Sarah Witkowski

Relationship between Physical Activity Level, Telomere Length, and Telomerase Activity

PURPOSE The purpose of this study was to examine the relationship of exercise energy expenditure (EEE) with both telomere length and telomerase activity in addition to accounting for hTERT C-1327T promoter genotype. METHODS Sixty-nine (n = 34 males; n = 35 females) participants 50-70 yr were assessed for weekly EEE level using the Yale Physical Activity Survey. Lifetime consistency of EEE was also determined. Subjects were recruited across a large range of EEE levels and separated into quartiles: 0-990, 991-2340, 2341-3540, and >3541 kcal x wk(-1). Relative telomere length and telomerase activity were measured in peripheral blood mononuclear cells (PBMC). RESULTS The second EEE quartile exhibited significantly longer telomere lengths [1.12 +/- 0.03 relative units (RU)] than both the first and fourth EEE quartiles (0.94 +/- 0.03 and 0.96 +/- 0.03 RU, respectively; P < 0.05) but was not different from the third quartile. Telomerase activity was not different among the EEE quartiles. An association was observed between telomerase enzyme activity and hTERT genotype with the TT genotype (1.0 x 10(-2) +/- 4.0 x 10(-3) attomoles (amol) per 10,000 cells; n = 19) having significantly greater telomerase enzyme activity than both the CT (1.3 x 10(-3) +/- 3.2 x 10(-3); n = 30) and CC groups (5.0 x 10(-4) +/- 3.9 x 10(-3); n = 20; P = 0.01). CONCLUSION These results indicate that moderate physical activity levels may provide a protective effect on PBMC telomere length compared with both low and high EEE levels.

Vasoconstrictor Reserve and Sympathetic Neural Control of Orthostasis

Background—We tested the hypothesis that individual variability in orthostatic tolerance is dependent on the degree of neural and vasomotor reserve available for vasoconstriction. Methods and Results—Muscle sympathetic nerve activity (MSNA) and hemodynamics were measured in 12 healthy young volunteers during 60° head-up tilt (HUT), followed by a cold pressor test (CPT) in HUT. Orthostatic tolerance was determined by progressive lower-body negative pressure (LBNP) to presyncope. The same protocols were performed randomly in normovolemic and hypovolemic conditions. We found that mean arterial pressure increased and stroke volume decreased, whereas heart rate (HR), MSNA, and total peripheral resistance (TPR) increased during HUT (all P<0.01). Application of the CPT in HUT did not increase HR or decrease stroke volume further but elevated mean arterial pressure (P<0.01) and increased MSNA and TPR in some subjects. There was a positive correlation between the time to presyncope from −50 mm Hg LBNP (equivalent to 60° HUT alone) and the changes in MSNA produced by the CPT under both conditions (r=0.442, P=0.039). Those who had greater increases in MSNA had greater increases in TPR during the CPT and longer time to presyncope (both P<0.05). One subject had dramatic increases in MSNA but small increases in TPR during the CPT, which indicates a disassociation between sympathetic activity and the increase in peripheral vascular resistance. Conclusions—These results support our hypothesis and suggest that vasoconstrictor capability is a contributor to orthostatic tolerance in humans. Vasoconstrictor reserve therefore may be one mechanism underlying individual variability in orthostatic intolerance.

