Healthy Aging Lab: Current Research Abstracts

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1 Healthy Aging Lab: Current Research Abstracts Arsenic Exposure and Women s Health Environmental exposure to inorganic arsenic is an indisputable source of increased risk of several human cancers and chronic diseases such as atherosclerosis and diabetes. Despite a lack of clear understanding of arsenic-induced toxicity, arsenic has multiple adverse effects including an increase in inflammatory markers. There is an intriguing parallel between the chronic inflammatory component recognized to contribute to diseases such as atherosclerosis and diabetes, and the increased risk for other chronic diseases such as sarcopenia (low skeletal muscle mass), high breast cancer risk (higher mammographic density), and osteoporosis (low bone density) in women. The primary aim of this study is to examine whether women who have higher arsenic exposures also have suboptimal body composition, sarcopenia. Secondarily, we will assess whether genes in the arsenic metabolic pathway modify the relationship between arsenic exposure and low skeletal muscle mass. Finally, we will explore the possibility that inflammatory factors are mediators of the relationship between arsenic exposure and sarcopenia. In addition, associations of the urinary arsenic concentration with osteoporosis and breast cancer risk will be examined and potential mechanisms for these associations will be explored using a similar approach in the study of sarcopenia. Participants in this study are women who were enrolled in a cross-sectional study called the Women s Breast and Bone Density Study and conducted by Dr. Zhao Chen. The age range was 41 to 70 and all women were recruited from southern Arizona. Their body composition, breast density and bone density have already been measured and the data are in a de-identified database. In this pilot study, we are planning to analyze 200 archived urine samples to investigate the association between urinary arsenic and metabolite levels and multiple health indicators in women, and how genetic variation might modify those relationships. Selected SNPs in arsenic metabolic pathways (AS3MT, MTHFR) will be analyzed using archived DNA. Selected inflammatory markers (CRP, IL-6sR, IL-1 RA) will be measured using serum specimens. Multiple linear regression analysis with interaction terms will be conducted to investigate associations between exposures and outcomes. Mediating effects for these associations will be assessed by comparing regression models with and without the mediators.

2 Biomarkers and Genetic Factors Related to Sarcopenia in Older Women Low relative skeletal muscle mass (SMM) or sarcopenia significantly contributes to the decline in physical functioning among the elderly. Very little is known about genetic risk factors and their interactions with environmental factors in aging-related SMM loss. There are some indications that inflammatory factors and reduced levels of anabolic hormones are associated with lower muscle mass. These associations need to be confirmed in larger prospective studies and the exact role of each identified biomarker in the development of sarcopenia remains to be investigated. Since physical function impairment and disability are more prevalent in women than in men during their later life, it is especially important to understand the mechanisms of muscle loss and to prevent sarcopenia among older women. The primary objective of this study is to investigate biological mechanisms for sarcopenia by identifying genetic factors and biomarkers that are relevant to low SMM and high rates of SMM loss in older women. We will achieve two specific aims: 1) assess the association of cytokines and hormonal factors with low SMM and the rate of SMM loss; and 2) evaluate the role of genetic variation in catabolic inflammatory cytokines (IL-6, IL-1, TNF-alpha) as well as in anabolic growth factors (IGF1, GH) related to SMM and the rate of SMM loss in ethnicitymatched postmenopausal women. Study participants will come from the Women s Health Initiative Observational Study. All these women have had repeat body composition measurements by using Dual-energy X-ray Absorptiometry (DXA) during the nine-year follow-up. Their SMM will be assessed using a DXA-derived method developed by this research team. Genetic variations in selected catabolic (e.g.il-1, IL6, TNF-a) as well as anabolic (e.g. IGF-1, and GH) factors will be assessed for the entire sample (n = 2800). Analyses of biomarkers, including IL-1a, IL-1b, IL-6, IL-10, TNF-a, TNF-b, Growth Hormone, Insulin, Leptin, C-reactive protein, IL-1ra, IL- 6sR, TNF RII, IGF-1, IGFBP-1 and IGFBP-3, will be conducted among 50% of the participants in this study. Logistic regressions and mixed effect models will be used in the final data analysis. This study is unique and innovative in the study design, selection of bioassays, and the study population. Results of this study may help us to identify high-risk groups for sarcopenia and to develop targeted therapy and preventions to reduce SMM loss and risk of sarcopenia among older women in the US.

