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Pathway enrichment analysis is a ubiquitous computational biology method to interpret a list of genes (typically derived from the association of large-scale omics data with phenotypes of interest) in terms of higher-level, predefined gene sets that share biological function, chromosomal location, or other common features. Among many tools developed so far, Gene Set Enrichment Analysis (GSEA) stands out as one of the pioneering and most widely used methods. Although originally developed for microarray data, GSEA is nowadays extensively utilized for RNA-seq data analysis. Here, we quantitatively assessed the performance of a variety of GSEA modalities and provide guidance in the practical use of GSEA in RNA-seq experiments. We leveraged harmonized RNA-seq datasets available from The Cancer Genome Atlas (TCGA) in combination with large, curated pathway collections from the Molecular Signatures Database to obtain cancer-type-specific target pathway lists across multiple cancer types. We carried out a detailed analysis of GSEA performance using both gene-set and phenotype permutations combined with four different choices for the Kolmogorov-Smirnov enrichment statistic. Based on our benchmarks, we conclude that the classic/unweighted gene-set permutation approach offered comparable or better sensitivity-vs-specificity tradeoffs across cancer types compared with other, more complex and computationally intensive permutation methods. Finally, we analyzed other large cohorts for thyroid cancer and hepatocellular carcinoma. We utilized a new consensus metric, the Enrichment Evidence Score (EES), which showed a remarkable agreement between pathways identified in TCGA and those from other sources, despite differences in cancer etiology. This finding suggests an EES-based strategy to identify a core set of pathways that may be complemented by an expanded set of pathways for downstream exploratory analysis. This work fills the existing gap in current guidelines and benchmarks for the use of GSEA with RNA-seq data and provides a framework to enable detailed benchmarking of other RNA-seq-based pathway analysis tools. [ABSTRACT FROM AUTHOR]

Geroscience poses that core biological mechanisms of aging contribute to chronic diseases and disabilities in late life and that health span and longevity can be modulated by pharmacological and behavioral interventions. Despite strong evidence from studies in model organisms and great potentials for translation, most geriatricians remain skeptical that geroscience will help them in the day‐by‐day battle with the consequences of aging in their patients. We believe that a closer collaboration between gerontologists and geriatricians is the key to overcome this impasse. There is evidence that trajectories of health with aging are rooted in intrinsic and extrinsic exposures that occur early in life and affect the pace of molecular and cellular damage accumulation with aging, also referred to as the "pace" of biological aging. Tools that measure the pace of aging currently allow for the identification of individuals experiencing accelerated aging and at higher risk of multimorbidity and disability. What we term "Translational Geroscience", i.e., the merger of fundamental and translational science with clinical practice, is thus poised to extend the action of geriatric care to a life course perspective. By targeting core mechanisms of aging, gerotherapeutics should be effective in treating patients with multimorbidity and disability, phenotypes that are all too common among geriatric patients nowadays. We call for initiatives that enhance the flow of ideas between gerontologists and geriatricians to facilitate the growth of translational geroscience. This approach can widen the scope of geriatric care, including a new role for geroscience in the promotion and operationalization of healthy longevity. [ABSTRACT FROM AUTHOR]

The skeletal muscle is a dynamic organ composed of contractile muscle fibers, connective tissues, blood vessels and nerve endings. Its main function is to provide motility to the body, but it is also deeply involved in systemic metabolism and thermoregulation. The skeletal muscle frequently encounters microinjury or trauma, which is primarily repaired by the coordinated actions of muscle stem cells (satellite cells, SCs), fibro-adipogenic progenitors (FAPs), and multiple immune cells, particularly macrophages. During aging, however, the capacity of skeletal muscle to repair and regenerate declines, likely contributing to sarcopenia, an age-related condition defined as loss of muscle mass and function. Recent studies have shown that resident macrophages in skeletal muscle are highly heterogeneous, and their phenotypes shift during aging, which may exacerbate skeletal muscle deterioration and inefficient regeneration. In this review, we highlight recent insight into the heterogeneity and functional roles of macrophages in skeletal muscle regeneration, particularly as it declines with aging. [ABSTRACT FROM AUTHOR]

Findings from the Study of Muscle, Mobility and Aging (SOMMA) in this issue of Aging Cell show that several biological pathways in skeletal muscle cells play an important role in determining mobility in older adults. These are based on assays in skeletal muscle biopsies obtained from participants, aged 70 years and older in SOMMA tested for association with assessments related to mobility, including muscle mass, strength, power, cardiopulmonary fitness, and 400 m walking speed. The papers show that, using mass spectrometry, oxidative modifications of proteins essential to myocellular function are associated with poorer mobility. Using RNA‐seq to quantify gene expression, lower levels of expression of antioxidant enzymes located in mitochondria, autophagy, patterns of expression of genes involved in autophagy, and higher levels of RNA transcripts that increase with denervation were associated with poorer performance on tests of mobility. These results extend previous research from the Baltimore Longitudinal Study of Aging and recent studies from SOMMA showing the importance of mitochondrial energetics in mobility. Together, these findings are painting a picture of how fundamental cellular processes influence the loss of mobility with aging. They may also be a window on aging in other cells, tissues, and systems. The data collected in SOMMA are publicly available and SOMMA welcomes collaborations with scientists who are interested in research about human aging. [ABSTRACT FROM AUTHOR]

This editorial comments on the article by Nguyen et al. in this issue. [ABSTRACT FROM AUTHOR]

Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials. [ABSTRACT FROM AUTHOR]

