Tina E. Brinkley

Effect of exercise training on chronic inflammation.

Persistent, sub-clinical inflammation, as indicated by higher circulating levels of inflammatory mediators, is a prominent risk factor for several chronic diseases, as well as aging-related disability. As such, the inflammatory pathway is a potential therapeutic target for lifestyle interventions designed to reduce disease and disability. Physical exercise is well recognized as an important strategy for reducing the risk of chronic disease, and recent research has focused on its role in the improvement of the inflammatory profile. This review summarizes the evidence for and against the role of increasing physical activity in the reduction of chronic inflammation. Large population-based cohort studies consistently show an inverse association between markers of systemic inflammation and physical activity or fitness status, and data from several small-scale intervention studies support that exercise training diminishes inflammation. However, data from large, randomized, controlled trials designed to definitively test the effects of exercise training on inflammation are limited, and results are inconclusive. Future studies are needed to refine our understanding of the effects of exercise training on systemic low-grade inflammation, the magnitude of such an effect, and the amount of exercise necessary to elicit clinically meaningful changes in the deleterious association between inflammation and disease.

Chronic Inflammation Is Associated With Low Physical Function in Older Adults Across Multiple Comorbidities

BACKGROUND Chronic subclinical inflammation may contribute to impaired physical function in older adults; however, more data are needed to determine whether inflammation is a common mechanism for functional decline, independent of disease or health status. METHODS We examined associations between physical function and inflammatory biomarkers in 542 older men and women enrolled in four clinical studies at Wake Forest University between 2001 and 2006. All participants were at least 55 years and had chronic obstructive pulmonary disease, congestive heart failure, high cardiovascular risk, or self-reported physical disability. Uniform clinical assessments were used across studies, including grip strength; a Short Physical Performance Battery (SPPB; includes balance, 4-m walk, and repeated chair stands); inflammatory biomarker assays for interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP); and anthropometric measures. RESULTS Higher levels of CRP and IL-6, but not TNF-alpha, were associated with lower grip strength and SPPB scores and longer times to complete the 4-m walk and repeated chair stands tests, independent of age, gender, and race. More importantly, these relationships were generally independent of disease status. Further adjustment for fat mass, lean mass, or percent body fat altered some of these relationships but did not significantly change the overall results. CONCLUSIONS Elevated CRP and IL-6 levels are associated with poorer physical function in older adults with various comorbidities, as assessed by a common battery of clinical assessments. Chronic subclinical inflammation may be a marker of functional limitations in older persons across several diseases/health conditions.

Exercise Training as a Treatment for Chronic Inflammation in the Elderly

Persistent subclinical inflammation predisposes to chronic disease, as well as the development of sarcopenia and disability, in frail elderly. Thus, the inflammatory pathway is a potential target for interventions to reduce aging-related disease and disability. This article highlights emerging data suggesting that increasing physical activity could be effective for reducing chronic inflammation in the elderly.

Renal sinus fat and poor blood pressure control in middle-aged and elderly individuals at risk for cardiovascular events.

Fat in the renal sinus (RS), a region of the kidney in which low pressure venous and lymphatic vessels are present, may indirectly influence blood pressure. The purpose of this study was to assess the association between RS fat and control of blood pressure on receipt of antihypertensive medications. A total of 205 participants aged 55 to 85 years at risk for cardiovascular events underwent MRI assessments of abdominal and RS fat, measurement of blood pressure, and determination of the number of prescribed antihypertensive medications. Multivariable linear regression was used to determine associations among RS fat, blood pressure, and the number of prescribed antihypertensive medications. Abdominal fat averaged 416±160 cm3 (median and interquartile range of 396 cm3 and 308 to 518 cm3); intraperitoneal fat averaged 141±73 cm3 (median and interquartile range of 129 cm3 and 86 to 194 cm3); and RS fat averaged 4.6±3.2 cm3 (median and interquartile range of 4.2 cm3 and 2.2 to 6.6 cm3). After accounting for age, sex, height, body mass index, and intraperitoneal fat, RS fat correlated with the number of prescribed antihypertensive medications (P=0.010), stage II hypertension (P=0.02), and renal size (P≤0.001). In conclusion, after accounting for other body fat depots and risk factors for hypertension, RS fat volume is associated with the number of prescribed antihypertensive medications and stage II hypertension. These results indicate that further studies are warranted to determine whether fat accumulation in the RS promotes hypertension.

Plasma Oxidized Low-Density Lipoprotein Levels and Arterial Stiffness in Older Adults The Health, Aging, and Body Composition Study

Arterial stiffness is a prominent feature of vascular aging and is strongly related to cardiovascular disease. Oxidized low-density lipoprotein (ox-LDL), a key player in the pathogenesis of atherosclerosis, may also play a role in arterial stiffening, but this relationship has not been well studied. Thus, we examined the cross-sectional association between ox-LDL and aortic pulse wave velocity (aPWV), a marker of arterial stiffness, in community-dwelling older adults. Plasma ox-LDL levels and aPWV were measured in 2295 participants (mean age: 74 years; 52% female; 40% black) from the Health, Aging, and Body Composition Study. Mean aPWV significantly increased across tertiles of ox-LDL (tertile 1: 869±376 cm/s; tertile 2: 901±394 cm/s; tertile 3: 938±415 cm/s; P=0.002). In multivariate analyses, ox-LDL remained associated with aPWV after adjustment for demographics and traditional cardiovascular disease risk factors (P=0.008). After further adjustment for hemoglobin A1c, abdominal visceral fat, antihypertensive and antilipemic medications, and C-reactive protein, the association with ox-LDL was attenuated but remained significant (P=0.01). Results were similar when ox-LDL was expressed in absolute (milligrams per deciliter) or relative amounts (percentage of low-density lipoprotein). Moreover, individuals in the highest ox-LDL tertile were 30% to 55% more likely to have high arterial stiffness, defined as aPWV >75th percentile (P≤0.02). In conclusion, we found that, among elderly persons, elevated plasma ox-LDL levels were associated with higher arterial stiffness, independent of cardiovascular disease risk factors. These data suggest that ox-LDL may be related to the pathogenesis of arterial stiffness.

