Designing pharmaceutical trials for sarcopenia in frail older adults: EU/US Task Force recommendations.

An international task force of academic and industry leaders in sarcopenia research met on December 5, 2012 in Orlando, Florida to develop guidelines for designing and executing randomized clinical trials of sarcopenia treatments. The Task Force reviewed results from previous trials in related disease areas to extract lessons relevant to future sarcopenia trials, including practical issues regarding the design and conduct of trials in elderly populations, the definition of appropriate target populations, and the selection of screening tools, outcome measures, and biomarkers. They discussed regulatory issues, the challenges posed by trials of different types of interventions, and the need for standardization and harmonization. The Task Force concluded with recommendations for advancing the field toward better clinical trials.

Genome-wide linkage scan for quantitative trait loci underlying normal variation in heel bone ultrasound measures.

Quantitative ultrasound (QUS) traits are correlated with bone mineral density (BMD), but predict risk for future fracture independent of BMD. Only a few studies, however, have sought to identify specific genes influencing calcaneal QUS measures. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing normal variation in QUS traits. QUS measures were collected from a total of 719 individuals (336 males and 383 females) from the Fels Longitudinal Study who have been genotyped and have at least one set of QUS measurements. Participants ranged in age from 18.0 to 96.6 years and were distributed across 110 nuclear and extended families. Using the Sahara ® bone sonometer, broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (QUI) were collected from the right heel. Variance components based linkage analysis was performed on the three traits using 400 polymorphic short tandem repeat (STR) markers spaced approximately 10 cM apart across the autosomes to identify QTL influencing the QUS traits. Age, sex, and other significant covariates were simultaneously adjusted. Heritability estimates (h²) for the QUS traits ranged from 0.42 to 0.57. Significant evidence for a QTL influencing BUA was found on chromosome 11p15 near marker D11S902 (LOD = 3.11). Our results provide additional evidence for a QTL on chromosome 11p that harbors a potential candidate gene(s) related to BUA and bone metabolism.

A systematic review of the literature concerning the relationship between obesity and mortality in the elderly.

INTRODUCTION: Obesity is a risk factor for chronic diseases and premature mortality, but the extent of these associations among the elderly is under debate. The aim of this systematic literature review (SR) is to collate and critically assess the available information of the impact of obesity on mortality in the elderly. METHODS: In PubMed, there are three-hundred twelve papers on the relationship between obesity and mortality among older adults. These papers were analysed on the basis of their abstracts, and sixteen studies were considered suitable for the purpose of the study. It was possible to perform a pooled estimate for aggregated data in three different studies. CONCLUSION: The results of this SR document that an increased mortality in obese older adults. The limitation of BMI to index obesity and the noted protective action of a moderate increase in BMI on mortality are highlighted. Waist circumference is an indicator of central adiposity and potentially as good a risk factor for mortality as BMI in obese elderly adults.

Sarcopenia: designing phase IIB trials.

Sarcopenia is the age-related involuntary loss of skeletal muscle mass and functionality that can lead to the development of disability, frailty and increased health care costs. The development of interventions aimed at preventing and/or treating sarcopenia is complex, requiring the adoption of assumptions and standards that are not well established scientifically or clinically. A number of investigators and clinicians (both from academia and industry) met in Rome (Italy) in 2009 to develop a consensus definition of sarcopenia. Subsequently, in Albuquerque (New Mexico, USA) in 2010, the same group met again to consider the complex issues necessary for designing Phase II clinical trials for sarcopenia. Current clinical trial data indicate that fat-free mass (FFM) parameters are responsive to physical activity/nutritional treatment modalities over short time periods, but pharmacological trials of sarcopenia have yet to show significant efficacy. In order to conduct a clinical trial within a reasonable time frame, groups that model or display accelerated aging and loss of FFM are necessary. Few studies have used acceptable designs for testing treatment effects, sample sizes or primary outcomes that could provide interpretable findings or effects across studies. Dual energy x-ray absorptiometry (DXA) is the measure of choice for assessing FFM, but sufficient time is needed for changes to be detected accurately and reliably. A tool set that would allow clinical, basic and epidemiological research on sarcopenia to advance rapidly toward diagnosis and treatment phases should be those reflecting function and strength.

The first seriatim study into old age for weight, stature and BMI: the Fels Longitudinal Study.

PURPOSE: To document the serial status of measures of weight, stature and BMI from birth into old age. METHODS: Longitudinal measures of weight, stature and BMI were taken from birth to 76 years of age for 5 men and 7 women as part of the Fels Longitudinal Study. RESULTS: Sex-specific plots of means for weight, stature and BMI are presented that describe the changes and sex differences in these measurements between birth (or the first year of life) into old age. These serial data demonstrate a continuous increase in body weight through much of adulthood and a small decline in stature starting in late middle age. The plots for BMI indicate the early onset of overweight and subsequent obesity early in adulthood and its continuance into old age for men and women. CONCLUSIONS: These are the first plots of serial means for weight, stature and BMI measured from the same group of individuals from birth into old age. These findings demonstrate the changes in these measurements through childhood and maturity into old age. Similar data are needed for individuals from other racial/ethnic groups and countries in order to understand the aging process better.

A review of body water status and the effects of age and body fatness in children and adults.