Cancer incidence substantially increases with ageing in both men and women, although the reason for this increase is unknown. In this Series paper, we propose that age-associated changes in gut commensal microbes, otherwise known as the microbiota, facilitate cancer development and growth by compromising immune fitness. Ageing is associated with a reduction in the beneficial commensal microbes, which control the expansion of pathogenic commensals and maintain the integrity of the intestinal barrier through the production of mucus and lipid metabolites, such as short-chain fatty acids. Expansion of gut dysbiosis and leakage of microbial products contributes to the chronic proinflammatory state (inflammaging), which negatively affects the immune system and impairs the removal of mutant and senescent cells, thereby enabling tumour outgrowth. Studies in animal models and the importance of commensals in cancer immunotherapy suggest that this status can be reversible. Thus, interventions that alter the composition of the gut microbiota might reduce inflammaging and rejuvenate immune functions to provide anticancer benefits in frail elderly people. [ABSTRACT FROM AUTHOR]

Causal inference with observational longitudinal data and time-varying exposures is complicated due to the potential for time-dependent confounding and unmeasured confounding. Most causal inference methods that handle time-dependent confounding rely on either the assumption of no unmeasured confounders or the availability of an unconfounded variable that is associated with the exposure (eg, an instrumental variable). Furthermore, when data are incomplete, validity of many methods often depends on the assumption of missing at random. We propose an approach that combines a parametric joint mixed-effects model for the study outcome and the exposure with g-computation to identify and estimate causal effects in the presence of time-dependent confounding and unmeasured confounding. G-computation can estimate participant-specific or population-average causal effects using parameters of the joint model. The joint model is a type of shared parameter model where the outcome and exposure-selection models share common random effect(s). We also extend the joint model to handle missing data and truncation by death when missingness is possibly not at random. We evaluate the performance of the proposed method using simulation studies and compare the method to both linear mixed- and fixed-effects models combined with g-computation as well as to targeted maximum likelihood estimation. We apply the method to an epidemiologic study of vitamin D and depressive symptoms in older adults and include code using SAS PROC NLMIXED software to enhance the accessibility of the method to applied researchers. [ABSTRACT FROM AUTHOR]

Importance: Benefits of granulocyte-macrophage colony-stimulating factor (GM-CSF) for improving walking ability in people with lower extremity peripheral artery disease (PAD) are unclear. Walking exercise may augment the effects of GM-CSF in PAD, since exercise-induced ischemia enhances progenitor cell release and may promote progenitor cell homing to ischemic calf muscle.Objectives: To determine whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance, compared with exercise alone and compared with GM-CSF alone; to determine whether GM-CSF alone improves 6-minute walk more than placebo and whether exercise improves 6-minute walk more than an attention control intervention.Design, Setting, and Participants: Randomized clinical trial with 2 × 2 factorial design. Participants were identified from the Chicago metropolitan area and randomized between January 6, 2012, and December 22, 2016, to 1 of 4 groups: supervised exercise + GM-CSF (exercise + GM-CSF) (n = 53), supervised exercise + placebo (exercise alone) (n = 53), attention control  + GM-CSF (GM-CSF alone) (n = 53), attention control + placebo (n = 51). The final follow-up visit was on August 15, 2017.Interventions: Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. The attention control consisted of weekly educational lectures by clinicians for 6 months. GM-CSF (250 μg/m2/d) or placebo were administered subcutaneously (double-blinded) 3 times/wk for the first 2 weeks of the intervention.Main Outcomes and Measures: The primary outcome was change in 6-minute walk distance at 12-week follow-up (minimum clinically important difference, 20 m). P values were adjusted based on the Hochberg step-up method.Results: Of 827 persons evaluated, 210 participants with PAD were randomized (mean age, 67.0 [SD, 8.6] years; 141 [67%] black, 82 [39%] women). One hundred ninety-five (93%) completed 12-week follow-up. At 12-week follow-up, exercise + GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference, -6.3 m [95% CI, -30.2 to +17.6]; P = .61) or more than GM-CSF alone (mean difference, +28.7 m [95% CI, +5.1 to +52.3]; Hochberg-adjusted P = .052). GM-CSF alone did not improve 6-minute walk more than attention control + placebo (mean difference, -1.4 m [95% CI, -25.2 to +22.4]; P = .91). Exercise alone improved 6-minute walk compared with attention control + placebo (mean difference, +33.6 m [95% CI, +9.4 to +57.7]; Hochberg-adjusted P = .02).Conclusions and Relevance: Among patients with PAD, supervised treadmill exercise significantly improved 6-minute walk distance compared with attention control + placebo, whereas GM-CSF did not significantly improve walking performance, either when used alone or when combined with supervised treadmill exercise. These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD.Trial Registration: clinicaltrials.gov Identifier: NCT01408901. [ABSTRACT FROM AUTHOR]

Objectives To derive lean mass cutpoints based on a less-conservative Foundation for the National Institutes of Health ( FNIH) Sarcopenia Project Weakness cutpoint for grip strength (WeakI) and to assess their agreement with European Working Group on Sarcopenia in Older People ( EWGSOP) and prediction of incident slow walking and mortality. Design Longitudinal analysis. Setting Baltimore Longitudinal Study of Aging. Participants Individuals aged 65 and older (287 men, 258 women) with 2 to 10 years of follow-up. Measurements Weakness was determined according to handgrip strength using a hand dynamometer, appendicular lean mass ( ALM) using dual-energy X-ray absorptiometry, and walking speed according to 6-m usual pace walk speed. Analyses were performed using classification and regression tree analysis, Cohen's kappa, and Cox models. Results Cutpoints derived from WeakI for ALM ( ALMI) were less than 21.4 kg in men and less than 14.1 kg in women and for ALM adjusted for body mass index ( ALM/ BMII) were less than 0.725 in men and less than 0.591 in women. Kappas with EWGSOP were 0.65 for men and 0.75 for women for ALMI and 0.34 for men and 0.47 for women for ALM/ BMII. Men with WeakI + ALMI were twice as likely to develop slow walking as those not weak with normal ALMI (Hazard ratio (HR) = 2.44, 95% confidence interval (CI) = 1.02-5.82). Under EWGSOP, men with weakness and low RALM were almost 3 times as likely to develop slow walking as those not weak with normal RALM (HR = 2.91, 95% CI = 1.11-7.62). Neither approach predicted incident slow walking in women. Conclusion The ALMI cutpoints agree with EWGSOP and predict slow walking in men. Future studies should explore sex differences in the relationship between body composition and physical function and the effect of change in muscle mass on muscle strength and physical function. [ABSTRACT FROM AUTHOR]