Obesity: Associations with Acute Mountain Sickness

Context A few small retrospective studies show associations between obesity and acute mountain sickness. Contribution This 24-hour study involving 9 obese and 10 nonobese men was conducted in a decompression chamber that simulated a rapid ascent to an altitude of 3658 m (12 000 ft). Obese men more often developed symptoms of mountain sickness and had lower nocturnal oxygen saturation values than did nonobese men. Cautions Although this elegant, short experiment suggests that obese men were more susceptible to acute mountain sickness, the study involved few people, simulated a steady rate of ascent, and did not simulate physical activity with altitude exposure. The Editors Rapid ascent from low to high altitude (above 2500 m or 8200 ft) often causes acute mountain sickness (AMS), a syndrome characterized by headache and other systemic symptoms, such as nausea, lassitude, and difficulty sleeping. The prevalence and severity of AMS depend on the speed of ascent, the altitude attained, preacclimatization, age, sex, exertion levels while at altitude, and the ventilatory response to acute hypoxia (1, 2). Few retrospective field studies of high altitude have reported that obesity, as evidenced by body mass index (BMI), might be associated with the development of AMS (3-7). However, this association has not been studied prospectively under controlled conditions at reasonably accessible altitudes or in individuals with mild to moderate obesity. We sought to determine whether obese individuals are more likely to develop AMS than nonobese individuals during decompression to a simulated altitude of 3658 m. We hypothesized that obese individuals were more susceptible to develop AMS than nonobese individuals during exposure to high altitudeinduced hypobaric hypoxia. Methods Participants Volunteers were recruited through local advertisements and were selected for participation on the basis of percentage body fat. Nonobese was defined as percentage body fat less than 25%. Obese was defined as a BMI of 30 kg/m2 or greater and percentage body fat of 30% or greater. None of the participants had a history of cardiovascular or respiratory abnormalities. No participant was taking long-term medications. All participants were nonsmokers. Nine obese men (mean age [SD], 35 8 years) and 10 nonobese men (mean age [SD], 34 8 years) were studied. All participants resided at sea level (100 m) in Dallas, Texas. One obese and three nonobese participants previously had mild AMS. One obese participant was exposed to a 2500-m altitude 4 days before this study; no other participant was exposed to a 1500-m or higher altitude before participating in the study. Each participant received both written and verbal explanations of the experiment before giving written consent. The Institutional Review Board of the University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas approved this study. Study Protocol The study was conducted in a large (40 ft long by 9 ft diameter) multiplace (room for >1 person) decompression chamber at the Institute for Exercise and Environmental Medicine in Dallas. The barometric pressure was held at 483 mm Hg, which is equivalent to an altitude of 3658 m (12 000 ft). The temperature (25 0.5 C), humidity (28% 1%), and concentration of CO2 (0.07% 0.02%) in the chamber were monitored continuously by trained medical staff. Four participants at a time were studied in the chamber during the 24 hours of exposure (Figure 3). Assessment of AMS According to guidelines established by the Lake Louise AMS consensus report (8), each participant completed an AMS self-report questionnaire at sea level (before decompression) and during decompression to 483 mm Hg at 6 hours, 12 hours, and 24 hours. The questionnaire included items for symptoms of headache, gastrointestinal symptoms, fatigue or weakness, dizziness or lightheadedness, and difficulty sleeping. Each symptom was graded on a scale from 0 to 3, with 0 representing no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms. A score of 15 was the maximum score possible. A self-score of 4 or more was an indication of AMS (8). This scoring system has been validated against the U.S. Army Environmental Symptoms Questionnaire, demonstrating similar sensitivity and specificity (9). Measurements of Sao 2 Daytime Sao 2 was measured by pulse oximetry (Ohmeda 3700 Pulse Oximeter, Datex-Ohmeda, Boulder, Colorado) at sea level and at 6 hours and 24 hours of simulated altitude. Nocturnal Sao 2 in each participant was continuously recorded in the chamber from 10:30 p.m. to 6:30 a.m. The mean nocturnal Sao 2 was calculated from values obtained every 30 minutes. Heart rate was measured at sea level and at altitude during the daytime and during sleep. Other Measurements Body composition was determined by hydrostatic weighing, and percentage body fat, fat mass, and lean mass were calculated. At sea level, all participants underwent standard spirometry (measuring lung volumes, maximal flow-volume loop, and maximal voluntary ventilation) and diffusing capacity of the lung in a whole-body plethysmograph (Model 6200, SensorMedics, Yorba Linda, California). Pulmonary function testing was performed according to the guidelines of the American Thoracic Society. Statistical Analysis Data are expressed as means (SD). The parameters of AMS score and Sao 2 were analyzed by a two-way analysis of variance (ANOVA) using SAS software, release 8.02 (SAS Institute, Inc., Cary, North Carolina), with repeated measures on one factor (altitude-time) and between-participant comparisons for the other factor (group, nonobese and obese). Comparisons were considered significant when the P value was less than 0.05. Role of the Funding Sources The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Participants The Table shows general characteristics of the participants. One participant in the obese group was removed from the chamber after 10 hours because of severe headache, nausea, and dizziness (AMS score, 8). As a result, this participant was not included in further analyses. Table. General Characteristics and Pulmonary Function of Participants at Baseline AMS Scores There was a significant interaction between altitude-time and group (P < 0.001) as a result of the two-way ANOVA. This indicated that the increase in AMS scores with altitude exposure was more pronounced in the obese participants (Figure 1). Overall, after 24 hours in the chamber, seven obese participants and four nonobese participants had an AMS score of 4 or more. The frequency of AMS symptoms at 24 hours in 18 participants was as follows: headache, 89%; gastrointestinal upset, 36%; fatigue and weakness, 36%; dizziness, 15%; and difficulty sleeping, 75%. Figure 1. Comparison of the acute mountain sickness ( AMS ) score at sea level and at simulated altitude for 24 hours in nonobese ( n = 10) and obese ( n = 8) participants. P Sao 2 There was also a significant interaction between altitude-time and group (P < 0.001) for Sao 2 as a result of the two-way ANOVA (Figure 2). This indicated that the decrease in Sao 2 with altitude exposure differed between the two groups. Figure 2. Comparison of Sao at sea level, during the daytime, and during sleep at night in nonobese ( n = 10) and obese ( n = 8) participants. o P Figure 3. Participants during simulated altitude exposure in decompression chamber. Discussion Our principal finding was that obese participants have higher AMS scores than nonobese participants during a 24-hour exposure to simulated altitude of 3658 m. Thus, obesity seems to be associated with the development of AMS. Also, the response of Sao 2 with exposure differed between nonobese and obese men; obese men had lower values than nonobese men. These findings suggest that impaired breathing during sleep may be an important pathophysiologic mechanism for the increased levels of AMS in obese individuals. Limitations Although our results suggest that obese individuals may be more susceptible to AMS, these results must be interpreted with caution. Possible limitations to generalization include the small sample size, the selected nature of the study sample, the narrow spectrum of obese participants studied, the steady rate of ascent, the lack of physical activity during altitude exposure, and the simulated environment in which the participants were studied. Obesity and AMS Obesity is characterized by an abnormally large adipose tissue mass. In particular, excess weight leads to the development of various pathophysiologic disorders and, specifically, cardiovascular and respiratory abnormalities. Obesity-related respiratory function abnormalities, such as sleep-disordered breathing and nocturnal hypercapnia and hypoxia, place obese individuals at risk for illness at higher altitudes (10-13). In addition, the prevalence of obesity in western society, especially in the United States (where 22% of the population has a BMI > 30 kg/m2 and roughly 30% of the population is overweight [14, 15]), further increases the potential for altitude-related difficulties at easily accessible high altitudes during recreational activities. A review of the literature revealed no prospective data on the effect of obesity on high-altitude illness. In our study, AMS scores increased with time during altitude exposure in both nonobese and obese participants, which is consistent with previous data demonstrating that AMS symptoms are common after 24 hours of rapid ascent to high altitude (1, 2). The severity of symptoms, however, significantly differed between nonobese and obese men, suggesting that the occurrences of AMS at high altitude may be closely related to increased body weight. Acute mountain sickness frequently occurs in travelers who rapidly ascend to an altitude of 2500 m without acclimatizing; the incidence and severity depend on the speed of asce

