Faculty Bibliography

OBJECTIVE: With aging, kidney function declines, as evidenced by reduced glomerular filtration rate. It is controversial whether or not high protein intake accelerates this decline. The aim of this study was to determine whether high protein intake was associated with declines in kidney function among older patients. METHODS: We examined whether dietary protein is associated with change in kidney function (mean follow-up 6.4 y [SD = 1.4, range = 2.5-7.9] in the Cardiovascular Health Study (N = 3623). We estimated protein intake using a food frequency questionnaire and estimated glomerular filtration rate from cystatin C. Associations between protein intake and kidney function were determined by linear and logistic regression models. RESULTS: Average protein intake was 19% of energy intake (SD = 5%). Twenty-seven percent (n = 963) of study participants had rapid decline in kidney function, as defined by (DeltaeGFRcysC > 3 mL*min*1.73 m(2)). Protein intake (characterized as g/d and % energy/d), was not associated with change in estimated glomerular filtration rate (P > 0.05 for all comparisons). There were also no significant associations when protein intake was separated by source (animal and vegetable). CONCLUSION: These data suggest that higher protein intake does not have a major effect on kidney function decline among elderly men and women.

BACKGROUND: The effects of dietary protein on bone health are controversial. OBJECTIVE: We examined the relation between protein intake with fracture and bone mineral density (BMD) within the Women's Health Initiative (WHI). DESIGN: This prospective analysis included 144,580 women aged 50-79 y at baseline in the WHI clinical trials (CTs) and observational study (OS) that recruited participants in 1993-1998 with follow-up through 2011. Self-reported clinical fractures were collected semiannually through the original end of the trials (WHI CTs) and annually (WHI OS) by questionnaires. Hip fracture was adjudicated by a central review of radiology reports. BMDs for total body, hip, and spine were measured at baseline and 3 and 6 y in 9062 women at 3 WHI clinics by using dual-energy X-ray absorptiometry. Protein intake was assessed via food-frequency questionnaire and calibrated by using biomarkers of energy and protein intakes. Associations between protein intake and fracture were estimated by using Cox proportional hazards regression, and the relation between protein intake and BMD was estimated by using linear regression. RESULTS: Median biomarker-calibrated protein intake was 15% of energy intake. Per 20% increase in calibrated protein intake (percentage of energy), there was no significant association with total fracture (HR: 0.99; 95% CI: 0.97, 1.02) or hip fracture (HR: 0.91; 95% CI: 0.84, 1.00), but there was an inverse association with forearm fracture (HR: 0.93; 95% CI: 0.88, 0.98). Each 20% increase in calibrated protein intake was associated with a significantly higher BMD for total body (mean 3-y change: 0.003 g/cm(2); 95% CI: 0.001, 0.005 g/cm(2)) and hip (mean 3-y change: 0.002 g/cm(2); 95% CI: 0.001, 0.004 g/cm(2)). CONCLUSIONS: Higher biomarker-calibrated protein intake within the range of usual intake was inversely associated with forearm fracture and was associated with better maintenance of total and hip BMDs. These data suggest higher protein intake is not detrimental to bone health in postmenopausal women.

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.