Instrumental variable (IV) methods have potential to consistently estimate the causal effect of an exposure on an outcome in the presence of unmeasured confounding. However, validity of IV methods relies on strong assumptions, some of which cannot be conclusively verified from observational data. One such assumption is that the effect of the proposed instrument on the outcome is completely mediated by the exposure. We consider the situation where this assumption is violated, but the remaining IV assumptions hold; that is, the proposed IV (1) is associated with the exposure and (2) has no unmeasured causes in common with the outcome. We propose a method to estimate multiplicative structural mean models of binary outcomes in this scenario in the presence of unmeasured confounding. We also extend the method to address multiple scenarios, including mediation analysis. The method adapts the asymptotically efficient G-estimation approach that was previously proposed for additive structural mean models, and it can be carried out using off-the-shelf software for generalized method of moments. Monte Carlo simulation studies show that the method has low bias and accurate coverage. We applied the method to a case study of circulating vitamin D and depressive symptoms using season of blood collection as a (potentially invalid) instrumental variable. Potential applications of the proposed method include randomized intervention studies as well as Mendelian randomization studies with genetic variants that affect multiple phenotypes, possibly including the outcome. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Mobility is the most studied and most relevant physical ability affecting quality of life with strong prognostic value for disability and survival. Natural selection has built the "engine" of mobility with great robustness, redundancy, and functional reserve. Efficient patterns of mobility can be acquired during development even by children affected by severe impairments. Analogously, age-associated impairments in mobility-related physiological systems are compensated and overt limitations of mobility only occur when the severity can no longer be compensated. Mobility loss in older persons usually results from multiple impairments in the central nervous system, muscles, joints, and energetic and sensory physiological systems. Early preclinical changes in these physiological systems that precede mobility loss have been poorly studied. Peak performance, rate of decline, compensatory behaviors, or subclinical deterioration of physiological resources may cumulatively influence both timing of mobility loss and chances of recovery, but their role as risk factors has not been adequately characterized. Understanding the natural history of these early changes and intervening on them would likely be the most effective strategy to reduce the burden of disability in the population. For example, young women with low bone peak mass could be counseled to start strength resistance exercise to reduce their high risk of developing osteoporosis and fracture later in life. Expanding this approach to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories of the mobility-relevant physiological domains. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is associated with increased risk of adverse outcomes in older people. Aim of the study was to explore the predictive value of the European Working Group on Sarcopenia in Older People (EWGSOP) diagnostic algorithm in terms of disability, hospitalization, and mortality and analyze the specific role of grip strength and walking speed as diagnostic criteria for sarcopenia.Methods: Longitudinal analysis of 538 participants enrolled in the InCHIANTI study. Sarcopenia was defined as having low muscle mass plus low grip strength or low gait speed (EWGSOP criteria). Muscle mass was assessed using bioimpedance analysis. Cox proportional and logistic regression models were used to assess risk of death, hospitalization, and disability for sarcopenic people and to investigate the individual contributions of grip strength and walking speed to the predictive value of the EWGSOP's algorithm.Results: Prevalence of EWGSOP-defined sarcopenia at baseline was 10.2%. After adjusting for potential confounders, sarcopenia was associated with disability (odds ratio 3.15; 95% confidence interval [CI] 1.41-7.05), hospitalization (hazard ratio [HR] 1.57; 95% CI 1.03-2.41), and mortality (HR 1.88; 95% CI 0.91-3.91). The association between an alternative sarcopenic phenotype, defined only by the presence of low muscle mass and low grip strength, and both disability and mortality were similar to the association with the phenotypes defined by low muscle mass and low walking speed or by the EWGSOP algorithm.Conclusions: The EWGSOP's phenotype is a good predictor of incident disability, hospitalization and death. Assessment of only muscle weakness, in addition to low muscle mass, provided similar predictive value as compared to the original algorithm. [ABSTRACT FROM AUTHOR]

Although negative age stereotypes have been found to predict adverse outcomes among older individuals, it was unknown whether the influence of stereotypes extends to brain changes associated with Alzheimer's disease. To consider this possibility, we drew on dementia-free participants, in the Baltimore Longitudinal Study of Aging, whose age stereotypes were assessed decades before yearly magnetic resonance images and brain autopsies were performed. Those holding more-negative age stereotypes earlier in life had significantly steeper hippocampal-volume loss and significantly greater accumulation of neurofibrillary tangles and amyloid plaques, adjusting for relevant covariates. These findings suggest a new pathway to identifying mechanisms and potential interventions related to the pathology of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Although the "anti-aging hormone" klotho is associated with sarcopenia in mice, the relationship between klotho and muscle strength in older adults is not well known.Methods: Plasma klotho concentrations were measured in 2,734 older adults, aged 71-80 years, who participated in the Health, Aging and Body Composition Study, a prospective observational cohort study conducted in Memphis, TN and Pittsburgh, PA. Knee extension strength was measured using isokinetic dynamometry at baseline and follow-up 2 and 4 years later. Knee extension strength was normalized for weight.Results: At baseline, participants in the highest tertile of plasma klotho had higher knee extension strength (β = .72, standard error [SE] = .018, p < .0001) compared with those in the lowest tertile in a multivariable linear regression model adjusting for age, sex, race, smoking, study site, C-reactive protein, interleukin-6, and diabetes. Participants in the highest tertile of plasma klotho at baseline had less of a decline in knee strength over 4 years of follow-up (β = -.025, SE = .011, p = .02) compared with those in the lowest tertile in a multivariable linear regression model adjusting for the same covariates above.Conclusions: Plasma klotho concentrations were an independent predictor of changes in knee strength over time in older adults. Further studies are needed to identify the biological mechanisms by which circulating klotho could modify skeletal muscle strength. [ABSTRACT FROM AUTHOR]

