Lisa H. Colbert

Circulating Levels of Inflammatory Markers and Cancer Risk in the Health Aging and Body Composition Cohort

Background: Chronic inflammation is associated with processes that contribute to the onset or progression of cancer. This study examined the relationships between circulating levels of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and total as well as site-specific cancer incidence. Methods: Study subjects (n = 2,438) were older adults (ages 70-79 years) participating in the Health Aging and Body Composition study, who did not report a previous cancer diagnosis (except for nonmelanoma skin cancer) at baseline. Incident cancer events (n = 296) were ascertained during an average follow-up of 5.5 years. Inflammatory markers were measured in stored baseline fasting blood samples. Results: The adjusted hazard ratios (95% confidence intervals) for incident cancer associated with a 1-unit increase on the natural log-scale were 1.13 (0.94-1.37), 1.25 (1.09-1.43), and 1.28 (0.96-1.70) for IL-6, CRP, and TNF-α, respectively. Markers were more strongly associated with cancer death: hazard ratios were 1.63 (1.19-2.23) for IL-6, 1.64 (1.20-2.24) for CRP, and 1.82 (1.14-2.92) for TNF-α. Although precision was low for site-specific analyses, our results suggest that all three markers were associated with lung cancer, that IL-6 and CRP were associated with colorectal cancer, and that CRP was associated with breast cancer. Prostate cancer was not associated with any of these markers. Conclusions: These findings suggest that (a) the associations between IL-6, CRP, and TNF-α and the risk of cancer may be site specific and (b) increased levels of inflammatory markers are more strongly associated with the risk of cancer death than cancer incidence.

Physical activity, exercise, and inflammatory markers in older adults: Findings from the health, aging and body composition study

Objectives: To examine the association between physical activity and inflammatory markers, with consideration for body fatness and antioxidant use.

Higher Inflammatory Marker Levels in Older Persons: Associations With 5-Year Change in Muscle Mass and Muscle Strength

BACKGROUND There is growing evidence that higher levels of inflammatory markers are associated with physical decline in older persons, possibly through the catabolic effects of inflammatory markers on muscle. The aim of this study was to investigate the association between serum levels of inflammatory markers and loss of muscle mass and strength in older persons. METHODS Using data on 2,177 men and women in the Health, Aging, and Body Composition Study, we examined 5-year change in thigh muscle area estimated by computed tomography and grip and knee extensor strength in relation to serum levels of interleukin-6 (IL-6), C-reactive protein, tumor necrosis factor-alpha (TNF-alpha), and soluble receptors (measured in a subsample) at baseline. RESULTS Higher levels of inflammatory markers were generally associated with greater 5-year decline in thigh muscle area. Most associations, with the exception of soluble receptors, were attenuated by adjustment for 5-year change in weight. Higher TNF-alpha and interleukin-6 soluble receptor levels remained associated with greater decline in grip strength in men. Analyses in a subgroup of weight-stable persons showed that higher levels of TNF-alpha and its soluble receptors were associated with 5-year decline in thigh muscle area and that higher levels of TNF-alpha were associated with decline in grip strength. CONCLUSIONS TNF-alpha and its soluble receptors showed the most consistent associations with decline in muscle mass and strength. The results suggest a weight-associated pathway for inflammation in sarcopenia.

Association of High Coronary Heart Disease Risk Status With Circulating Oxidized LDL in the Well-Functioning Elderly: Findings From the Health, Aging, and Body Composition Study

Objective—Although circulating oxidized LDL (oxLDL) is elevated in persons with coronary heart disease (CHD), whether oxLDL is elevated in persons with high CHD risk before any events is unknown. Therefore, we studied the association between high, predicted CHD risk and oxLDL in the Health ABC cohort. Methods and Results—This cohort included 385 persons with CHD and 1183 persons at high risk; the latter were all persons with CHD risk equivalents: noncoronary forms of clinical atherosclerotic disease, diabetes, and a 10-year risk for CHD >20% by Framingham scoring. The remaining 1535 participants were at low risk. Levels of oxLDL were 1.18±0.61 mg/dL for low-risk persons, 1.50±0.81 mg/dL for high-risk persons without diagnosed CHD, and 1.32±0.83 mg/dL for persons with CHD (P <0.001). The odds ratio for high CHD risk in the highest quintile of oxLDL, compared with the lowest quintile and after adjusting for age, sex, race, LDL cholesterol, smoking status, and C-reactive protein, was 2.79 (P <0.001). Conclusion—The odds ratio for elevated oxLDL among persons with high CHD risk before any CHD events was higher than that among persons with established CHD. A likely explanation is that once CHD is diagnosed, individuals are frequently treated with a statin, which is associated with lowering of LDL cholesterol and oxLDL levels.

Sedentary behavior, physical activity, and markers of health in older adults.

