Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men

Cardiovagal baroreflex sensitivity (BRS) declines with advancing age in healthy men. We tested the hypothesis that oxidative stress contributes mechanistically to this age-associated reduction. Eight young (23 +/- 1 yrs, means +/- SE) and seven older (63 +/- 3) healthy men were studied. Cardiovagal BRS was assessed using the modified Oxford technique (bolus infusion of 50-100 microg sodium nitroprusside, followed 60 s later by a 100- to 150-microg bolus of phenylephrine hydrochloride) in triplicate at baseline and during acute intravenous ascorbic acid infusion. At baseline, cardiovagal BRS (slope of the linear portion of the R-R interval-systolic blood pressure relation during pharmacological changes in arterial blood pressure) was 56% lower (P < 0.01) in older (8.3 +/- 1.6 ms/mmHg) compared with young (19.0 +/- 3.1 ms/mmHg) men. Ascorbic acid infusion increased plasma concentrations similarly in young (62 +/- 9 vs. 1,249 +/- 72 micromol/l for baseline and during ascorbic acid; P < 0.05) and older men (62 +/- 4 vs. 1,022 +/- 55 micromol/l; P < 0.05) without affecting baseline blood pressure, heart rate, carotid artery compliance, or the magnitude of change in systolic blood pressure in response to bolus sodium nitroprusside and phenylephrine hydrochloride infusion. Ascorbic acid (vitamin C) infusion increased cardiovagal BRS in older (Delta58 +/- 16%; P < 0.01), but not younger (Delta - 4 +/- 4%) men. These data provide experimental support for the concept that oxidative stress contributes mechanistically to age-associated reductions in cardiovagal BRS in healthy men.     

Aldosterone impairs baroreflex sensitivity in healthy adults

Animal studies suggest that acute and chronic aldosterone administration impairs baroreceptor/baroreflex responses. We tested the hypothesis that aldosterone impairs baroreflex control of cardiac period [cardiovagal baroreflex sensitivity (BRS)] and muscle sympathetic nerve activity (MSNA, sympathetic BRS) in humans. Twenty-six young (25 +/- 1 yr old, mean +/- SE) adults were examined in this study. BRS was determined by using the modified Oxford technique (bolus infusion of nitroprusside, followed 60 s later by bolus infusion of phenylephrine) in triplicate before (Pre) and 30-min after (Post) beginning aldosterone (experimental, 12 pmol.kg(-1).min(-1); n = 10 subjects) or saline infusion (control; n = 10). BRS was quantified from the R-R interval-systolic blood pressure (BP) (cardiovagal BRS) and MSNA-diastolic BP (sympathetic BRS) relations. Aldosterone infusion increased serum aldosterone levels approximately fourfold (P < 0.05) and decreased (P < 0.05) cardiovagal (19.0 +/- 2.3 vs. 15.6 +/- 1.7 ms/mmHg Pre and Post, respectively) and sympathetic BRS [-4.4 +/- 0.4 vs. -3.0 +/- 0.4 arbitrary units (AU).beat(-1).mmHg(-1)]. In contrast, neither cardiovagal (19.3 +/- 3.3 vs. 20.2 +/- 3.3 ms/mmHg) nor sympathetic BRS (-3.8 +/- 0.5 vs. -3.6 +/- 0.5 AU.beat(-1).mmHg(-1)) were altered (Pre vs. Post) in the control group. BP, heart rate, and MSNA at rest were similar in experimental and control subjects before and after the intervention. Additionally, neural and cardiovascular responses to a cold pressor test and isometric handgrip to fatigue were unaffected by aldosterone infusion (n = 6 subjects). These data provide direct experimental support for the concept that aldosterone impairs baroreflex function (cardiovagal and sympathetic BRS) in humans. Therefore, aldosterone may be an important determinant/modulator of baroreflex function in humans.     