Persistent Sympathetic Activation During Chronic Antihypertensive Therapy: A Potential Mechanism for Long Term Morbidity?

Previous studies have demonstrated that antihypertensive treatment resets baroreflex control of heart rate (HR) and increases cardiac vagal baroreflex sensitivity. However, it is uncertain whether baroreflex control of muscle sympathetic nerve activity (MSNA) also resets after treatment. We tested the hypothesis that chronic antihypertensive therapy alters baroreflex regulation of MSNA in patients with untreated moderate hypertension. Seven newly diagnosed patients with systolic blood pressure (BP) of 159±5 mm Hg (mean±SE) and diastolic BP of 103±4 mm Hg were studied before and after 1 to 2 weeks ´ and 3 months (chronic) of antihypertensive treatment with losartan–hydrochlorothiazide (Hyzaar). MSNA and hemodynamics were measured supine, during a Valsalva maneuver (VM), and at 70° head-up tilt (HUT) for 10 minutes. Data were compared with those obtained in 7 age-matched healthy controls. We found that Hyzaar lowered mean BP acutely and chronically by 20±4 and 23±3 mm Hg (both P<0.01) but did not change HR. Supine MSNA increased by 43±11% and 34±11% after acute and chronic treatment (both P<0.01). However, MSNA responses to VM and HUT did not differ after treatment compared with before treatment, indicating unchanged reflex control. These data indicate that sympathetic neural activity was augmented substantially by antihypertensive treatment with Hyzaar, consistent with an ongoing baroreflex unloading, and did not return to baseline or “reset” after 3 months of therapy. We speculate that persistent and marked sympathetic activation by the baroreflex may be a potential mechanism for hypertension that is refractory to antihypertensive therapy and may provide a target mechanism for persistent morbidity despite adequate BP control.

Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers.

Performance on the Sternberg working memory task, and MEG cortical response on a variation of the Sternberg task were examined in middle-aged carriers and non-carriers of the APOE epsilon4 allele. Physical activity was also assessed to examine whether exercise level modifies the relationship between APOE genotype and neurocognitive function. Regression revealed that high physical activity was associated with faster RT in the six- and eight-letter conditions of the Sternberg in epsilon4 carriers, but not in the non-carriers after controlling for age, gender, and education (N=54). Furthermore, the MEG analysis revealed that sedentary epsilon4 carriers exhibited lower right temporal lobe activation on matching probe trials relative to high-active epsilon4 carriers, while physical activity did not distinguish non-carriers (N=23). The M170 peak was identified as a potential marker for pre-clinical decline as epsilon4 carriers exhibited longer M170 latency, and highly physically active participants exhibited greater M170 amplitude to matching probe trials.

Cerebral Hemodynamics After Short- and Long-Term Reduction in Blood Pressure in Mild and Moderate Hypertension

This study tested the hypothesis that acute reduction in blood pressure (BP) at the initial stage of antihypertensive therapy compromises brain perfusion and dynamic cerebral autoregulation in patients with hypertension. Cerebral blood flow velocity and BP were measured in patients with mild and moderate hypertension and in healthy volunteers at baseline upon reduction of BP within 1 to 2 weeks of administration of losartan/hydrochlorothiazide and after 3 to 4 months of treatment. The transfer function between beat-to-beat changes in BP and cerebral blood flow velocity was estimated to assess dynamic autoregulation. After 1 to 2 weeks of treatment, BP was reduced in mild (143±7/88±4 versus 126±12/77±6 mm Hg) and moderate hypertension (163±11/101±9 versus 134±17/84±9 mm Hg; P<0.05). These reductions in BP were well maintained over the 3 to 4 month period. Cerebral blood flow velocity did not change, whereas cerebrovascular resistance index was reduced by 17% (P<0.05) after reduction in BP. Responses of cerebral blood flow velocity to head-up tilt remained unchanged. Baseline transfer function gain at the low frequencies (0.07 to 0.20 Hz) was reduced in moderate hypertension, consistent with cerebral vasoconstriction and/or enhanced dynamic autoregulation. However, this reduced transfer function gain was restored to the level of control subjects after reduction in BP. These findings, contrary to our hypothesis, demonstrate that there is a rapid adaptation of the cerebral vasculature to protect the brain from hypoperfusion even at the initial stage of antihypertensive therapy in patients with mild and moderate hypertension.

Relationship between circulating progenitor cells, vascular function and oxidative stress with long-term training and short-term detraining in older men

Exercise may contribute to the maintenance of vascular function via enhanced liberation and action of bone-marrow-derived progenitor cells. Activity related changes in oxidative stress may also influence the number and function of these cells. In the present study, we sought to determine (i) whether adaptations in reactive hyperaemic FBF (forearm blood flow) response associated with long-term endurance exercise and short-term detraining were related to resting putative progenitor cell number and function, and (ii) whether oxidative stress affected these factors. Participants included men with a history of more than 30 years of moderate-to-high intensity exercise (HI group) and healthy low-active age- and BMI (body mass index)-matched control subjects (LO group). Vascular reactive hyperaemic FBF response, resting CD34+ and CD34+/VEGFR2+ (vascular endothelial growth factor receptor 2+] cell number, CFU-EC (colony forming unit-endothelial cell) count and CFU-EC senescence were evaluated. Oxidative stress measures included OxLDL (oxidized low-density lipoprotein) and TAC (total antioxidant capacity).These measures were assessed following 10 days of detraining in the HI group. The HI group had greater peak reactive hyperaemic FBF responses compared with the LO group, despite no difference in resting CD34+ cell number, CD34+/VEGFR2+ cell number, CFU-EC colonies or CFU-EC senescence. With detraining in the HI group, CD34+ cells declined 44 %, and the percentage change in CD34+/VEGFR2+ cells was positively correlated with the change in FBF response to reactive hyperaemia. The percentage change in CD34+/VEGFR2+ cells and the percentage change in EPC (endothelial progenitor cell) senescence with detraining were related to the percentage change in TAC. These results reveal that changes in reactive hyperaemic FBF are closely related to activity dependent dynamic changes in CD34+/VEGFR2+ cell number, which may be influenced by alterations in oxidative stress.