This document is a response to a letter to the editor regarding a study on the relationship between skeletal muscle and lower urinary tract symptoms (LUTS) in older men. The authors agree that the relationship between skeletal muscle and LUTS is complex and potentially bidirectional. They also acknowledge the co-occurrence of LUTS and poor sleep, which may accelerate biological aging mechanisms and worsen the functional impact of LUTS. The authors express skepticism about the proposed role of testosterone in this relationship and suggest that other factors, such as decreased mobility and physical activity, may play a more significant role. They propose further research to identify and test plausible conceptual models and interventions to improve symptom burden and functional status in older men with LUTS. The study was supported by various grants and the authors declare no conflicts of interest. [Extracted from the article]

The development of bipedal mobility was a monumental advance in the evolution of the human being. Human walking is a complex activity, taking a full year to develop after birth and a few more years to be refined and fully functional. Walking is such an important evolutionary advantage and it is so important to survival that its functional architecture is supported by multiple redundant systems, which can be called on to maintain mobility when problems occur. The adaptive plasticity of walking physiology is so robust that children with impairments in physiological systems devoted to gait can still develop a fully functional pattern of gait that, at least on a superficial level, appears indistinguishable from normal development. As people age and develop physiologic deficits such as loss of balance or strength, adaptation can help to maintain mobility, but continued physiologic decrements can overwhelm their adaptive capacity. Loss of mobility occurs when these compensatory mechanisms fail, and often, this failure represents a turning point in the older person's life course—a catastrophic juncture with consequences in almost every aspect of life. In recent years, we have come to realize that understanding the physiology of mobility is important not only because of the catastrophic consequence of mobility loss on daily life but also because performance in mobility tasks offers a unique view of multiple aspects of the aging process. In this article, we propose that mobility is a unifying concept whose importance has emerged in the field of geriatrics and gerontology but that is potentially relevant to multiple medical specialties and other nonmedical research disciplines. In different words, we believe that the study of gait and mobility could be the Rosetta stone for different humans' scientific disciplines to compare ideas, integrate experiments, and amplify the value of the data collected. Ultimately, we propose that the study of mobility loss may provide a looking glass through which we can observe multisystem deterioration in anatomical integrity and function, which may result in further development of susceptibility to pathologic conditions that are often interpreted as inherent characteristics of the aging process. We provide an overview of the available evidence that supports our claim and outlines priorities for a future research agenda in this field. [ABSTRACT FROM AUTHOR]

Abstract: Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD. [Copyright &y& Elsevier]

Objectives To examine relationships between eight markers of inflammation (interleukin ( IL)-6, IL-6 receptor (R), C-reactive protein ( CRP), tumor necrosis factor ( TNF)-alpha, TNF receptor 1 (R1), TNFR2, IL-1 receptor antagonist, IL-18) and incident loss of ability to walk 400 m. Design Prospective cohort study. Setting Older adults enrolled in the Invecchiare in Chianti Study. Participants Community-dwelling participants aged 65 and older (N = 1,006). Measurements The eight inflammatory markers were measured at baseline, and an inflammation score was calculated based on the number of inflammatory markers for which the participant was in the highest quartile. Incidence of mobility disability was determined in participants able to walk 400 m at baseline. Logistic regression models were used to determine whether each of the inflammatory markers and the inflammation score predicted loss of the ability to walk 400 m at 6-year follow-up. Results After adjusting for covariates, individuals with a TNFR1 level in each of the highest three quartiles (Q2, 3, 4) were more likely to be unable to walk 400 m at follow-up than those with TNFR1 levels in Q1. When adjusting for the same covariates, participants with an inflammation score of 3 or 4 were more likely to become unable to walk 400 m at follow-up than participants with a score of 0. Conclusion These results provide additional evidence that inflammation is a factor in the mechanisms that cause incident mobility disability and suggest that a combined measure of inflammatory markers may improve prediction of functional prognosis. [ABSTRACT FROM AUTHOR]

Objectives To examine the relationship between erythrocyte mean corpuscular volume ( MCV) and cognitive performance over time. Design Longitudinal. Setting Sample from the Baltimore Longitudinal Study of Aging ( BLSA). Participants Eight hundred twenty-seven participants from the BLSA (mean age 67, range 50-96). Measurements Mean corpuscular volume and several other blood indices were measured, including hemoglobin, iron, ferritin, vitamin B12, folate, white blood cell count, albumin, and erythrocyte sedimentation rate. Cognitive performance was examined using neuropsychological measures of visual memory, verbal memory, language, attention, executive function, and global mental status. Results High MCV levels were significantly associated with lower global mental status even after adjusting for potential confounders. High MCV levels were also significantly associated with high rates of decline on tasks of global mental status, long delay memory, and attention, even after adjusting for potential confounders. Conclusion The findings confirm a previous observation that larger erythrocytes in older adults are associated with poorer cognitive function. Anemia and inflammation do not appear to explain the relationship between MCV and cognition. Further research is needed to clarify the mechanisms behind this association. [ABSTRACT FROM AUTHOR]