Cyclooxygenase inhibition and baroreflex sensitivity in humans

Animal studies suggest that prostanoids (i.e., such as prostacyclin) may sensitize or impair baroreceptor and/or baroreflex responsiveness depending on the site of administration and/or inhibition. We tested the hypothesis that acute inhibition of cyclooxygenase (COX), the rate-limiting enzyme in prostanoid synthesis, impairs baroreflex regulation of cardiac period (R-R interval) and muscle sympathetic nerve activity (MSNA) in humans and augments pressor reactivity. Baroreflex sensitivity (BRS) was determined at baseline (preinfusion) and 60 min after (postinfusion) intravenous infusion of a COX antagonist (ketorolac; 45 mg) (24 +/- 1 yr; n = 12) or saline (25 +/- 1 yr; n = 12). BRS was assessed by using the modified Oxford technique (bolus intravenous infusion of nitroprusside followed by phenylephrine). BRS was quantified as the slope of the linear portion of the 1) R-R interval-systolic blood pressure relation (cardiovagal BRS) and 2) MSNA-diastolic blood pressure relation (sympathetic BRS) during pharmacological changes in arterial blood pressure. Ketorolac did not alter cardiovagal (19.4 +/- 2.1 vs. 18.4 +/- 2.4 ms/mmHg preinfusion and postinfusion, respectively) or sympathetic BRS (-2.9 +/- 0.7 vs. -2.6 +/- 0.4 arbitrary units.beat(-1).mmHg(-1)) but significantly decreased a plasma biomarker of prostanoid generation (plasma thromboxane B2) by 53 +/- 11%. Cardiovagal BRS (21.3 +/- 3.8 vs. 21.2 +/- 3.0 ms/mmHg), sympathetic BRS (-3.4 +/- 0.3 vs. -3.2 +/- 0.2 arbitrary units.beat(-1).mmHg(-1)), and thromboxane B2 (change in -1 +/- 12%) were unchanged in the control (saline infusion) group. Pressor responses to steady-state incremental (0.5, 1.0, and 1.5 microg.kg(-1).min(-1)) infusion (5 min/dose) of phenylephrine were not altered by ketorolac (n = 8). Collectively, these data indicate that acute pharmacological antagonism of the COX enzyme does not impair BRS (cardiovagal or sympathetic) or augment pressor reactivity in healthy young adults.     

Gender difference in cardiovagal baroreflex gain in humans.

We tested the hypothesis that women would demonstrate lower cardiovagal baroreflex gain compared with men. If so, we further hypothesized that the lower cardiovagal baroreflex gain in women would be associated with their lower aerobic fitness and higher body fat percentage compared with men. To accomplish this, we measured cardiovagal baroreflex gain (modified Oxford technique) in sedentary, nonobese (body mass index < 25 kg/m2) men (age = 26.0 +/- 2.1 yr, n = 11) and women (age = 26.9 +/- 1.6 yr, n = 14). Resting R-R interval and diastolic blood pressure were similar in the two groups, but systolic blood pressure was lower (P < 0.05) in the women. Cardiovagal baroreflex gain was significantly lower in the women compared with the men (13.3 +/- 1.5 vs. 20.0 +/- 2.8 ms/mmHg, P < 0.05). The lower cardiovagal baroreflex gain in the women was not related (P > 0.05) to their lower aerobic fitness and was only marginally related to their higher body fat percentage (r = -0.34, P < 0.05). There were no gender differences in the threshold and saturation, operating range, or operating point (all P > 0.05), although the operating point fell significantly to left (i.e., at a lower systolic blood pressure) compared with men. Therefore, the findings of this study suggest that the gain of the cardiovagal baroreflex is reduced whereas other parameters were similar in women compared with men. The mechanisms responsible for the reduced cardiovagal baroreflex gain remain unclear.     

Effect of acute hyperlipidemia on autonomic and cardiovascular control in humans.

