Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial.

BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. FINDINGS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). INTERPRETATION: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. FUNDING: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.

Mitochondrial genetic variation and risk of chronic kidney disease and acute kidney injury in UK Biobank participants.

Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFRCr-CysC, N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m2. MtDNA haplotype was significantly associated with eGFR (p = 2.8E-12), but not with prevalent ESKD (p = 5.9E-2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E-10). When compared to the reference haplotype, mtDNA haplotypes I (ß = 0.402, standard error (SE) = 0.111; p = 2.7E-4), IV (ß = 0.430, SE = 0.073; p = 4.2E-9), and V (ß = 0.233, SE = 0.050; p = 2.7E-6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria.

Mean nocturnal respiratory rate predicts cardiovascular and all-cause mortality in community-dwelling older men and women.

Respiratory frequency (f R) predicts in-hospital and short-term mortality in patients with a variety of pathophysiological conditions, but its predictive value for long-term cardiovascular and all-cause mortality in the general population is unknown. Here, we investigated the relationship between mean nocturnal f R and mortality in community-dwelling older men and women.We measured mean nocturnal f R during sleep from overnight polysomnography in 2686 men participating in the Osteoporotic Fractures in Men Study (MrOS) Sleep study and 406 women participating in the Study of Osteoporotic Fractures (SOF) to investigate the relationship between mean nocturnal f R and long-term cardiovascular and all-cause mortality.166 (6.1%) men in the MrOS cohort (8.9±2.6 years' follow-up) and 46 (11.2%) women in the SOF cohort (6.4±1.6 years' follow-up) died from cardiovascular disease. All-cause mortality was 51.2% and 26.1% during 13.7±3.7 and 6.4±1.6 years' follow-up in the MrOS Sleep study and the SOF cohorts, respectively. Multivariable Cox regression analysis adjusted for significant covariates demonstrated that f R dichotomised at 16 breaths·min-1 was independently associated with cardiovascular mortality (MrOS: hazard ratio (HR) 1.57, 95% CI 1.14-2.15; p=0.005; SOF: HR 2.58, 95% CI 1.41-4.76; p=0.002) and all-cause mortality (MrOS: HR 1.18, 95% CI 1.04-1.32; p=0.007; SOF: HR 1.50, 95% CI 1.02-2.20; p=0.04).In community-dwelling older men and women, polysomnography-derived mean nocturnal f R ≥16 breaths·min-1 is an independent predictor of long-term cardiovascular and all-cause mortality. Whether nocturnal mean f R can be used as a risk marker warrants further prospective studies.

Determinants of Change in Objectively Assessed Sleep Duration Among Older Men.

We examined potential risk factors for changes in objectively assessed sleep duration within a large sample of community-dwelling older men. Participants (n = 1,055; mean baseline age = 74.6 (standard deviation (SD), 4.7) years) had repeated ActiGraph assessments (ActiGraph LLC, Pensacola, Florida) taken at the baseline (2003-2005) and follow-up (2009-2012) waves of the Outcomes of Sleep Disorders in Older Men Study (an ancillary study to the Osteoporotic Fractures in Men (MrOS) Study conducted in 6 US communities). Among men with a baseline nighttime sleep duration of 5-8 hours, we assessed the odds of becoming a short-duration (<5 hours) or long-duration (>8 hours) sleeper at follow-up. The odds of becoming a short-duration sleeper were higher among men with peripheral vascular disease (adjusted odds ratio (aOR) = 6.54, 95% confidence interval (CI): 2.30, 18.55) and ≥1 impairment in Instrumental Activities of Daily Living (IADL) (aOR = 2.57, 95% CI: 0.97, 6.78). The odds of becoming a long-duration sleeper were higher among those with greater baseline age (per SD increment, aOR = 1.49, 95% CI: 1.12, 2.00), depression symptoms (aOR = 3.13, 95% CI: 1.05, 9.36), and worse global cognitive performance (per SD increment of Modified Mini-Mental State Examination score, aOR = 0.74, 95% CI: 0.58, 0.94). Peripheral vascular disease and IADL impairment, but not chronological age, may be involved in the etiology of short sleep duration in older men. The risk factors for long-duration sleep suggest that deteriorating brain health predicts elongated sleep duration in older men.

Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels.

Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10(-12)) and SNP rs13144478 (P = 6.19 × 10(-18)), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10(-7)). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03-1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.

Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.

BACKGROUND: Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. METHODS: We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. RESULTS: We analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56-0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0·58, 0·51-0·66; p<0·0001 vs 25%, 0·75, 0·61-0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47-2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59-0·73), but only a small effect for non-vertebral fractures (0·93, 0·87-0·99). INTERPRETATION: For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. FUNDING: Cancer Research UK.

The relationship between 11 different polygenic longevity scores, parental lifespan, and disease diagnosis in the UK Biobank.

Large-scale genome-wide association studies (GWAS) strongly suggest that most traits and diseases have a polygenic component. This observation has motivated the development of disease-specific "polygenic scores (PGS)" that are weighted sums of the effects of disease-associated variants identified from GWAS that correlate with an individual's likelihood of expressing a specific phenotype. Although most GWAS have been pursued on disease traits, leading to the creation of refined "Polygenic Risk Scores" (PRS) that quantify risk to diseases, many GWAS have also been pursued on extreme human longevity, general fitness, health span, and other health-positive traits. These GWAS have discovered many genetic variants seemingly protective from disease and are often different from disease-associated variants (i.e., they are not just alternative alleles at disease-associated loci) and suggest that many health-positive traits also have a polygenic basis. This observation has led to an interest in "polygenic longevity scores (PLS)" that quantify the "risk" or genetic predisposition of an individual towards health. We derived 11 different PLS from 4 different available GWAS on lifespan and then investigated the properties of these PLS using data from the UK Biobank (UKB). Tests of association between the PLS and population structure, parental lifespan, and several cancerous and non-cancerous diseases, including death from COVID-19, were performed. Based on the results of our analyses, we argue that PLS are made up of variants not only robustly associated with parental lifespan, but that also contribute to the genetic architecture of disease susceptibility, morbidity, and mortality.

Relationships between serum and urine phosphorus with all-cause and cardiovascular mortality: the Osteoporotic Fractures in Men (MrOS) Study.

BACKGROUND: Serum phosphorus is associated with cardiovascular disease (CVD) in the general population, but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus-creatinine ratio (a marker of intestinal absorption) or urine fractional excretion of phosphorus (FEPi; a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,325 community-dwelling men 65 years or older participating in the MrOS Study. PREDICTOR: Serum phosphorus, urine phosphorus-creatinine ratio, and FEPi. OUTCOMES: All-cause and CVD death. RESULTS: Mean age was 74 ± 6 (SD) years, estimated glomerular filtration rate was 75 ± 16 mL/min/1.73 m(2), and serum phosphorus level was 3.2 ± 0.4 mg/dL. During a median follow-up of 9.3 years, there were 364 (120 CVD) deaths. After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), urine phosphorus-creatinine ratio (≥0.55), and FEPi (≥18%) were 1.63 (95% CI, 1.23-2.17), 1.22 (95% CI, 0.90-1.65), and 0.88 (95% CI, 0.64-1.23), respectively, compared to the lowest quartiles of each. Results were similar for CVD death. Results also were similar in those with estimated glomerular filtration rate ≥60 and <60 mL/min/1.73 m(2). LIMITATIONS: Older all-male cohort. Few had advanced chronic kidney disease. Spot urine specimens were used. CONCLUSIONS: In community-living older men, higher serum phosphorus concentrations are associated with all-cause and CVD death. In contrast, urine phosphorus-creatinine ratio and FEPi are not. These findings do not support using urine phosphorus-creatinine ratio or FEPi as adjuvant measures to predict risk of mortality or CVD in the general population.

Longitudinal change in energy expenditure and effects on energy requirements of the elderly.

