Faculty Bibliography

It is well established that protein-energy malnutrition decreases serum insulin-like growth factor (IGF)-I levels, and supplementation of 30 g of whey protein daily has been shown to increase serum IGF-I levels by 8 % after 2 years in a clinical trial. Cohort studies provide the opportunity to assess associations between dietary protein intake and IGF axis protein levels under more typical eating conditions. In the present study, we assessed the associations of circulating IGF axis protein levels (ELISA, Diagnostic Systems Laboratories) with total biomarker-calibrated protein intake, as well as with dairy product and milk intake, among postmenopausal women enrolled in the Women's Health Initiative (n 747). Analyses were carried out using multivariate linear regression models that adjusted for age, BMI, race/ethnicity, education, biomarker-calibrated energy intake, alcohol intake, smoking, physical activity and hormone therapy use. There was a positive association between milk intake and free IGF-I levels. A three-serving increase in milk intake per d (approximately 30 g of protein) was associated with an estimated average 18.6 % higher increase in free IGF-I levels (95 % CI 0.9, 39.3 %). However, total IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were not associated with milk consumption and nor were there associations between biomarker-calibrated protein intake, biomarker-calibrated energy intake, and free IGF-I, total IGF-I or IGFBP-3 levels. The findings of the present study carried out in postmenopausal women are consistent with clinical trial data suggesting a specific relationship between milk consumption and serum IGF-I levels, although in the present study this association was only statistically significant for free, but not total, IGF-I or IGFBP-3 levels.

Regression calibration using biomarkers provides an attractive approach to strengthening nutritional epidemiology. We consider this approach to assessing the relationship of fat and total energy consumption with postmenopausal breast cancer. In analyses that included fat density data, biomarker-calibrated total energy was positively associated with postmenopausal breast cancer incidence in cohorts of the US Women's Health Initiative from 1994-2010. The estimated hazard ratio for a 20% increment in calibrated food frequency questionnaire (FFQ) energy was 1.22 (95% confidence interval (CI): 1.15, 1.30). This association was not evident without biomarker calibration, and it ceased to be apparent following control for body mass index (weight (kg)/height (m)(2)), suggesting that the association is mediated by body fat deposition over time. The hazard ratio for a corresponding 40% increment in FFQ fat density was 1.05 (95% CI: 1.00, 1.09). A stronger fat density association, with a hazard ratio of 1.19 (95% CI: 1.00, 1.41), emerged from analyses that used 4-day food records for dietary assessment. FFQ-based analyses were also carried out by using a second dietary assessment in place of the biomarker for calibration. This type of calibration did not correct for systematic bias in energy assessment, but may be able to accommodate the "noise" component of dietary measurement error. Implications for epidemiologic applications more generally are described.

Sarcopenia is defined as an age-related decrease in muscle mass and performance. Several consensus definitions of sarcopenia exist, each providing different cut points and methodologies for assessing muscle mass and muscle strength. Thus, wide variation in the prevalence of sarcopenia has been reported, generally ranging up to 45% for men and 26% for women. Risk factors for sarcopenia include age, malnutrition, and physical inactivity. Additional evidence suggests a protective role for protein supplementation in older adults to preserve lean body mass and prevent frailty, accepted intervention targets for reducing the risk of sarcopenia. Protein supplements vary widely in their composition, and small trials of heterogeneous study designs have made it difficult to extrapolate findings to develop data-driven, evidence-based recommendations for protein supplementation in sarcopenia prevention. Short-term randomized controlled trials of muscle protein synthesis have demonstrated that whey protein increases synthesis more so than casein or soy isolates. Studies also suggest that essential amino acids stimulate muscle protein synthesis to a greater extent than nonessential amino acids. This review summarizes the epidemiological and clinical trial evidence establishing the current definitions for sarcopenia and provides an overview of the state of the evidence for protein supplementation to prevent and/or mitigate sarcopenia.

OBJECTIVES: To determine whether preservation of physical function with aging may be partially met through modification in dietary protein intake. DESIGN: Prospective cohort study. SETTING: Women's Health Initiative (WHI) Clinical Trials (CT) and Observational Study (OS) conducted at 40 clinical centers. PARTICIPANTS: Women aged 50 to 79 (N = 134,961) with dietary data and one or more physical function measures. MEASUREMENTS: Physical function was assessed using the short-form RAND-36 at baseline and annually beginning in 2005 for all WHI participants and at closeout for CT participants (average ~7 years after baseline). In a subset of 5,346 participants, physical performance measures (grip strength, number of chair stands in 15 seconds, and timed 6-m walk) were assessed at baseline and Years 1, 3, and 6. Calibrated energy and protein intake were derived from regression equations using baseline food frequency questionnaire data collected on the entire cohort and doubly labeled water and 24-hour urinary nitrogen collected from a representative sample as reference measures. Associations between calibrated protein intake and each of the physical function measures were assessed using generalized estimating equations. RESULTS: Calibrated protein intake ranged from 6.6% to 22.3% energy. Higher calibrated protein intake at baseline was associated with higher self-reported physical function (quintile (Q)5, 85.6, 95% confidence interval (CI) = 81.9-87.5; Q1, 75.4, 95% CI = 73.2-78.5, P trend = .002) and a slower rate of functional decline (annualized change: Q5, -0.47, 95% CI = -0.63 to -0.39; Q1, -0.98, 95% CI = -1.18 to -0.75, P trend = .02). Women with higher calibrated protein intake also had greater grip strength at baseline (Q5, 24.7 kg, 95% CI = 24.3-25.2 kg; Q1, 24.1 kg, 95% CI = 23.6-24.5 kg, P trend = .04) and slower declines in grip strength (annualized change: Q5, -0.45 kg, 95% CI = -0.39 to -0.63 kg; Q1, -0.59 kg, 95% CI = -0.50 to -0.66 kg, P trend = .03). Women with higher calibrated protein intake also completed more chair stands at baseline (Q5, 7.11, 95% CI = 6.91-7.26; Q1, 6.61, 95% CI = 6.46-6.76, P trend = .002). CONCLUSION: Higher calibrated protein intake is associated with better physical function and performance and slower rates of decline in postmenopausal women.