Blood lipids may detrimentally affect autonomic and circulatory control. We tested the hypotheses that acute elevations in free fatty acids and triglycerides (acute hyperlipidemia) impair baroreflex control of cardiac period [cardiovagal baroreflex sensitivity (BRS)] and muscle sympathetic nerve activity (MSNA: sympathetic BRS), increase MSNA at rest, and augment physiological responses to exercise. Eighteen young adults were examined in this randomized, double-blinded, and placebo-controlled study. BRS was determined using the modified Oxford technique before (pre) and 60 min (post) after initiating infusion of Intralipid (0.8 ml x m(-2) x min(-1)) and heparin (1,000 U/h) (experimental; n = 12) to induce acute hyperlipidemia, or saline (0.8 ml x m(-2) x min(-1)) and heparin (1,000 U/h) (control; n = 6). Responses to isometric handgrip to fatigue (IHG) were also determined. Blood pressure increased more (P < 0.05) in experimental than control subjects during the infusion. MSNA at rest (14 +/- 2 vs. 11 +/- 1 bursts/min), cardiovagal (19.8 +/- 1.8 vs. 19.1 +/- 2.4 ms/mmHg pre and post, respectively) and sympathetic BRS (-5.5 +/- 0.6 vs. -5.2 +/- 0.4 au x beat(-1) x mmHg(-1)), and the neural and cardiovascular responses to IHG were unchanged by acute hyperlipidemia (pre vs. post) in experimental subjects. Similarly, MSNA at rest (10 +/- 2 vs. 12 +/- 2 bursts/min), cardiovagal (22.1 +/- 4.0 vs. 21.0 +/- 4.6 ms/mmHg) and sympathetic BRS (-5.8 +/- 0.5 vs. -5.5 +/- 0.5 au x beat(-1) x mmHg(-1)), and the neural and cardiovascular responses to IHG were unchanged by the infusion in control subjects. These data do not provide experimental support for the concept that acute hyperlipidemia impairs reflex cardiovagal or sympathetic regulation in humans.     

Preserved autonomic function in amenorrheic athletes.

Reproductive hormones such as estradiol and progesterone are known to influence autonomic cardiovascular regulation. The purpose of this study was to determine whether amenorrheic athletes (AA) have impaired autonomic cardiovascular regulation compared with eumenorrheic athletes (EA). Thirty-five athletes were tested: 13 AA (19 +/- 1 yr), 13 EA (21 +/- 1 yr), and 9 EA (23 +/- 1 yr) on oral contraceptives (EA-OC). Multiple indexes of autonomic cardiovascular regulation were assessed: respiratory sinus arrhythmia (RSA), cardiovagal baroreflex sensitivity (BRS) via phase IV and phase II of the Valsalva maneuver, a spontaneous index of BRS, and the heart rate and blood pressure responses to orthostatic stress (20-min 60 degrees head-up tilt). RSA was not different among the groups. There were no group differences in the spontaneous index of BRS (AA = 30 +/- 6, EA = 24 +/- 3, EA-OC = 29 +/- 5 ms/mmHg) or in phase II (AA = 8 +/- 2, EA = 7 +/- 1, EA-OC = 8 +/- 1 ms/mmHg) of the Valsalva. There was a difference in BRS during phase IV (AA = 21 +/- 3, EA = 15 +/- 1, EA-OC = 26 +/- 6 ms/mmHg; ANOVA P = 0.04). Tukey's post hoc test indicated that BRS was greater in the EA-OC group compared with the EA group (P = 0.04). There were no differences in cardiovascular responses to orthostatic stress among the groups. In conclusion, AA do not display signs of impaired autonomic function and orthostatic responses compared with EA or EA-OC during the follicular phase of the menstrual cycle.     

Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat.

Exercise improves glucose metabolism and delays the onset and/or reverses insulin resistance in the elderly by an unknown mechanism. In the present study, we examined the effects of exercise training on glucose metabolism, abdominal adiposity, and adipocytokines in obese elderly. Sixteen obese men and women (age = 63 +/- 1 yr, body mass index = 33.2 +/- 1.4 kg/m2) participated in a 12-wk supervised exercise program (5 days/wk, 60 min/day, treadmill/cycle ergometry at 85% of heart rate maximum). Visceral fat (VF), subcutaneous fat, and total abdominal fat were measured by computed tomography. Fat mass and fat-free mass were assessed by hydrostatic weighing. An oral glucose tolerance test was used to determine changes in insulin resistance. Exercise training increased maximal oxygen consumption (21.3 +/- 0.8 vs. 24.3 +/- 1.0 ml.kg(-1).min(-1), P < 0.0001), decreased body weight (P < 0.0001) and fat mass (P < 0.001), while fat-free mass was not altered (P > 0.05). VF (176 +/- 20 vs. 136 +/- 17 cm2, P < 0.0001), subcutaneous fat (351 +/- 34 vs. 305 +/- 28 cm2, P < 0.03), and total abdominal fat (525 +/- 40 vs. 443 +/- 34 cm2, P < 0.003) were reduced through training. Circulating leptin was lower (P < 0.003) after training, but total adiponectin and tumor necrosis factor-alpha remained unchanged. Insulin resistance was reversed by exercise (40.1 +/- 7.7 vs. 27.6 +/- 5.6 units, P < 0.01) and correlated with changes in VF (r = 0.66, P < 0.01) and maximal oxygen consumption (r = -0.48, P < 0.05) but not adipocytokines. VF loss after aerobic exercise training improves glucose metabolism and is associated with the reversal of insulin resistance in older obese men and women.     