INTRODUCTION The purpose of this study was to examine the association between sedentary behavior (SB), cardiometabolic risk factors, and self-reported physical function by level of moderate-vigorous physical activity (MVPA). METHODS Cross-sectional analysis was completed on 1914 older adults age ≥ 65 yr from the 2003-2006 U.S. National Health and Nutrition Examination Survey. MVPA and SB were derived from ActiGraph accelerometers worn for 1 wk. MVPA was categorized as sufficient to meet the current U.S. guidelines (≥ 150 min · wk(-1)) or not; SB was split into quartiles. Various biomarkers were examined in laboratory analyses and physical exams, and the number of functional limitations was self-reported. Statistical interaction between SB and MVPA on the biomarker associations was the primary analysis, followed by an examination of their independent associations with relevant covariate adjustment. RESULTS Average SB was 9.4 ± 2.3 h · d(-1) (mean ± SD), and approximately 35% were classified as sufficiently active. Overall, no significant meaningful statistical interactions were found between SB and MVPA for any of the outcomes; however, strong independent positive associations were found between SB and weight (P < 0.01), body mass index (P < 0.01), waist circumference (P < 0.01), C-reactive protein (P < 0.01), plasma glucose (P = 0.04), and number of functional limitations (P < 0.01) after adjustment for MVPA. Similarly, MVPA was negatively associated with weight (P = 0.01), body mass index (P < 0.01), waist circumference (P < 0.01), diastolic blood pressure (P = 0.04), C-reactive protein (P < 0.01), and number of functional limitations (P < 0.01) after adjustment for SB. CONCLUSIONS The results suggest that sufficient MVPA did not ameliorate the negative associations between SB and cardiometabolic risk factors or functional limitations in the current sample and that there was independence on a multiplicative scale in their associations with the outcomes examined. Thus, older adults may benefit from the joint prescription to accumulate adequate MVPA and avoid prolonged sitting.

Physical activity and cancer prevention : pathways and targets for intervention.

The prevalence of obesity, an established epidemiological risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Modulation of energy balance, via increased physical activity, has been shown in numerous comprehensive epidemiological reviews to reduce cancer risk. Unfortunately, the effects and mechanistic targets of physical activity interventions on the carcinogenesis process have not been thoroughly characterized.Studies to date suggest that exercise can exert its cancer-preventive effects at many stages during the process of carcinogenesis, including both tumour initiation and progression. As discussed in this review, exercise may be altering tumour initiation events by modifying carcinogen activation, specifically by enhancing the cytochrome P450 system and by enhancing selective enzymes in the carcinogen detoxification pathway, including, but not limited to, glutathione-S-transferases. Furthermore, exercise may reduce oxidative damage by increasing a variety of anti-oxidant enzymes, enhancing DNA repair systems and improving intracellular protein repair systems.In addition to altering processes related to tumour initiation, exercise may also exert a cancer-preventive effect by dampening the processes involved in the promotion and progression stages of carcinogenesis, including scavenging reactive oxygen species (ROS); altering cell proliferation, apoptosis and differentiation; decreasing inflammation; enhancing immune function; and suppressing angiogenesis. A paucity of data exists as to whether exercise may be working as an anti-promotion strategy via altering ROS in initiated or preneoplastic models; therefore, no conclusions can be made about this possible mechanism. The studies directly examining cell proliferation and apoptosis have shown that exercise can enhance both processes, which is difficult to interpret in the context of carcinogenesis. Studies examining the relationship between exercise and chronic inflammation suggest that exercise may reduce pro-inflammatory mediators and reduce the state of low-grade, chronic inflammation. Additionally, exercise has been shown to enhance components of the innate immune response (i.e. macrophage and natural killer cell function). Finally, only a limited number of studies have explored the relationship between exercise and angiogenesis; therefore, no conclusions can be made currently about the role of exercise in the angiogenesis process as it relates to tumour progression.In summary, exercise can alter biological processes that contribute to both antiinitiation and anti-progression events in the carcinogenesis process. However, more sophisticated, detailed studies are needed to examine each of the potential mechanisms contributing to an exercise-induced decrease in carcinogenesis in order to determine the minimum dose, duration and frequency of exercise needed to yield significant cancer-preventive effects, and whether exercise can be used prescriptively to reverse the obesity-induced physiological changes that increase cancer risk.

Comparative Validity of Physical Activity Measures in Older Adults

PURPOSE To compare the validity of various physical activity measures with doubly labeled water (DLW)-measured physical activity energy expenditure (PAEE) in free-living older adults. METHODS Fifty-six adults aged ≥65 yr wore three activity monitors (New Lifestyles pedometer, ActiGraph accelerometer, and a SenseWear (SW) armband) during a 10-d free-living period and completed three different surveys (Yale Physical Activity Survey (YPAS), Community Health Activities Model Program for Seniors (CHAMPS), and a modified Physical Activity Scale for the Elderly (modPASE)). Total energy expenditure was measured using DLW, resting metabolic rate was measured with indirect calorimetry, the thermic effect of food was estimated, and from these, estimates of PAEE were calculated. The degree of linear association between the various measures and PAEE was assessed, as were differences in group PAEE, when estimable by a given measure. RESULTS All three monitors were significantly correlated with PAEE (r=0.48-0.60, P<0.001). Of the questionnaires, only CHAMPS was significantly correlated with PAEE (r=0.28, P=0.04). Statistical comparison of the correlations suggested that the monitors were superior to YPAS and modPASE. Mean squared errors for all correlations were high, and the median PAEE from the different tools was significantly different from DLW for all but the YPAS and regression-estimated PAEE from the ActiGraph. CONCLUSIONS Objective devices more appropriately rank PAEE than self-reported instruments in older adults, but absolute estimates of PAEE are not accurate. Given the cost differential and ease of use, pedometers seem most useful in this population when ranking by physical activity level is adequate.