3 Anemia and Its Relationship With Sarcopenia, Physical Function, and Mortality Anemia is a common health problem in US older populations; and it increases the risk for disability, decline in physical performance, low muscle strength, and premature death in the elderly. A recent study from NHANES III reported the prevalence of anemia being larger than 10% in the US population over age 65, and the prevalence of anemia varied by ethnicity, suggesting significant health disparities in minorities, especially in the African American population. In this study, a large (N >160,000) multiethnic (non-hispanic white, Hispanic, African American, Native American, Asian/Pacific Islander) cohort from the nationwide Women s Health Initiative (WHI) study will be used to investigate the relationships of aging with anemia epidemiology, pathology and prognosis. Specifically, we will 1) evaluate the frequency of and risk factors for anemia overall and according to race-ethnicity and co-morbidity; 2) determine the association between anemia and risk of death over 10 years of follow-up in the WHI overall and by race-ethnicity; 3) determine associations between anemia and changes in physical function over 9 years of followup in the WHI cohort overall and by race-ethnicity; 4) examine associations of anemia with muscle loss (sarcopenia) among those with baseline and prospective measurements of body composition from dualenergy x-ray absorptiometry; and 5) study the association of anemia with bone loss and risk for osteoporotic fractures in older women. In addition, the frequency of anemia subtypes by morphologic categories and optimal cutoff points of hemoglobin concentrations for anemia in older women will be evaluated. This study will use archived observational and clinical trial data from 40 WHI clinical centers. Additional data entering for blood analysis from existing reports, and data merging (body composition measurements) will be conducted in the WHI DXA cohort from Arizona, Birmingham and Pittsburgh. Multivariate data analyses will be conducted for the specific aims. The WHI provides a unique and invaluable resource for answering the research questions proposed above, as the WHI is the only study in the nation that has prospective co-morbidities and body composition data as well as hemoglobin values in multiethnic groups of older women. This study has a great potential to provide new and critical evidence that is needed for preventing and managing anemia in older women from different health, age and ethnic backgrounds.

4 Longitudinal Changes in Hip Geometry and Skeletal Muscle This study will be conducted among a large multiethnic cohort (N = 11,432) from the nationwide Women's Health Initiative (WHI), which includes an observational study and three clinic trials. The age range of this cohort is between years at the baseline, and it has multiple minority groups: 1583 black, 739 Hispanic and 149 Native American women. The maximal follow-up time of this cohort will be 9 years by Dual-energy x-ray absorptiometry (DXA) is used to measure bone mineral density (BMD) and body composition. The randomized clinical trials and longitudinal nature of the WHI study provide a unique opportunity to investigate: 1) treatment effects of hormone replacement therapy (HRT) and calcium and vitamin D supplementation on hip structural geometry; 2) longitudinal changes in skeletal muscle mass as a factor in hip fragility; and 3) ethnic differences of mean and rates of changes in hip geometry and muscle mass. Special computer software will be used for analyzing hip scans by dual-energy x-ray absorptiometry (DXA). Cross-sectional area, subperiosteal width, estimated endocortical diameter, estimated mean cortical thickness, buckling ratio and section modulus at the femoral neck, at the intertrochanteric and the femoral shaft regions will be assessed. MRI scans will be used as references to calibrate total, appendicular and leg skeletal muscle measurements from DXA subregion analyses. Prevalence rates of sarcopenia (low muscle mass) among each age and ethnic group will be studied. Random Effects Models will be used to analyze the longitudinal data. This proposed study is not funded by the WHI program. Recourses that the WHI will provide include DXA scans, fall and fracture data, and information on covariates. Since the majority of data collection work has been or will be done by the WHI, we will be able to cost-effectively test multiple important scientific hypotheses in this study. The novel approaches in this ancillary study will enhance scientific contributions of the WHI program. The significance of the proposed study is that it may demonstrate the utility of bone structural analysis in addition to bone mass measurements for understanding ethnic differences in fracture risk and/or for assessing the effect of pharmacologic therapy (i.e. HRT) on bone health. Furthermore, if the muscle variables are found to be a strong determinant of bone structure in the proximal femur and the risk of fall, then it may be important to develop interventions to increase muscle mass in this region to prevent hip fracture.