Excess body fat in men decreases plasma fatty acid availability and oxidation during endurance exercise

The effect of relative body fat mass on exercise-induced stimulation of lipolysis and fatty acid oxidation was evaluated in 15 untrained men (5 lean, 5 overweight, and 5 obese with body mass indexes of 21 +/- 1, 27 +/- 1, and 34 +/- 1 kg/m2, respectively, and %body fat ranging from 12 to 32%). Palmitate and glycerol kinetics and substrate oxidation were assessed during 90 min of cycling at 50% peak aerobic capacity (VO2 peak) by use of stable isotope-labeled tracer infusion and indirect calorimetry. An inverse relationship was found between %body fat and exercise-induced increase in glycerol appearance rate relative to fat mass (r2 = 0.74; P < 0.01). The increase in total fatty acid uptake during exercise [(micromol/kg fat-free mass) x 90 min] was approximately 50% smaller in obese (181 +/- 70; P < 0.05) and approximately 35% smaller in overweight (230 +/- 71; P < 0.05) than in lean (354 +/- 34) men. The percentage of total fatty acid oxidation derived from systemic plasma fatty acids decreased with increasing body fat, from 49 +/- 3% in lean to 39 +/- 4% in obese men (P < 0.05); conversely, the percentage of nonsystemic fatty acids, presumably derived from intramuscular and possibly plasma triglycerides, increased with increasing body fat (P < 0.05). We conclude that the lipolytic response to exercise decreases with increasing adiposity. The blunted increase in lipolytic rate in overweight and obese men compared with lean men limits the availability of plasma fatty acids as a fuel during exercise. However, the rate of total fat oxidation was similar in all groups because of a compensatory increase in the oxidation of nonsystemic fatty acids.     

Increased circadian prolactin release is blunted after body weight loss in obese premenopausal women

We recently showed that prolactin (PRL) release is considerably enhanced in obese women in proportion to the size of their visceral fat mass. PRL release is inhibited by dopamine 2 receptor (D2R) activation, and dietary restriction/weight loss are associated with increased dopaminergic signaling in animals. Therefore, we hypothesized that enhanced PRL release in obese humans would be reversed by weight loss. To evaluate this postulate, we measured 24-h plasma PRL concentrations at 10-min intervals in 11 obese premenopausal women (BMI 33.3 +/- 0.7 kg/m2) before and after weight loss (50% reduction of overweight/15% absolute weight loss, using a very low-calorie diet) in the follicular phase of their menstrual cycle. The 24-h PRL concentration profiles were analyzed by a peak detection program (Cluster) and a wave form-independent deconvolution technique (Pulse). Spontaneous 24-h PRL secretion was significantly reduced in obese women [mean daily release, before 128 +/- 24 vs. after weight loss 110 +/- 17 microg/liter distribution volume (Vdl)(-1) x 24 h, P = 0.05]. Body weight loss particularly blunted PRL secretory burst mass (Pulse area, before 230 +/- 28 vs. after weight loss 221 +/- 31 microg/Vdl(-1) x 24 h, P = 0.03), whereas burst frequency was unaffected (no. of pulses, before 11 +/- 1 vs. after weight loss 12 +/- 1 n/24 h, P = 0.69). Thus elevated PRL secretion rate in obese women is significantly reduced after loss of 50% of overweight. We speculate that amelioration of deficit D2R-mediated neurotransmission and/or diminutions of circulating leptin/estrogen levels might be involved in the physiology of this phenomenon.     

Carotid distensibility, baroreflex sensitivity, and orthostatic stress.

