older women. Thus, if the more probable explanation is that the relation between leg oxygen uptake and work rate is altered with age in women, then the preservation of work capacity with reduced leg blood flow could be reflective of age-related changes in parameters such as exercise efficiency, fiber-type size and/or distribution, capillary recruitment, and/or muscle metabolism (20, 33, 37, 48). Additional research is necessary to address these possibilities.
Experimental Considerations
Previous studies have suggested that there may be an influence of contraction frequency on estimates of mean blood flow measured during knee extensor exercise, especially when contraction frequency alters the time spent in the relaxation portion of the duty cycle (15, 29). Thus we cannot predict the effect that the 40 kicks/min cadence used in the present study vs. the more commonly used cadence of 60 kicks/min utilized in other knee extensor studies may have on comparing leg blood flow estimates between studies, because the time spent in contraction and relaxation within a duty cycle is not often reported. However, given that the purpose of the investigation was to examine age x sex interactions within a normally active population, and that our hemodynamic data are in agreement with several other published studies using Doppler ultrasound and comparable work rates (14, 15, 24), we do not believe using a cadence of 40 kicks/min significantly altered the interpretations and applicability of the study.
Finally, although we did not directly measure cardiac output, it is unlikely that cardiac reserve was significantly challenged in any of these four groups of healthy subjects. This is suggested by the fact that 1) heart rate increases were modest and similar among groups (<40 beats/min; Fig. 2), 2) stroke volume was likely maximized by testing subjects in the supine posture (45), and 3) previous studies involving cardiac limited older adults (e.g., heart failure) indicate that the rise in cardiac output during single knee extensor exercise approximately doubles the rise in total active leg blood flow (26).
Potential Significance and Conclusions
The present findings suggest that peripheral factors play a significant role in the sex-specific effects of aging on the leg hemodynamic responses to exercise in healthy humans. The nature of this age effect in women vs. men, and the modulatory influence of fitness in older men, also supports the idea that biological changes (i.e., the loss of estrogen, impact of exercise/physical activity, as well as reductions in muscle mass) have a greater impact on active muscle vasodilation in humans than the effect of aging per se. Further studies are needed to determine the precise mechanisms underlying the persistent attenuation of leg vasodilatory responses to exercise in older women, as well as the apparent plasticity of these vascular responses in aging men.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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O2max. Am J Physiol Heart Circ Physiol 286: H1565–H1572, 2004.This article has been cited by other articles:
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  B. Parker and D. Proctor Commentary on Viewpoint: Exercise and cardiovascular risk reduction: Time to update the rationale for exercise? J Appl Physiol, August 1, 2008; 105(2): 778 - 778. [Full Text] [PDF]
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Significant difference between young and older women, P < 0.05.