BACKGROUND: Very little is known about the longitudinal changes in energy requirements in late life. The purposes of this study were to: (1) determine the energy requirements in late life and how they changed during a 7 year time-span, (2) determine whether changes in fat free mass (FFM) were related to changes in resting metabolic rate (RMR), and (3) determine the accuracy of predicted total energy expenditure (TEE) to measured TEE. METHODS: TEE was assessed via doubly labeled water (DLW) technique in older adults in both 1999 (n = 302; age: 74 ± 2.9 yrs) and again in 2006 (n = 87 age: 82 ± 3.1 yrs). RMR was measured with indirect calorimetry, and body composition was assessed with dual-energy x-ray absorptiometry. RESULTS: The energy requirements in the 9th decade of life were 2208 ± 376 kcal/d for men and 1814 ± 337 kcal/d for women. This was a significant decrease from the energy requirements in the 8th decade of life in men (2482 ± 476 kcal/d vs. 2208 ± 376 kcal/d) but not in women (1892 ± 271 kcal/d vs. 1814 ± 337 kcal/d). In addition to TEE, RMR, and activity EE (AEE) also decreased in men, but not women, while FFM decreased in both men and women. The changes in FFM were correlated with changes in RMR for men (r = 0.49, p < 0.05) but not for women (r = -0.08, ns). Measured TEE was similar to Dietary Reference Intake (DRI) predicted TEE for men (2208 ± 56 vs. 2305 ± 35 kcal/d) and women (1814 ± 42 vs. 1781 ± 20 kcal/d). However, measured TEE was different than the World Health Organization (WHO) predicted TEE in men (2208 ± 56 vs. 2915 ± 31 kcal/d (p < 0.05)) and women (1814 ± 42 vs. 2315 ± 21 kcal/d (p < 0.05)). CONCLUSIONS: TEE, RMR and AEE decreased in men, but not women, from the 8th to 9th decade of life. The DRI equation to predict TEE was comparable to measured TEE, while the WHO equation over-predicted TEE in our elderly population.

The relationship between visual function and physical performance in the Study of Muscle, Mobility and Aging (SOMMA).

PURPOSE: The relationship of types of visual function to different aspects of physical function, especially strength and coordination, has been understudied, but delineation of these relationships could suggest potentially modifiable targets prior to the onset of disability. METHODS: Cross-sectional analysis of visual function (self-reported eyesight and eye disease, visual acuity, contrast sensitivity) and physical function tests in 877 older adults (mean age 76.36±5.01 years, 59.2% women, and 13.3% Black race). Separate linear regression models were constructed for short physical performance battery (SPPB), expanded SPPB (eSPPB), their components (gait speed, chair stand, balance, narrow walk), stair climb, four-square step, leg extension peak power and strength, and grip strength. RESULTS: In adjusted models, worse acuity, worse contrast sensitivity, and self-reported poor vision were significantly associated with worse performance on the eSPPB and four-square step test. Worse contrast sensitivity, but not acuity, was significantly associated with shorter balance times, slower chair stand pace, longer stair climb time, and worse SPPB score. Associations of worse acuity and contrast sensitivity with weaker leg extension power, leg strength, and grip strength were attenuated by covariate adjustment. Self-reported macular degeneration, but not cataract or glaucoma, was associated with worse performance on SPPB, eSPPB, balance, stair climb, and four-square step tests in adjusted models. Worse contrast sensitivity and macular degeneration remained associated with worse SPPB and balance after controlling for visual acuity and self-reported eyesight. CONCLUSIONS: Poor contrast sensitivity was more strongly associated with worse physical performance than acuity, especially for complex tasks that dynamically challenge coordination and balance. Future studies should examine if older adults with contrast sensitivity impairment would benefit from targeted intervention to decrease their risk of disability.

Serum phosphorus levels and the spectrum of ankle-brachial index in older men: the Osteoporotic Fractures in Men (MrOS) study.

A higher serum phosphorus level is associated with cardiovascular disease (CVD) events among community-living populations. Mechanisms are unknown. The ankle-brachial index (ABI) provides information on both atherosclerosis and arterial stiffness. In this cross-sectional study (2000-2002), the authors evaluated the association of serum phosphorus levels with low (<0.90) and high (> or =1.40 or incompressible) ABI as compared with intermediate ABI in 5,330 older US men, among whom the mean serum phosphorus level was 3.2 mg/dL (standard deviation, 0.4), 6% had a low ABI, and 5% had a high ABI. Each 1-mg/dL increase in serum phosphorus level was associated with a 1.6-fold greater prevalence of low ABI (95% confidence interval (CI): 1.2, 2.1; P < 0.001) and a 1.4-fold greater prevalence of high ABI (95% CI: 1.0, 1.9; P = 0.03) in models adjusted for demographic factors, traditional CVD risk factors, and kidney function. However, the association of phosphorus with high ABI differed by chronic kidney disease (CKD) status (in persons with CKD, prevalence ratio = 2.96, 95% CI: 1.61, 5.45; in persons without CKD, prevalence ratio = 1.14, 95% CI: 0.81, 1.61; interaction P = 0.04). In conclusion, among community-living older men, higher phosphorus levels are associated with low ABI and are also associated with high ABI in persons with CKD. These associations may explain the link between serum phosphorus levels and CVD events.