In this study, we tested the hypothesis that carotid arteries undergo rapid changes in distensibility on moving from the supine to head-up tilt (HUT) postures and, subsequently, that this change in carotid distensibility (cDa) might be associated with concurrent reductions in cardiovagal baroreflex sensitivity (BRS). Thus the effect of posture on carotid vascular mechanics and cardiovagal BRS with consideration for altered central hemodynamics (i.e., stroke volume; Doppler ultrasound) was examined. Carotid pulse pressure (cPP; Millar transducer) and contralateral B-mode ultrasound images were assessed at the carotid artery during supine and 60 degrees HUT postures. From these measures, cDa was calculated at 5-mmHg pressure increments experienced during the cardiac cycle (n = 6). cPP (n = 9) was not different in the two postures. A smaller stroke volume being ejected into a smaller carotid artery in HUT explained the maintenance of cPP in HUT. Also, compared with supine, cDa was reset to a lower level in HUT (main effect of posture; P < 0.05). Cardiovagal BRS (sequence method) was diminished in HUT vs. supine (P < 0.05). A positive correlation was observed between the tilt-induced changes in maximal cDa (in early systole) and cardiovagal BRS (r2 = 0.75; P < 0.05), but there was little predictive relationship between changes in cPP, systolic vessel dimensions, or average cDa and the corresponding change in BRS. The present results indicate that HUT elicits rapid changes in carotid artery mechanics and further suggest that reductions in the maximal cDa measured in early systole contribute to reduced cardiovagal BRS with HUT.     

Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO.     

Exercise but not diet-induced weight loss decreases skeletal muscle inflammatory gene expression in frail obese elderly persons.

Many obese elderly persons have impaired physical function associated with an increased chronic inflammatory response. We evaluated 12 wk of exercise (aerobic and resistance) or 12 wk of weight loss (approximately 7% reduction) on skeletal muscle mRNAs for toll-like receptor-4 (TLR-4), mechanogrowth factor (MGF), TNF-alpha, and IL-6 in 16 obese (body mass index 38+/-2 kg/m2) older (69+/-1 yr) physically frail individuals. Vastus lateralis muscle biopsies were obtained at 0 and 12 wk and analyzed by real-time RT-PCR. Body composition was assessed by dual-energy x-ray absorptiometry. Body weight decreased (-7.5+/-1.2 kg, P=0.001) in the weight loss group but not in the exercise group (-0.3+/-0.8 kg, P=0.74). Fat-free mass (FFM) decreased (-2.9+/-0.6 kg, P=0.010) in the weight loss group and increased (1.6+/-0.6 kg, P=0.03) in the exercise group. Exercise resulted in a 37% decrease in TLR-4 mRNA (P<0.05) while weight loss had no significant effect. Additionally, exercise led to a significant (50%) decrease in IL-6 and TNF-alpha mRNA (P<0.05) while weight loss had no effect. Exercise increased MGF mRNA (approximately 2 fold, P<0.05), but weight loss had no effect. In conclusion, exercise but not weight loss had a beneficial effect on markers of muscle inflammation and anabolism in frail obese elderly individuals.     

Subcutaneous obesity is not associated with sympathetic neural activation

We tested the hypothesis that muscle sympathetic nerve activity (MSNA) would not differ in subcutaneously obese (SUBOB) and nonobese (NO) men with similar levels of abdominal visceral fat despite higher plasma leptin concentrations in the former. We further hypothesized that abdominal visceral fat would be the strongest body composition- or regional fat distribution-related correlate of MSNA among these individuals. To accomplish this, we measured MSNA (via microneurography), body composition (via dual-energy X-ray absorptiometry), and abdominal fat distribution (via computed tomography) in 15 NO (body mass index 0.05, respectively) despite approximately 2.6-fold higher (P < 0.05) plasma leptin concentration in the SUBOB men. Furthermore, abdominal visceral fat was the only body composition- or regional fat distribution-related correlate (r = 0.45; P < 0.05) of MSNA in the pooled sample. In addition, abdominal visceral fat was related to MSNA in NO (r = 0.58; P = 0.0239) but not SUBOB (r = 0.39; P = 0.3027) men. Taken together with our previous observations, our findings suggest that the relation between obesity and MSNA is phenotype dependent. The relation between abdominal visceral fat and MSNA was evident in NO but not in SUBOB men and at levels of abdominal visceral fat below the level typically associated with elevated cardiovascular and metabolic disease risk. Our observations do not support an obvious role for leptin in contributing to sympathetic neural activation in human obesity and, in turn, are inconsistent with the concept of selective leptin resistance.     