5 Women s Breast and Bone Density Study The primary aim of this study is to examine relationship between the risk of breast cancer and the risk of osteoporosis among non-hispanic and Hispanic white women. Secondly, we will study whether obesity has an effect on mammographic density. In addition, we will explore what factors may alter or modify the relationship between the risk of breast cancer and the risk of osteoporosis. In the proposed cross-sectional study, 150 premenopausal women between the ages of and 150 postmenopausal women between the ages of will be recruited. The participants will be either Non-Hispanic or Hispanic white women who reside in the Tucson metropolitan area. The proportion of Hispanic women will be 50% in both the pre- and the postmenopausal groups. Premenopausal will be defined as women who have had regular menses over the past year. Women have had a hysterectomy or have not had a menstrual cycle for at least one year will be considered postmenopausal if their FSH level is more than 40 miu/1. Participants will be recruited from mammography centers and the local Tucson metropolitan area. Mammographic breast density, bone mineral density, body composition and anthropometric measurements will be assessed on all the participants. The participant's most recent mammogram (within 4 months at the time of bone mineral density test) will be used for the mammographic breast density analysis. Bone density and body composition will be measured by dual-energy x-ray absorptiometry (DXA) with a very low dose of radiation exposure to the subjects. A 12-hour fasting blood (40 ml) will be drawn for FSH analysis on postmenopausal women and stored for hormonal analysis among all participants in the future. An overnight or first morning urine sample will be collected from all the participants for metabolic analysis in the future. Questionnaires will be used to collect information on medical history, family history, dietary intake, physical activity, reproductive history and other lifestyle factors. Statistical analysis will be conducted.

6 Ethnicity, Body Composition, Bone Density, and Breast Cancer Recently two studies reported a strong association between high bone mass and increased risk of breast cancer. This result raised new questions in decision-making for HRT and suggests a potential use of bone mass as an indicator of lifetime estrogen for assessing the risk of breast cancer. Additional studies should be conducted in different ethnic groups, because there significant ethnic variation in frequencies, distributions and severity levels of both osteoporosis and breast cancer. Given the fact that the bone mineral density (BMD) is higher, but the rate of breast cancer in lower in Hispanic older women compared with Anglo women, the Hispanic postmenopausal women will be a very interesting model to further evaluate this interrelationship between breast cancer and bone mass. To date, most of our knowledge of risk factor of osteoporosis and breast cancer are mainly based on results from Anglo women. It is critical to examine those risk factors in the Hispanic women population in order to form specific prevention strategies for this population. The women s Health Initiative (WHI) provided a unique opportunity to undertake nested casecontrol studies (NCCS) to further examine these issues in different ethnic groups. The number of Hispanic women in the WHI BMD study cohorts is small (Nexpected = 800) and the breast cancer rate is lower in Hispanic women compared with Anglo. Therefore within the WHI there will not be a sufficient number of breast cancer cases to form a NCCS in Hispanic women. The proposed study is a case control research design. The controls will be chosen from Hispanic participants of the Arizona WHI observation study group. No additional data will be collected from the controls. The cases (N=140). Will be newly diagnosed Hispanic and White postmenopausal breast cancer patients in Arizona (obtained through collaborative oncologists and surgeons). The measurement will include anthropometry, body composition, BMD, peripheral white blood cells and WHI questionnaires. The interrelationship between BMD and breast cancer will be evaluated using logistic regression analysis.