Heterogeneity of Physical Function Responses to Exercise Training in Older Adults

To describe the interindividual variability in physical function responses to supervised resistance and aerobic exercise training interventions in older adults.

Pericardial fat is associated with carotid stiffness in the Multi-Ethnic Study of Atherosclerosis

BACKGROUND AND AIMS Arterial stiffness is a prominent feature of vascular aging and a risk factor for cardiovascular disease (CVD). Fat around the heart and blood vessels (i.e. pericardial fat, Pfat) may contribute to arterial stiffness via a local paracrine effect of adipose tissue on the surrounding vasculature. Thus, we determined the association between Pfat and carotid stiffness in 5770 participants (mean age 62 years, 53% female, 25% African American, 24% Hispanic, and 13% Chinese) from the Multi-Ethnic Study of Atherosclerosis. METHODS AND RESULTS Pfat was measured by computed tomography, and ultrasonography of the common carotid artery was used to calculate the distensibility coefficient (DC) and Youngs modulus (YM). Lower DC and higher YM values indicate stiffer arteries. Pfat quartile was highly associated with demographic, behavioral, anthropometric, hemodynamic, metabolic, and disease variables in both men and women. After adjusting for height, clinical site, CVD risk factors, and medications, a 1 standard deviation (41.91 cm(3)) increment in Pfat was associated with a 0.00007±0.00002 1/mm Hg lower DC (p=0.0002) in men and a 48.1±15.1 mm Hg/mm higher YM in women (p=0.002). Additional adjustment for C-reactive protein, coronary artery calcification, and carotid intima-media thickness had only modest effects. More importantly, adjusting for body mass index and waist circumference did not significantly change the overall results. CONCLUSION Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.

Effect of ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women

BACKGROUND Accumulating evidence suggests that Ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure (BP)-lowering effects in humans is lacking. METHODS We determined the effects of G. biloba extract (240 mg/day) on BP and incident hypertension in 3,069 participants (mean age, 79 years; 46% female; 96% white) from the Ginkgo Evaluation of Memory (GEM) study. We also examined whether the treatment effects are modified by baseline hypertension status. RESULTS At baseline, 54% of the study participants were hypertensive, 28% were prehypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in BP and pulse pressure (PP) in the G. biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of G. biloba, it did influence the changes in BP variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in prehypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the odds ratio (95% confidence interval (CI)) for being a never-user in the G. biloba group was 0.75 (0.48-1.16). The rate of incident hypertension also did not differ between participants assigned to G. biloba vs. placebo (hazard ratio (HR), 0.99, 95% CI, 0.84-1.15). CONCLUSIONS Our data indicate that G. biloba does not reduce BP or the incidence of hypertension in elderly men and women.

Exercise training, NADPH oxidase p22phox gene polymorphisms, and hypertension

INTRODUCTION Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives. METHODS Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% VO2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC). RESULTS Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2alpha levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in VO2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2alpha (P = 0.002) and plasma TAC (P=0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables. CONCLUSIONS We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2alpha but not the aerobic exercise-induced responses.

Total and Abdominal Adiposity Are Associated With Inflammation in Older Adults Using a Factor Analysis Approach

BACKGROUND Obesity-related increases in multiple inflammatory markers may contribute to the persistent subclinical inflammation common with advancing age. However, it is unclear if a specific combination of markers reflects the underlying inflammatory state. We used factor analysis to identify inflammatory factor(s) and examine their associations with adiposity in older adults at risk for disability. METHODS Adiponectin, CRP, IL-1ra, IL-1sRII, IL-2sRα, IL-6, IL-6sR, IL-8, IL-15, sTNFRI, sTNFRII, and TNF-α were measured in 179 participants from the Lifestyle Interventions and Independence for Elders Pilot (Mean ± SD age 77 ± 4 years, 76% white, 70% women). Body mass index, waist circumference, and total fat mass were assessed by anthropometry and dual-energy x-ray absorptiometry. RESULTS IL-2sRα, sTNFRI, and sTNFRII loaded highest on the first factor (factor 1). CRP, IL-1ra, and IL-6 loaded highest on the second factor (factor 2). Factor 2, but not factor 1, was positively associated with 1-SD increments in waist circumference (β = 0.160 ± 0.057, p = .005), body mass index (β = 0.132 ± 0.053, p = .01), and total fat mass (β = 0.126 ± 0.053, p = .02) after adjusting for age, gender, race/ethnicity, site, smoking, anti-inflammatory medications, comorbidity index, health-related quality of life, and physical function. These associations remained significant after further adjustment for grip strength, but only waist circumference remained associated with inflammation after adjusting for total lean mass. There were no significant interactions between adiposity and muscle mass or strength for either factor. CONCLUSIONS Greater total and abdominal adiposity are associated with higher levels of an inflammatory factor related to CRP, IL-1ra, and IL-6 in older adults, which may provide a clinically useful measure of inflammation in this population.