Influence of physical training on heart rate variability and baroreflex circulatory control

Nineteen males (aged 45-68 yr) were studied before and after either a period of regular endurance exercise [walk/jog 3-4 days/wk for 30 +/- 1 (SE) wk, n = 11] or unchanged physical activity (38 +/- 2 wk, n = 8) (controls) to determine the influence of physical training on cardiac parasympathetic (vagal) tone and baroreflex control of heart rate (HR) and limb vascular resistance (VR) at rest in middle-aged and older men. Training resulted in a marked increase in maximal O2 uptake (31.6 +/- 1.2 vs. 41.0 +/- 1.8 ml.kg-1.min-1, 2.56 +/- 0.16 vs. 3.20 +/- 0.18 l/min, P less than 0.05) and small (P less than 0.05) reductions in body weight (81.2 +/- 3.5 vs. 78.7 +/- 4.0 kg) and body fat (23.8 +/- 1.3 vs. 20.9 +/- 1.3%). HR at rest was slightly, but consistently, lower after training (63 +/- 2 vs. 58 +/- 1 beats/min, P less than 0.05). In general, HR variability (index of cardiac vagal tone) was greater after training. Chronotropic responsiveness to either brief carotid baroreflex stimulation (neck suction) or inhibition (neck pressure), or to non-specific arterial baroreflex inhibition induced by a hypotensive level of lower body suction, was unchanged after training. In contrast, the magnitude of the reflex increase in forearm VR in response to three levels of lower body suction was markedly attenuated after training (38-59%; P less than 0.05 at -10 and -30 mmHg; P = 0.07 at -20 mmHg). None of these variables or responses was altered over time in the controls. These findings indicate that in healthy, previously sedentary, middle-aged and older men, strenuous and prolonged endurance training 1) elicits large increases in maximal exercise capacity and small reductions in HR at rest, 2) may increase cardiac vagal tone at rest, 3) does not alter arterial baroreflex control of HR, and 4) results in a diminished forearm vasoconstrictor response to reductions in baroreflex sympathoinhibition.     

Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited

We previously reported an "athlete's paradox" in which endurance-trained athletes, who possess a high oxidative capacity and enhanced insulin sensitivity, also have higher intramyocellular lipid (IMCL) content. The purpose of this study was to determine whether moderate exercise training would increase IMCL, oxidative capacity of muscle, and insulin sensitivity in previously sedentary overweight to obese, insulin-resistant, older subjects. Twenty-five older (66.4 +/- 0.8 yr) obese (BMI = 30.3 +/- 0.7 kg/m2) men (n = 9) and women (n = 16) completed a 16-wk moderate but progressive exercise training program. Body weight and fat mass modestly but significantly (P < 0.01) decreased. Insulin sensitivity, measured using the euglycemic hyperinsulinemic clamp, was increased (21%, P = 0.02), with modest improvements (7%, P = 0.04) in aerobic fitness (Vo2peak). Histochemical analyses of IMCL (Oil Red O staining), oxidative capacity [succinate dehydrogenase activity (SDH)], glycogen content, capillary density, and fiber type were performed on skeletal muscle biopsies. Exercise training increased IMCL by 21%. In contrast, diacylglycerol and ceramide, measured by mass spectroscopy, were decreased (n = 13; -29% and -24%, respectively, P < 0.05) with exercise training. SDH (19%), glycogen content (15%), capillary density (7%), and the percentage of type I slow oxidative fibers (from 50.8 to 55.7%), all P < or = 0.05, were increased after exercise. In summary, these results extend the athlete's paradox by demonstrating that chronic exercise in overweight to obese older adults improves insulin sensitivity in conjunction with favorable alterations in lipid partitioning and an enhanced oxidative capacity within muscle. Therefore, several key deleterious effects of aging and/or obesity on the metabolic profile of skeletal muscle can be reversed with only moderate increases in physical activity.     