Objectives. To examine the association between openness to experience and conscientiousness and incident reported walking limitation. Method. The study population consisted of 786 men and women aged 71–81 years (M = 75 years, SD = 2.7) participating in the Health, Aging, and Body Composition—Cognitive Vitality Substudy. Results. Nearly 20% of participants (155/786) developed walking limitation during 6 years of follow-up. High openness was associated with a reduced risk of walking limitation (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.69–0.98), independent of sociodemographic factors, health conditions, and conscientiousness. This association was not mediated by lifestyle factors and was not substantially modified by other risk factors for functional disability. Conscientiousness was not associated with risk of walking limitation (HR = 0.91, 95% CI = 0.77–1.07). Discussion. Findings suggest that personality dimensions, specifically higher openness to experience, may contribute to functional resilience in late life. [ABSTRACT FROM PUBLISHER]

Background: Low vitamin B12 and high homocysteine (Hcy) levels are common in older adults and may be associated with worse neurological function. The aim of this study is to determine whether changes in B12 or Hcy levels are associated with longitudinal changes in peripheral nerve function and clinical neurological signs and symptoms. Methods: Participants aged 60 years and older at baseline (n = 678; 72.2 ± 6.2 years; 43.5% male) were from the InCHIANTI Study. Low B12 (<260 pmol/L) and high Hcy (≥13 μmol/L) were measured at baseline and 3-year follow-up. Neurological function was assessed by peroneal nerve conduction amplitude (compound motor action potential) and velocity, neurological examination, and peripheral neuropathy symptoms at baseline, 3-year, and 6-year follow-up. Results: At baseline, 43.8% had low B12 levels and 58.6% had high Hcy levels. Over 6 years, 12.4% declined to poor compound motor action potential (<1 mV) and 42.1% declined to poor nerve conduction velocity (<40 m/s). In mixed models analyses, sustained high Hcy was associated with worse compound motor action potential compared with sustained normal Hcy (p = .04), adjusting for demographics, diabetes, and folate level. Participants whose Hcy level became high at follow-up were more likely to become unable to detect monofilament at 6-year follow-up compared with those with sustained normal Hcy (odds ratio: 5.4; 95% CI: 1.5–19.0), adjusting for demographics, diabetes, body mass index, and peripheral arterial disease. There was no association with vitamin B12 level or with symptoms. Conclusions: High Hcy may be associated with worse sensory and motor peripheral nerve function. Because poor nerve function has been associated with lower strength and physical performance, these results have important implications for disability in older adults. [ABSTRACT FROM PUBLISHER]

The editors discuss research into aging-related muscle mass and strength losses, arguing that more accurate animal models are needed to understand the processes controlling these declines in humans. Various issues related to clinical research are explored, including the correct muscle mass threshold for the diagnosis of sarcopenia, the assessment of physical performance, and the use of muscular strength loss as a predictor of mobility loss.

Personality traits contribute to health outcomes, in part through their association with major controllable risk factors, such as obesity. Body weight, in turn, reflects our behaviors and lifestyle and contributes to the way we perceive ourselves and others. In this study, the authors use data from a large (N = 1,988) longitudinal study that spanned more than 50 years to examine how personality traits are associated with multiple measures of adiposity and with fluctuations in body mass index (BMI). Using 14,531 anthropometric assessments, the authors modeled the trajectory of BMI across adulthood and tested whether personality predicted its rate of change. Measured concurrently, participants higher on Neuroticism or Extraversion or lower on Conscientiousness had higher BMI; these associations replicated across body fat, waist, and hip circumference. The strongest association was found for the impulsivity facet: Participants who scored in the top 10% of impulsivity weighed, on average, 11 Kg more than those in the bottom 10%. Longitudinally, high Neuroticism and low Conscientiousness, and the facets of these traits related to difficulty with impulse control, were associated with weight fluctuations, measured as the variability in weight over time. Finally, low Agreeableness and impulsivity-related traits predicted a greater increase in BMI across the adult life span. BMI was mostly unrelated to change in personality traits. Personality traits are defined by cognitive, emotional, and behavioral patterns that likely contribute to unhealthy weight and difficulties with weight management. Such associations may elucidate the role of personality traits in disease progression and may help to design more effective interventions. [ABSTRACT FROM AUTHOR]

We hypothesized that, in the absence of clinically recognized dementia, cognitive dysfunction measured by the clock draw test (CDT) is associated with greater functional impairment in men and women with peripheral artery disease (PAD). Participants were men and women aged 60 years and older with Mini-Mental Status Examination scores ≥ 24 with PAD (n = 335) and without PAD (n = 234). We evaluated the 6-minute walk test, 4-meter walking velocity at usual and fastest pace, the Short Physical Performance Battery (SPPB), and accelerometer-measured physical activity. CDTs were scored using the Shulman system as follows: Category 1 (worst): CDT score 0—2; Category 2: CDT score 3; Category 3 (best): CDT score 4—5. Results were adjusted for age, sex, race, education, ankle—brachial index (ABI), and comorbidities. In individuals with PAD, lower CDT scores were associated with slower 4-meter usual-paced walking velocity (Category 1: 0.78 meters/second; Category 2: 0.83 meters/second; Category 3: 0.86 meters/second; p-trend = 0.025) and lower physical activity (Category 1: 420 activity units; Category 2: 677 activity units; Category 3: 701 activity units; p-trend = 0.045). Poorer CDT scores were also associated with worse functional performance in individuals without PAD (usual and fast-paced walking velocity and SPPB, p-trend = 0.022, 0.043, and 0.031, respectively). In conclusion, cognitive impairment identified with CDT is independently associated with greater functional impairment in older, dementia-free individuals with and without PAD. Longitudinal studies are necessary to explore whether baseline CDT scores and changes in CDT scores over time can predict long-term decline in functional performance in individuals with and without PAD. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits biological activity on vascular cells in vitro. Rapid variation of circulating TRAIL levels occurs during acute coronary ischemia, suggesting that biological pathways involving TRAIL may be activated during ischemic heart disease. However, whether differential levels of soluble TRAIL in normal individuals are associated with adverse health outcomes has not been investigated. We tested the hypothesis that TRAIL levels predict mortality in a population based sample of community dwelling men and women. Methods: Plasma TRAIL level was measured by ELISA at baseline in 1282 adults (mean age 68 years) enrolled in the InCHIANTI study. Vital status was ascertained over the six-year follow-up. Results: In multivariable Cox regression analysis adjusted for potential confounders including prevalent cardiovascular diseases (CVD), ankle-brachial index, electrocardiogram abnormalities, and inflammatory markers, baseline TRAIL levels were inversely related to all-cause mortality (p =0.008). In stratified analyses, the prognostic effect of TRAIL level was strong and highly significant in participants with prevalent CVD (N =321), (lowest versus highest quartile: HR 3.1; 95% CI 1.5–6.5) while it was negligible in those free of CVD (p value for the interaction term between CVD status and TRAIL levels=0.038). Similar findings were obtained when CVD mortality was considered as the outcome of interest. Conclusions: In older patients with CVD, low levels of TRAIL were associated with increased risk of death over a period of 6 years. Lower concentration of circulating TRAIL may be related to the clinical evolution of older adults with CVD. [Copyright &y& Elsevier]