Diabetes, Hyperglycemia, and Inflammation in Older Individuals The Health, Aging and Body Composition study

OBJECTIVE—The objective of this study was to assess the association of inflammation with hyperglycemia (impaired fasting glucose [IFG]/impaired glucose tolerance [IGT]) and diabetes in older individuals. RESEARCH DESIGN AND METHODS—Baseline data from the Health, Aging and Body Composition study included 3,075 well-functioning black and white participants, aged 70–79 years. RESULTS—Of the participants, 24% had diabetes and 29% had IFG/IGT at baseline. C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels (P < 0.001) were significantly higher among diabetic participants and those with IFG/IGT. Odds of elevated IL-6 and TNF-α (>75th percentile) were, respectively, 1.95 (95% CI 1.56–2.44) and 1.88 (1.51–2.35) for diabetic participants and 1.51 (1.21–1.87) and 1.14 (0.92–1.42) for those with IFG/IGT after adjustment for age, sex, race, smoking, alcohol intake, education, and study site. Odds ratios for elevated CRP were 2.90 (2.13–3.95) and 1.45 (1.03–2.04) for diabetic women and men and 1.33 (1.07–1.69) for those with IFG/IGT regardless of sex. After adjustment for obesity, fat distribution, and inflammation-related conditions, IL-6 remained significantly related to both diabetes and IFG/IGT. CRP in women and TNF-α in both sexes were significantly related to diabetes, respectively, whereas risk estimates for IFG/IGT were decreased by adjustment for adiposity. Among diabetic participants, higher levels of HbA1c were associated with higher levels of all three markers of inflammation, but only CRP remained significant after full adjustment. CONCLUSIONS—Our findings show that dysglycemia is associated with inflammation, and this relationship, although consistent in diabetic individuals, also extends to those with IFG/IGT.

Reducing the weight of cancer: mechanistic targets for breaking the obesity–carcinogenesis link

The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the US. The increasing rates of obesity among children are especially alarming and suggest continuing increases in the rates of obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects on the carcinogenesis process and mechanistic targets of interventions that modulate energy balance, such as reduced-calorie diets and physical activity, have not been well characterized. The purpose of this review is to provide a strong foundation for the translation of mechanism-based research in this area by describing key animal and human studies of energy balance modulations involving diet or physical activity and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention is placed on signaling through the insulin and insulin-like growth factor-1 receptors, including components of the Akt and mammalian target of rapamycin (mTOR) signaling pathways downstream of these growth factor receptors. These pathways have emerged as potential targets for disrupting the obesity-cancer link. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.

Are Women with Fibromyalgia Less Physically Active than Healthy Women

PURPOSE The primary purpose was to quantify and compare physical activity in fibromyalgia (FM) patients to age-matched healthy controls using both objective and self-report measures. Secondary purposes were to compare self-reported and objective measurement of physical activity and to evaluate the relationship between physical activity and pain and mood. METHOD Patients with FM (n=39) and healthy controls (n=40) completed the International Physical Activity Questionnaire and wore an accelerometer at the hip for 7 d. Pain and mood were measured using the McGill Pain Questionnaire, Pain Catastrophizing Scale, Beck Depression Inventory, State-Trait Anxiety Inventory, Profile of Mood States, and Fibromyalgia Impact Questionnaire. RESULTS FM patients had significantly lower physical activity than controls measured by both the International Physical Activity Questionnaire and accelerometer (P<0.05). Both groups self-reported significantly greater moderate and vigorous physical activities than were measured by the accelerometer (P < 0.05). Self-reported and objective measures of time spent in different intensities of activity showed significant correlations in healthy controls (r=0.41-0.51, ρ=0.41, P<0.05). No significant correlations between measures were found in FM patients (P>0.05). Finally, physical activity levels were negatively related (r=-0.37, P<0.05) to depressed mood for FM patients and positively related (r=-0.41, P<0.05) to self-reported vigor for healthy controls. CONCLUSIONS This controlled study objectively demonstrates that FM patients are less physically active than healthy controls, thus extending on two earlier investigations that did not show differences in total physical activity levels using wrist-mounted actigraphy methods. Physical activity levels were not predictive of pain in FM but were significantly related to depressed mood. FM patients may also have a greater variability in their manner of self-report than healthy controls. Therefore, physical activity measurement in FM patients should not be limited solely to self-report measures.