Weight stability masks sarcopenia in elderly men and women

Skeletal muscle loss or sarcopenia in aging has been suggested in cross-sectional studies but has not been shown in elderly subjects using appropriate measurement techniques combined with a longitudinal study design. Longitudinal skeletal muscle mass changes after age 60 yr were investigated in independently living, healthy men (n = 24) and women (n = 54; mean age 73 yr) with a mean +/- SD follow-up time of 4.7 +/- 2.3 yr. Measurements included regional skeletal muscle mass, four additional lean components (fat-free body mass, body cell mass, total body water, and bone mineral), and total body fat. Total appendicular skeletal muscle (TSM) mass decreased in men (-0.8 +/- 1.2 kg, P = 0.002), consisting of leg skeletal muscle (LSM) loss (-0.7 +/- 0.8 kg, P = 0.001) and a trend toward loss of arm skeletal muscle (ASM; -0.2 +/- 0.4 kg, P = 0.06). In women, TSM mass decreased (-0.4 +/- 1.2 kg, P = 0.006) and consisted of LSM loss (-0.3 +/- 0.8 kg, P = 0.005) and a tendency for a loss of ASM (-0.1 +/- 0.6 kg, P = 0.20). Multiple regression modeling indicates greater rates of LSM loss in men. Body weight in men at follow-up did not change significantly (-0.5 +/- 3.0 kg, P = 0.44) and fat mass increased (+1.2 +/- 2.4 kg, P = 0.03). Body weight and fat mass in women were nonsignificantly reduced (-0.8 +/- 3.9 kg, P = 0.15 and -0.8 +/- 3.5 kg, P = 0.12). These observations suggest that sarcopenia is a progressive process, particularly in elderly men, and occurs even in healthy independently living older adults who may not manifest weight loss.     

High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men.

Resting whole leg blood flow and vascular conductance decrease linearly with advancing age in healthy adult men. The potential role of age-related increases in oxidative stress in these changes is unknown. Resting leg blood flow during saline and ascorbic acid infusion was studied in 10 young (25 +/- 1 yr) and 11 older (63 +/- 2 yr) healthy normotensive men. Plasma oxidized LDL, a marker of oxidative stress, was greater in the older men (P < 0.05). Absolute resting femoral artery blood flow at baseline (iv saline control infusion) was 25% lower in the older men (238 +/- 25 vs. 316 +/- 38 ml/min; P < 0.05), and it was inversely related to plasma oxidized LDL (r = -0.56, P < 0.01) in all subjects. Infusion of supraphysiological concentrations of ascorbic acid increased femoral artery blood flow by 37% in the older men (to 327 +/- 52 ml/min; P < 0.05), but not in the young men (352 +/- 41 ml/min; P = 0.28), thus abolishing group differences (P = 0.72). Mean arterial blood pressure was greater in the older men at baseline (86 +/- 4 vs. 78 +/- 2 mmHg; P < 0.05), but it was unaffected by ascorbic acid infusion (P >/= 0.70). As a result, the lower baseline femoral artery blood flow in the older men was mediated solely by a 32% lower femoral artery vascular conductance (P < 0.05). Baseline femoral vascular conductance also was inversely related to plasma oxidized LDL (r = -0.65, P < 0.01). Ascorbic acid increased femoral vascular conductance by 36% in the older men (P < 0.05) but not in the young men (P = 0.31). In conclusion, ascorbic acid infused at concentrations known to scavenge reactive oxygen species restores resting femoral artery blood flow in healthy older adult men by increasing vascular conductance. These results support the hypothesis that oxidative stress plays a major role in the reduced resting whole leg blood flow and increased leg vasoconstriction observed with aging in men.     

The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss

Age‐related increases in ectopic fat accumulation are associated with greater risk for metabolic and cardiovascular diseases, and physical disability. Reducing skeletal muscle fat and preserving lean tissue are associated with improved physical function in older adults. PPARγ‐agonist treatment decreases abdominal visceral adipose tissue (VAT) and resistance training preserves lean tissue, but their effect on ectopic fat depots in nondiabetic overweight adults is unclear. We examined the influence of pioglitazone and resistance training on body composition in older (65–79 years) nondiabetic overweight/obese men (n = 48, BMI = 32.3 ± 3.8 kg/m²) and women (n = 40, BMI = 33.3 ± 4.9 kg/m²) during weight loss. All participants underwent a 16‐week hypocaloric weight‐loss program and were randomized to receive pioglitazone (30 mg/day) or no pioglitazone with or without resistance training, following a 2 × 2 factorial design. Regional body composition was measured at baseline and follow‐up using computed tomography (CT). Lean mass was measured using dual X‐ray absorptiometry. Men lost 6.6% and women lost 6.5% of initial body mass. The percent of fat loss varied across individual compartments. Men who were given pioglitazone lost more visceral abdominal fat than men who were not given pioglitazone (?1,160 vs. ?647 cm³, P = 0.007). Women who were given pioglitazone lost less thigh subcutaneous fat (?104 vs. ?298 cm³, P = 0.002). Pioglitazone did not affect any other outcomes. Resistance training diminished thigh muscle loss in men and women (resistance training vs. no resistance training men: ?43 vs. ?88 cm³, P = 0.005; women: ?34 vs. ?59 cm³, P = 0.04). In overweight/obese older men undergoing weight loss, pioglitazone increased visceral fat loss and resistance training reduced skeletal muscle loss. Additional studies are needed to clarify the observed gender differences and evaluate how these changes in body composition influence functional status.     