Objectives: We hypothesized that women with lower extremity peripheral arterial disease (PAD) would have greater mobility loss and faster functional decline than men with PAD. Background: Whether rates of mobility loss or functional decline differ between men and women with PAD is currently unknown. Methods: Three hundred eighty men and women with PAD completed the 6-min walk, were assessed for mobility disability, and underwent measures of 4-m walking velocity at baseline and annually for up to 4 years. Computed tomography-assessed calf muscle characteristics were measured biannually. Outcomes included becoming unable to walk for 6 min continuously among participants who walked continuously for 6 min at baseline. Mobility loss was defined as becoming unable to walk for a quarter mile or to walk up and down 1 flight of stairs without assistance among those without baseline mobility disability. Results were adjusted for age, race, body mass index, physical activity, the ankle brachial index, comorbidities, and other confounders. Results: At 4 years of follow-up, women were more likely to become unable to walk for 6 min continuously (hazard ratio: 2.30, 95% confidence interval: 1.30 to 4.06, p = 0.004), more likely to develop mobility disability (hazard ratio: 1.79, 95% confidence interval: 1.30 to 3.03, p = 0.030), and had faster declines in walking velocity (p = 0.022) and the distance achieved in the 6-min walk (p = 0.041) compared with men. Sex differences in functional decline were attenuated after additional adjustment for baseline sex differences in calf muscle area. Conclusions: Women with PAD have faster functional decline and greater mobility loss than men with PAD. These sex differences may be attributable to smaller baseline calf muscle area among women with PAD. [ABSTRACT FROM AUTHOR]

Chronic diseases often determine pathologic phenotypes similar to those traditionally attributed to aging, such as accelerated decline of muscle mass and increments of basic metabolic rate, suggesting that the true nature of aging is progressively increasing entropy in the face of failing homeostatic mechanisms. Aging in different animal species and in humans suggest that increasing entropy causes major problems in four domains; body composition, energetic imbalance between availability and demand, homeostatic dysregulation, and neurodegeneration. In humans, loss of integrity and function in these domains causes manifestations similar to frailty, especially if the damage is severe and/or involves multiple domains, and has catastrophic consequences, such as physical and cognitive disability. Characterizing these phenotypes, and understanding the mechanisms by which they emerge with increasing entropy is a necessary step to find interventions that can prevent, delay or moderate the effects of aging. Pharmacological and non-pharmacological interventions that may effectively modulate the aging phenotypes are actively studied and will certainly be ready in the near future. Until then, creating a "senior friendly society", that allows maximal independence but also promotes an active and healthy lifestyle may be the most cost-effective intervention to improve the quality of life in the population. [ABSTRACT FROM AUTHOR]

Study Type - Diagnosis (validating cohort) Level of Evidence 1b OBJECTIVE To present an effective approach to the early detection of lethal prostate cancer using longitudinal data on prostate-specific antigen (PSA) and its rate of change, i.e. PSA velocity (PSAV). This longitudinal approach might also be extendible to other biomarkers. SUBJECTS AND METHODS PSAV was calculated using five techniques for 634 subjects with at least three PSA measurements in a longitudinal ageing study, censoring PSA levels of >10 ng/mL. The efficacy for predicting death from prostate cancer was assessed with concordance indices and by using net reclassification improvement (NRI), which indicated the net increase in sensitivity and specificity when adding a biomarker to a base Cox proportional hazards model. The PSAV techniques were compared for the 5-10 years before the clinical diagnosis of prostate cancer. The most effective technique was then applied at the transition point when each man's PSA history curve transformed from linear to exponentially increasing, and its predictive value was compared to that of concurrent PSA level. RESULTS A PSA transition point was found in 522 (82%) of the 634 men, including all 11 who died from prostate cancer. At the transition point, the mean PSA level was 1.4 ng/mL, and PSAV but not PSA level was significantly higher among men who died from prostate cancer than among men who did not ( P= 0.021 vs P= 0.112; Wilcoxon two-sample test). At the transition point, adding PSAV to a base model consisting of age and date of diagnosis improved the concordance index by 0.05, and significantly improved the overall sensitivity and specificity (NRI, P= 0.028), while adding PSA level to the same base model resulted in little improvement (concordance index increase <0.01 and NRI P= 0.275). CONCLUSION When the shape of a man's PSA history curve changes from linear to exponential, PSAV might help in the early identification of life-threatening prostate cancer at a time when PSA values are still low in most men. [ABSTRACT FROM AUTHOR]