Indicators of "healthy aging" in older women (65-69 years of age). A data-mining approach based on prediction of long-term survival.

BACKGROUND: Prediction of long-term survival in healthy adults requires recognition of features that serve as early indicators of successful aging. The aims of this study were to identify predictors of long-term survival in older women and to develop a multivariable model based upon longitudinal data from the Study of Osteoporotic Fractures (SOF). METHODS: We considered only the youngest subjects (n = 4,097) enrolled in the SOF cohort (65 to 69 years of age) and excluded older SOF subjects more likely to exhibit a "frail" phenotype. A total of 377 phenotypic measures were screened to determine which were of most value for prediction of long-term (19-year) survival. Prognostic capacity of individual predictors, and combinations of predictors, was evaluated using a cross-validation criterion with prediction accuracy assessed according to time-specific AUC statistics. RESULTS: Visual contrast sensitivity score was among the top 5 individual predictors relative to all 377 variables evaluated (mean AUC = 0.570). A 13-variable model with strong predictive performance was generated using a forward search strategy (mean AUC = 0.673). Variables within this model included a measure of physical function, smoking and diabetes status, self-reported health, contrast sensitivity, and functional status indices reflecting cumulative number of daily living impairments (HR >or= 0.879 or RH

Establishing the Link Between Lean Mass and Grip Strength Cut Points With Mobility Disability and Other Health Outcomes: Proceedings of the Sarcopenia Definition and Outcomes Consortium Conference.

BACKGROUND: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. METHODS: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. RESULTS: The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed <0.8 m/s), whereas dual-energy X-ray absorptiometry-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability, and instrumental activities of daily living disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert Panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature. CONCLUSIONS: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength-absolute or adjusted for body mass index-is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities.

Activity energy expenditure and mobility limitation in older adults: differential associations by sex.

In this study, the authors aimed to determine whether higher activity energy expenditure, assessed by using doubly labeled water, was associated with a reduced decline in mobility limitation among 248 older community-dwelling US adults aged 70-82 years enrolled in 1998-1999. Activity energy expenditure was calculated as total energy expenditure (assessed over 2 weeks by using doubly labeled water) minus resting metabolic rate (measured with indirect calorimetry), with adjustment for the thermic effect of food. Across sex-specific tertiles of activity energy expenditure, men in the lowest activity group experienced twice the rate of mobility limitation as men in the highest activity group (41% (n = 18) vs. 18% (n = 8)). Conversely, women in the lowest and highest activity groups exhibited similarly high rates of mobility limitation (40% (n = 16) vs. 38% (n = 15)). After adjustment for potential confounders, men with higher activity energy expenditure levels continued to show reduced risk of mobility limitation (per standard deviation (284 kcal/day): hazard ratio = 0.61, 95% confidence interval: 0.41, 0.92). Women showed no association (per standard deviation (226 kcal/day): hazard ratio = 1.34, 95% confidence interval: 0.98, 1.85). Greater energy expenditure from any and all physical activity was significantly associated with reduced risk of developing mobility limitation among men, but not among women.

Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health, Aging and Body Composition Study.