Separate and combined effects of exercise training and weight loss on exercise efficiency and substrate oxidation

Perturbations in body weight have been shown to affect energy expenditure and efficiency during physical activity. The separate effects of weight loss and exercise training on exercise efficiency or the proportion of energy derived from fat oxidation during physical activity, however, are not known. The purpose of this study was to determine the separate and combined effects of exercise training and weight loss on metabolic efficiency, economy (EC), and fat oxidation during steady-state moderate submaximal exercise. Sixty-four sedentary older (67 +/- 0.5 yr) overweight to obese (30.7 +/- 0.4 kg/m(2)) volunteers completed 4 mo of either diet-induced weight loss (WL; n = 11), exercise training (EX; n = 36), or the combination of both interventions (WLEX; n = 17). Energy expenditure, gross efficiency (GE), EC, and proportion of energy expended from fat (EF) were determined during a 1-h submaximal (50% of peak aerobic capacity) cycle ergometry exercise before the intervention and at the same absolute work rate after the intervention. We found that EX increased GE by 4.7 +/- 2.2%. EC was similarly increased by 4.2 +/- 2.1% by EX. The addition of concomitant WL to EX (WLEX) resulted in greater increases in GE (9.0 +/- 3.3%) compared with WL alone but not compared with EX alone. These effects remained after adjusting for changes in lean body mass. The proportion of energy derived from fat during the bout of moderate exercise increased with EX and WLEX but not with WL. From these findings, we conclude that exercise training, either alone or in combination with weight loss, increases both exercise efficiency and the utilization of fat during moderate physical activity in previously sedentary, obese older adults. Weight loss alone, however, significantly improves neither efficiency nor utilization of fat during exercise.     

Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men

Large elastic artery compliance is reduced and arterial blood pressure (BP) is increased in the central (cardiothoracic) circulation with aging. Reactive oxygen species may tonically modulate central arterial compliance and BP in humans, and oxidative stress may contribute to adverse changes with aging. If so, antioxidant administration may have beneficial effects. Young (Y; 26 +/- 1 yr, mean +/- SE) and older (O; 63 +/- 2 yr, mean +/- SE) healthy men were studied at baseline and during acute (intravenous infusion; Y: n = 13, O: n = 12) and chronic (500 mg/day for 30 days; Y: n = 10, O: n = 10) administration of ascorbic acid (vitamin C). At baseline, peripheral (brachial artery) BP did not differ in the two groups, but carotid artery compliance was 43% lower (1.2 +/- 0.1 vs. 2.1 +/- 0.1 mm(2)/mmHg x 10(-1), P < 0.01) and central (carotid) BP (systolic: 116 +/- 5 vs. 101 +/- 3 mmHg, P < 0.05, and pulse pressure: 43 +/- 4 vs. 36 +/- 3 mmHg, P = 0.16), carotid augmentation index (AIx; 27.8 +/- 7.8 vs. -20.0 +/- 6.6%, P < 0.001), and aortic pulse wave velocity (PWV; 950 +/- 88 vs. 640 +/- 38 cm/s, P < 0.01) were higher in the older men. Plasma ascorbic acid concentrations did not differ at baseline (Y: 71 +/- 5 vs. O: 61 +/- 7 micromol/l, P = 0.23), increased (P < 0.001) to supraphysiological levels during infusion (Y: 1240 +/- 57 and O: 1,056 +/- 83 micromol/l), and were slightly elevated (P < 0.001 vs. baseline) with supplementation (Y: 96 +/- 5 micromol/l vs. O: 85 +/- 6). Neither ascorbic acid infusion nor supplementation affected peripheral BP, heart rate, carotid artery compliance, central BP, carotid AIx, or aortic PWV (all P > 0.26). These results indicate that the adverse changes in large elastic artery compliance and central BP with aging in healthy men are not 1). mediated by ascorbic acid-sensitive oxidative stress (infusion experiments) and 2). affected by short-term, moderate daily ascorbic acid (vitamin C) supplementation.