BACKGROUND: Most investigations of TBW, ECW and body composition and reports of their intra-body relationships were published prior to 1980. Distributional TBW and ECW relationships within the body have been considered fixed, but there was evidence these relationships were affected by the level of fatness. Body composition models based on past findings and assumptions could produce inaccurate estimates when the majority of the population is overweight to obese. METHODS: TBW and ECW volumes, their proportions of body weight, FFM and percent body fat and associations with age are considered in U.S. children and adults. This review focuses on studies reporting measured body water volumes from large samples except for the national predicted values from NHANES III. RESULTS: Measured TBW volumes for children and adults are almost exclusively from whites with the exception of the estimated values from NHANES III for non-Hispanic black and Mexican-Americans. Mean adult TBW volumes are as much as 9 liters greater than those reported prior to 1980. Low mean percentages of TBW%WT reflect the greater level of adiposity in children and adults, and this level of adiposity affects the value of TBW% FFM. Mean ECW volumes for white adults are 10 to 12 liters larger than those reported previously. With greater fatness in adults, ECW%TBW has increased to near 60%, and this implies that a calculation of FFM based on 73% and an ECW%TBW of 25-45% could produce an overestimation but more important clinically an underestimation of body fatness. CONCLUSION: There is inadequate timely information on measured total and extra-cellular water volumes for the population. Available data indicate a coincident increase in body water with overweight and obesity, and a shifting in the proportion of ECW in TBW. Clinical and pharmacological treatments based upon past assumptions of body water volumes, proportions and relationships could produce inaccurate estimates.

Quantitative genetic analysis of cellular adhesion molecules: the Fels Longitudinal Study.

Circulating concentrations of inflammatory markers predict cardiovascular disease (CVD) risk and are closely associated with obesity. However, little is known concerning genetic influences on serum levels of inflammatory markers. In this study, we estimated the heritability (h2) of soluble cellular adhesion molecule (sCAM) concentrations and examined the correlational architecture between different sCAMs. The study population included 234 men and 270 women aged 18-76 years, belonging to 121 families participating in the Fels Longitudinal Study. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sESEL-1) and P-selectin (sPSEL-1) were assayed using commercially available kits. A variance components-based maximum likelihood method was used to estimate the h2 of the different serum inflammatory markers while simultaneously adjusting for the effects of known CVD risk factors, such as age and smoking. Additionally, we used bivariate extensions of these methods to estimate genetic and random environmental correlations among sCAMs. Levels of sCAMs were significantly heritable: h2=0.24+/-0.10 for sICAM-1, h2=0.22+/-0.10 for sVCAM-1, h2=0.50+/-0.11 for sESEL-1, and h2=0.46+/-0.10 for sPSEL-1. In addition, a significant genetic correlation (rho(G)=0.63) was found between sICAM-1 and sVCAM-1 indicating some degree of shared genetic control. In the Fels Longitudinal Study, the levels of four sCAMs are significantly influenced by genetic effects, and sICAM-1 shares a common genetic background with sVCAM-1.

Cumulative effects of cardiovascular disease risk factors on quality of life.

OBJECTIVES: The Medical Outcomes Study Short-Form Health Survey (SF-36) was used to assess the quality of life for adults who differed in level of risk for cardiovascular disease. METHODS: Subjects were 51 men and 80 women from southwestern Ohio between the ages of 20 and 86 years. Individuals level of risk was based on the culmination of four cardiovascular disease risk factors: hypertension (i.e., systolic BP>or=140 mmHg or diastolic BP>or= 90 mmHg), obesity (i.e., BMI>or=30), high cholesterol (i.e., total cholesterol>or=240 mg/dL), and presence/absence of smoking. RESULTS: Each risk factor was analyzed independently and cumulatively for effects on the SF-36 dimensions (i.e., Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, Mental Health). The data suggested that quality of life impairment (indicated by lower scores on the SF-36 dimensions) increased as the number of cardiovascular disease risk factors an individual had increased. CONCLUSIONS: Cardiovascular disease risk factors unknown to the participants had differential effects on the SF-36 dimensions, and quality of life decreased as the number of risk factors individuals had increased.

Maturity and its relationship to plasma lipid and lipoprotein levels in adolescents: The Fels longitudinal study.

During adolescence, changes in lipid and lipoprotein levels have been reported to be associated with changes in body composition and changes in endogenous testosterone and estradiol. These hormone levels are directly correlated with sexual and skeletal maturity levels. The purpose of the present study was to determine if there are associations during pubescence and adolescence, independent of chronological age, between measures of maturity and body composition or plasma lipid and lipoprotein cholesterols. Skeletal maturity was measured on the basis of skeletal assessments of the bones of the knee joint. Age at peak height velocity was determined from serial stature measurements and, in girls, age at menarche was recorded. These measures of maturity, as well as measures of percent body fat, total body fat, total body fat mass, fat-free mass from underwater weighing, and plasma cholesterol, triglyceride, highdensity lipoprotein-cholesterol, and low-density lipoprotein-cholesterol levels from 502 observations on 174 boys and girls enrolled in the Fels Longitudinal Study were used in the analysis. Within annual chronological age groups, no associations were found between level of maturity and lipid and lipoprotein level or percent body fat in boys or girls. However, changes in lipid and lipoprotein levels over time appeared to be more apparent when age grouping were based on skeletal age than when they were based on chronological age.