Effects of acute and chronic endurance exercise on intracellular nitric oxide in putative endothelial progenitor cells: role of NAPDH oxidase

We sought to delineate the effects of acute and chronic exercise on the regulation of intracellular nitric oxide (NO(i)) production in putative endothelial progenitor cells (EPCs). Putative EPC colony-forming units (CFU-EC) were cultured from blood drawn before and after 30 min of treadmill exercise at 75% of maximal oxygen uptake in active (n = 8) and inactive (n = 8) men. CFU-EC were similar between groups at baseline, but increased after exercise in active men only (P = 0.04). CFU-EC expressed lower NADPH oxidase subunit gp91(phox) mRNA and elevated endothelial nitric oxide synthase mRNA in active relative to inactive men at baseline (P < 0.05). Acute exercise reduced gp91(phox) mRNA in CFU-EC of both groups (P < 0.05), whereas p47(phox) mRNA levels were reduced in the inactive group only (P = 0.02). There were no differences between groups or with acute exercise in xanthine oxidase, superoxide dismutase isoforms, or gluthathione peroxidase-1 mRNA levels. NO(i) was significantly greater in CFU-EC of active men at baseline (P = 0.004). NO(i) increased in CFU-EC of inactive men with acute exercise, and in vitro experiments with apocynin indicated the increased NO(i) production was caused by suppression of NADPH oxidase. However, the increases in NO(i) with the different treatments in the inactive group did not reach the baseline levels in the active group (P < 0.05). We conclude that acute exercise increases NO(i) in cells generated by the CFU-EC assay through an NADPH oxidase-inhibition mechanism in sedentary men. However, differences due to chronic exercise must involve additional factors. Our findings support exercise as a means to improve putative EPC function and suggest a novel mechanism that may explain this effect.

Defining the “dose” of altitude training: how high to live for optimal sea level performance enhancement

Chronic living at altitudes of ∼2,500 m causes consistent hematological acclimatization in most, but not all, groups of athletes; however, responses of erythropoietin (EPO) and red cell mass to a given altitude show substantial individual variability. We hypothesized that athletes living at higher altitudes would experience greater improvements in sea level performance, secondary to greater hematological acclimatization, compared with athletes living at lower altitudes. After 4 wk of group sea level training and testing, 48 collegiate distance runners (32 men, 16 women) were randomly assigned to one of four living altitudes (1,780, 2,085, 2,454, or 2,800 m). All athletes trained together daily at a common altitude from 1,250-3,000 m following a modified live high-train low model. Subjects completed hematological, metabolic, and performance measures at sea level, before and after altitude training; EPO was assessed at various time points while at altitude. On return from altitude, 3,000-m time trial performance was significantly improved in groups living at the middle two altitudes (2,085 and 2,454 m), but not in groups living at 1,780 and 2,800 m. EPO was significantly higher in all groups at 24 and 48 h, but returned to sea level baseline after 72 h in the 1,780-m group. Erythrocyte volume was significantly higher within all groups after return from altitude and was not different between groups. These data suggest that, when completing a 4-wk altitude camp following the live high-train low model, there is a target altitude between 2,000 and 2,500 m that produces an optimal acclimatization response for sea level performance.

Chronic Exercise Modifies Age-Related Telomere Dynamics in a Tissue-Specific Fashion

We evaluated the impact of long-term exercise on telomere dynamics in wild-derived short telomere mice (CAST/Ei) over 1 year. We observed significant telomere shortening in liver and cardiac tissues in sedentary 1-year-old mice compared with young (8 weeks) baseline mice that were attenuated in exercised 1-year-old animals. In contrast, skeletal muscle exhibited significant telomere shortening in exercise mice compared with sedentary and young mice. Telomerase enzyme activity was increased in skeletal muscle of exercise compared with sedentary animals but was similar in cardiac and liver tissues. We observed significant age-related decreases in expression of telomere-related genes that were attenuated by exercise in cardiac and skeletal muscle but not liver. Protein content of TRF1 was significantly increased in plantaris muscle with age. In summary, long-term exercise altered telomere dynamics, slowing age-related decreases in telomere length in cardiac and liver tissue but contributing to shortening in exercised skeletal muscle.