Previous reports suggest that the severity of peripheral arterial disease (PAD), measured by the ankle-brachial index (ABI), is not associated with the magnitude of walking impairment, measured by treadmill testing. These prior studies have had small sample sizes and included only PAD participants with symptoms of intermittent claudication. We studied the association of the ABI with diverse measures of walking performance in a cross-sectional study of 156 participants with PAD with and without intermittent claudication symptoms. Outcomes included the Gardner-Skinner treadmill test, 6-minute walk, 4-meter walking velocity at usual and fastest pace, and the walking impairment questionnaire (WIQ). Adjusting for age, sex, race, comorbidities, leg symptoms, and other confounders, lower ABI values were associated with shorter distance achieved in the 6-minute walk (ABI < 0.50: 286 meters; ABI 0.50-0.70: 316 meters; ABI 0.71-0.95: 355 meters, p trend < 0.001), shorter maximal treadmill walking time (ABI < 0.50: 6.0 minutes; ABI 0.50-0.70: 6.9 minutes; ABI 0.71-0.95: 8.3 minutes, p trend = 0.009), and lower WIQ distance scores (p trend = 0.007) among PAD participants. The ABI was not associated significantly with walking velocity over 4 meters, treadmill time to onset of leg symptoms, or the WIQ speed or stair-climbing scores. In conclusion, among 156 participants with PAD with and without intermittent claudication, lower ABI values are associated significantly with poorer walking endurance, assessed by three distinct measures. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine whether asymptomatic lower extremity peripheral arterial disease (PAD) and leg symptoms other than intermittent claudication (IC) in PAD are associated with faster functional decline than in people with both PAD and IC. DESIGN: Prospective, observational study. SETTING: Chicago-area medical center. PARTICIPANTS: Four hundred fifteen people with PAD followed annually for up to 7 years. MEASUREMENTS: At baseline, patients with PAD were categorized into symptom categories, including IC; leg pain on exertion and rest; participants who could walk through exertional leg pain (pain/carry on); and participants who never experienced exertional leg pain, even during the 6-minute walk (always asymptomatic). Outcomes included mobility loss (becoming unable to walk one-quarter of a mile or walk up and down one flight of stairs without assistance) and becoming unable to complete the 6-minute walk without stopping. Analyses adjusted for age, sex, comorbidities, ankle brachial index, and other confounders. RESULTS: Always-asymptomatic participants (hazard ratio (HR)=2.94, 95% confidence interval (CI)=1.39–6.19, P=.005) and those with leg pain on exertion and rest (HR=2.89, 95% CI=1.47–5.68, P=.002) had greater mobility loss than participants with IC. Participants with PAD with leg pain/carry on were less likely ( P=.047) to become unable to walk for 6 minutes continuously without stopping than participants with IC. CONCLUSION: The ABI identifies patients with asymptomatic PAD and those with atypical leg symptoms who are at risk for greater mobility decline than participants without PAD and participants with PAD with IC. [ABSTRACT FROM AUTHOR]

Study Type – Prognosis (inception cohort) Level of Evidence 1b OBJECTIVE To evaluate the relationship between testosterone levels and the development of high-risk prostate cancer, by prospectively examining serum androgen concentrations in a well-studied cohort, as the role of testosterone in prostate cancer progression is debated. PATIENTS AND METHODS The study comprised 781 men in the Baltimore Longitudinal Study of Aging who had sex steroid measurements before a diagnosis of prostate cancer, or at their last visit for those without cancer (no cancer, 636; cancer, not high risk, 109; cancer, high risk, 36). High-risk cancer was defined as death from prostate cancer, a prostate specific antigen (PSA) level of ≥20 ng/mL at diagnosis, or a Gleason score of ≥8. The hazard ratio (HR) of high-risk disease was determined using a Cox proportional hazards regression model with simple updating, and risk rates were stratified by age and tercile for androgens of interest based on the proportional hazards analyses. RESULTS The likelihood of high-risk prostate cancer doubled per unit (0.1) increase in the free testosterone index (FTI) for patients aged >65 years (HR 2.07, 95% confidence interval, CI, 1.01–4.23; P = 0.047); the likelihood for men aged ≤65 years was inversely related to the FTI (HR 0.96, 95% CI 0.35–2.6; P = 0.9). The risk rate per person-years increased from lowest to highest tercile of FTI for the oldest men (age >70 years) but this trend was not apparent among younger men. CONCLUSION Higher levels of serum free testosterone are associated with an increased risk of aggressive prostate cancer among older men. These data highlight the importance of prospective trials to insure the safety of testosterone-replacement therapy. [ABSTRACT FROM AUTHOR]

An introduction to the journal is presented in which the editor discusses various reports published within the issue including an article on metabolic syndrome and weight gain in adulthood by D.E. Alley and V.W. Chang, survival in older men who are slightly obese by T.W. Auyeung, J.S.W. Lee and J. Leung, and the effect of obesity and metabolic syndrome on mobility in older adults by S. Stenholm, A. Koster and D.E. Alley.

Objective: to determine whether serum carboxymethyl-lysine, a dominant advanced glycation end product (AGE), and circulating total receptor for AGEs (sRAGE) and endogenous secretory receptor for AGEs (esRAGE) are associated with anaemia, Design: cross-sectional analysis. Setting: moderately severely disabled women, ⩾65 years, living in the community in Baltimore, MD (the Women's Health and Aging Study I). Participants: 519 women with and without anaemia. Main outcome measure: haemoglobin and anaemia (haemoglobin <12 g/dL). Results: of 519 women, 128 (24.7%) had anaemia. All odds ratios (OR) were expressed per one standard deviation. Serum CML was associated with anaemia [OR 1.47, 95% confidence interval (CI) 1.11-1.95, P = 0.008] in a multivariate logistic regression model adjusting for age, race, smoking, education and chronic diseases. Serum sRAGE (ng/mL) and esRAGE (ng/mL) were associated with anaemia (OR 1.52,95%CT 1.21-1.92, P= 0.0004; OR 1.49, 95% CI 1.18-1.87, P= 0.0006, respectively) in separate multivariate logistic regression models, adjusting for the same covariates mentioned above. Serum CML (P = 0.004), sRAGE (P < 0.0001) and esRAGE (P < 0.0001) were inversely and independently associated with haemoglobin concentrations. Conclusion: AGEs and circulating RAGE are independently associated with haemoglobin and anaemia in older women. AGEs are amenable to interventions, as serum AGEs can be lowered by a change in dietary pattern and pharmacological treatment. [ABSTRACT FROM AUTHOR]