Nonalcoholic fatty liver disease (NAFLD) is an emerging global health concern. It is the most common form of chronic liver disease in Western countries, affecting both adults and children. NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), and is strongly associated with obesity, insulin resistance, and dyslipidemia. First-line therapy for NAFLD includes weight loss achieved through diet and physical activity. However, there is a lack of evidenced-based dietary recommendations. The American Diabetes Association's (ADA) recommendations that aim to reduce the risk of diabetes and cardiovascular disease may also be applicable to the NAFLD population. The objectives of this review are to: (1) provide an overview of NAFLD in the context of insulin resistance, and (2) provide a rationale for applying relevant aspects of the ADA recommendations to the nutritional management of NAFLD.

Examining the role of dietary protein and establishing intake guidelines among individuals with diabetes is complex. The 2013 American Diabetes Association (ADA) standards of care recommend an individualized approach to decision making with regard to protein intake and dietary macronutrient composition. Needs may vary based on cardiometabolic risk factors and renal function. Among individuals with impaired renal function, the ADA recommends reducing protein intake to 0.8-1.0 g/kg per day in earlier stages of chronic kidney disease (CKD), and to 0.8 g/kg per day in the later stages of CKD. Epidemiological studies suggest animal protein may increase risk of diabetes; however, few data are available to suggest how protein sources influence diabetes complications.

PURPOSE: Higher physical activity (PA) has been associated with greater attenuation of body fat gain and preservation of lean mass across the lifespan. These analyses aimed to determine relationships of change in PA to changes in fat and lean body mass in a longitudinal prospective study of postmenopausal women. METHODS: Among 11,491 women enrolled at three Women's Health Initiative clinical centers who were selected to undergo dual-energy x-ray absorptiometry, 8352 had baseline body composition measurements, with at least one repeated measure at years 1, 3, and 6. PA data were obtained by self-report at baseline and 3 and 6 yr of follow-up. Time-varying PA effect on change in lean and fat mass during the 6-yr study period for age groups (50-59 yr, 60-69 yr, and 70-79 yr) was estimated using mixed effects linear regression. RESULTS: Baseline PA and body composition differed significantly among the three age groups. The association of change in fat mass from baseline and time-varying PA differed across the three age groups (P = 0.0006). In women age 50-59 yr, gain in fat mass from baseline was attenuated with higher levels of PA. Women age 70-79 yr lost fat mass at all PA levels. In contrast, change in lean mass from baseline and time-varying PA did not differ by age group (P = 0.1935). CONCLUSIONS: The association between PA and change in fat mass varies by age group, with younger, but not older, women benefiting from higher levels of aerobic PA. Higher levels of aerobic activity are not associated with changes in lean mass, which tends to decrease in older women regardless of activity level. Greater attention to resistance training exercises may be needed to prevent lean mass loss as women age.

BACKGROUND: To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living. METHODS: Data from Women's Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services). RESULTS: We identified a multidimensional phenotype of positive aging that included two factors: Physical-Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical-Social Functioning was the strongest predictor. Each standard deviation of increase in Physical-Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living. CONCLUSIONS: Physical-Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical-Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.

IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses' Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR](q5-q1) = 0.17 [95% CI 0.08-0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (OR(q5-q1) = 0.37 [0.18-0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (OR(q5-q1) = 2.05 [1.20-3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (OR(q5-q1) = 0.48 [0.26-0.90]; P trend = 0.0001) versus below the median (OR(q5-q1) = 2.52 [1.05-6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk.

Obese and underweight women who develop breast cancer may have poorer survival compared with normal-weight women. However, the optimal weight for best prognosis is still under study. We conducted a prospective investigation of pre-diagnosis body mass index (BMI) and mortality among 14,948 breast cancer patients in the After Breast Cancer Pooling Project. Breast cancer patients diagnosed from 1990 to 2006 with AJCC Stage I-III breast tumors were drawn from four prospective cohorts. Hazard ratios (HR) and 95% confidence intervals (CI) representing the associations of BMI categories (World Health Organization international classifications) with recurrence and mortality were estimated using delayed entry Cox proportional hazards models. Obese (30 to < 35 kg/m(2)), severely obese (35 to < 40 kg/m(2)), and morbidly obese (>/= 40 kg/m(2)) were examined. After a mean follow-up of 7.8 years, 2,140 deaths and 2,065 recurrences were documented. Both underweight (HR = 1.59; 95% CI: 1.18, 2.13) and morbidly obese women (HR = 1.81; 95% CI: 1.42, 2.32) had the greatest risk of overall mortality compared with normal weight (18.5-24.9 kg/m(2)) women. Severe obesity (HR = 1.09; 95% CI: 0.88, 1.36) and obesity (HR = 1.11; 95% CI: 0.97, 1.27) were related to small non-significant increased risks. Overweight (25.0-29.9 kg/m(2)) was not associated with any excess risk compared with normal weight. Similar associations were found for breast cancer death and non-breast cancer death but not recurrence. Women who were underweight and morbidly obese before breast cancer diagnosis were at the greatest risk of all-cause mortality. Morbidly obese women were also at increased risk of death from breast cancer. These results suggest that degree of obesity confers differential risk on survival.