BACKGROUND: Accumulating evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D- and obesity-related traits in a bi-racial sample of 2985 subjects at baseline and after 7 years of follow-up. METHODS: We examined six T2D-related traits (T2D status, HbA(1c), fasting glucose, insulin, adiponectin and HOMA-IR) as well as six obesity-related traits (obesity status, BMI, leptin, % body fat, visceral and subcutaneous fat mass) using logistic and linear regression models. RESULTS: In all subjects at baseline, oxLDL was positively associated with T2D (OR = 1.3, 95% CI:1.1-1.5), fasting glucose (ss = 0.03 +/- 0.006), HbA(1c) (ss = 0.02 +/- 0.004), fasting insulin (ss = 0.12 +/- 0.02), HOMA-IR (ss = 0.13 +/- 0.02) and negatively with adiponectin (ss = -0.16 +/- 0.03), (all p < 0.001). The strength and magnitude of these associations did not differ much between blacks and whites. In both blacks and whites, oxLDL was also associated with obesity (OR = 1.3, 95% CI:1.1-1.4) and three of its related traits (ss = 0.60 +/- 0.14 for BMI, ss = 0.74 +/- 0.17 for % body fat, ss = 0.29 +/- 0.06 for visceral fat; all p < 0.001). Furthermore, of four traits measured after 7 years of follow-up (fasting glucose, HbA1c, BMI and % fat), their relationship with oxLDL was similar to baseline observations. No significant association was found between oxLDL and incident T2D. Interestingly, oxLDL was significantly associated with % change in T2D- and obesity-related traits in whites but not in blacks. CONCLUSION/INTERPRETATION: Our data suggest that systemic oxidative stress may be a novel risk factor for T2D and obesity.

D3 -Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass.

Sarcopenia has been described as the age-associated decrease in skeletal muscle mass. However, virtually every study of sarcopenia has measured lean body mass (LBM) or fat free mass (FFM) rather than muscle mass, specifically. In a number of published sarcopenia studies, LBM or FFM is referred to as muscle mass, leading to an incorrect assumption that measuring LBM or FFM is an accurate measure of muscle mass. As a result, the data on the effects of changes in LBM or FFM in older populations on outcomes such as functional capacity, disability, and risk of injurious falls have been inconsistent resulting in the conclusion that muscle mass is only weakly related to these outcomes. We review and describe the assumptions for the most commonly used measurements of body composition. Dual-energy X-ray absorptiometry (DXA) has become an increasingly common tool for the assessment of LBM or FFM and appendicular lean mass as a surrogate, but inaccurate, measurement of muscle mass. Other previously used methods (total body water, bioelectric impedance, and imaging) also have significant limitations. D3 -Creatine (D3 -Cr) dilution provides a direct and accurate measurement of creatine pool size and skeletal muscle mass. In a recent study in older men (MrOS cohort), D3 -Cr muscle mass was associated with functional capacity and risk of injurious falls and disability, while assessments of LBM or appendicular lean mass by DXA were only weakly or not associated with these outcomes. Inaccurate measurements of muscle mass by DXA and other methods have led to inconsistent results and potentially erroneous conclusions about the importance of skeletal muscle mass in health and disease. The assessment of skeletal muscle mass using the D3 -Cr dilution method in prospective cohort studies may reveal sarcopenia as a powerful risk factor for late life disability and chronic disease.

Glycated Peptide Levels Are Associated With Cognitive Decline Among Nondiabetic Older Women.

BACKGROUND: The association between diabetes and dementia may be explained in part by elevated levels of glycated peptides; we sought to determine whether serum-glycated peptides predicted cognitive decline in nondiabetic older adults. METHODS: We prospectively studied 525 community-dwelling nondiabetic women, mean age of 82 years, and analyzed baseline glycated peptides (serum level of fructosamine and glycated albumin). Cognitive outcomes included 5-year decline on the short Mini-Mental State Examination (sMMSE), Trails B, and performance on a battery of five other cognitive tests at the follow-up visit. Generalized linear models were adjusted for education, age, race, physical activity, body mass index, and vascular disease. RESULTS: Women with higher level of fructosamine (upper two tertiles) had greater 5-year decline in Trails B performance compared with women in the lowest tertile (adjusted mean change = 67 vs 50 seconds, p = .046), but change in sMMSE was not different between groups. Higher fructosamine was also associated with worse cognitive function 5 years later: adjusted mean score for the California Verbal Learning Test-II Short Form was 22.7 versus 23.9 (p = .010) and for Category Fluency was 10.1 versus 11.1 (p = .003). Higher glycated albumin was also associated with worse performance on Category Fluency (10.1 vs 11.1, p = .003) but not on any other test. CONCLUSIONS: Among older nondiabetic women, higher concentrations of glycated peptides may be associated with greater cognitive decline, especially in measures of executive function. These associations may present new opportunities for targeted prevention and therapeutic strategies in cognitive aging.