The article presents a study on the association between red blood cells distribution width (RDW) and mortality in patients with symptomatic cardiovascular disease (CVD). It measured RDW in a national sample of 8175 adults of 45 years and above who participated in the 1988-1994 National Health and Nutrition Examination Survey, and mortality follow up was conducted through December 31, 2000. It finds out that higher RDW values have significant association with an increase risk of death, concluding that RDW is a potent predictor of mortality.

Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with α-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the α-Tocopherol, β-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the β-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher n-carotene (p = 1.6 x 10-24) and a-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10-5), and lutein (p = 7.3 x 10-15) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOAS gene, was associated with α-tocopherol (meta-analysis p = 7.8 x 10-10) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health. [ABSTRACT FROM AUTHOR]

The effect of smoking and physical activity on active and disabled life expectancy was estimated using data from the Established Populations for Epidemiologic Studies of the Elderly (EPESE). Population-based samples of persons aged >65 years from the East Boston, Massachusetts, New Haven, Connecticut, and Iowa sites of the EPESE were assessed at baseline between 1981 and 1983 and followed for mortality and disability over six annual follow-ups. A total of 8,604 persons without disability at baseline were classified as “ever” or “never” smokers and doing “low,” “moderate,” or “high” level physical activity. Active and disabled life expectancies were estimated using a Markov chain model. Compared with smokers, men and women nonsmokers survived 1.6–3.9 and 1.6–3.6 years longer, respectively, depending on level of physical activity. When smokers were disabled and close to death, most nonsmokers were still nondisabled. Physical activity, from low to moderate to high, was significantly associated with more years of life expectancy in both smokers (9.5, 10.5, 12.9 years in men and 11.1,12.6,15.3 years in women at age 65) and nonsmokers (11.0, 14.4,16.2 years in men and 12.7,16.2,18.4 years in women at age 65). Higher physical activity was associated with fewer years of disability prior to death. These findings provide strong and explicit evidence that refraining from smoking and doing regular physical activity predict a long and healthy life. Am J Epidemiol 1999; 149:645–53. [ABSTRACT FROM PUBLISHER]

Background. Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetes, heart disease, and kidney failure and may potentially affect skeletal muscle. Whether AGEs are associated with poor muscle strength is unknown. Methods. Serum carboxymethyl-lysine (CML), a dominant AGE, circulating soluble form of receptor for advanced glycation end products (sRAGE), and endogenous secretory receptor for advanced glycation end product (esRAGE) and grip strength were measured in 559 moderately to severely disabled women, age 65 and older, in the Women's Health and Aging Study I in Baltimore, Md. Results. Mean (standard deviation) grip strength among women in the highest quartile of serum CML compared with women in the lower three quartiles was 18.6 and 20.0 kg, respectively (p = .002), adjusting for age, race, body mass index, cognitive dysfunction, depression, and diabetes. Serum sRAGE and esRAGE were not significantly associated with grip strength. Conclusions. Women with high serum AGEs have greater muscle weakness. Further studies are needed to determine whether AGEs, a potentially modifiable risk factor, are associated with physical performance and disability in older adults. [ABSTRACT FROM AUTHOR]

The author reflects on the Baltimore Longitudinal Study of Aging (BLSA) of the U.S. National Institutes of Health (NIH) that began in 1958. He describes that in the U.S., the BLSA is one of the largest and longest-running longitudinal studies of aging. The author elaborates the made major contributions of the BLSA to the understanding of normal aging in humans.

The article examines the association of fast-adapting receptor-mediated vibrotactile sensitivity and slow-adapting receptor-mediated pressure sensitivity with self-selected usual gait speed and gait speed in older people. It was found that vibrotactile and monofilament sensitivity were significantly worse in slower gait speed in 6 meter and 6-m narrow course. However, vibrotactile but not monofilament sensitivity was independently associated with self-selected normal gait speed when covariates such as standing balance, visual acuity and arterial disease, were adjusted.

Abstract: Objective: The objective of this study was to determine whether total serum carotenoids, α-tocopherol, selenium, and obesity were independently associated with oxidized low-density lipoproteins (ox-LDLs) in moderately to severely disabled older women living in the community. Methods: Serum ox-LDLs, carotenoids, α-tocopherol, and selenium were measured in a population-based sample of 543 moderately to severely disabled women ≥65 y in the Women''s Health and Aging Study I in Baltimore, Maryland. Results: Total serum carotenoids, smoking, overweight (body mass index 25–29.9 kg/m2), and obesity (body mass index ≥30 mg/kg2) were significantly associated with the ox-LDL/LDL cholesterol ratio after adjusting for age, C-reactive protein, and chronic diseases. α-Tocopherol and selenium were not significantly associated with the ox-LDL/LDL cholesterol ratio. Conclusion: Older women who are overweight or obese or who have low total serum carotenoids are more likely to have higher lipoprotein oxidation. Weight reduction in overweight/obese women and increased intake of carotenoid-rich foods may potentially reduce lipoprotein oxidation. [Copyright &y& Elsevier]

Background. Elevated interleukin (IL)-6 is associated with adverse outcomes. Our objective was to determine whether serum protein carbonyls, an indicator of oxidative protein damage and oxidative stress, were associated with IL-6. Methods. Serum protein carbonyls and IL-6 were measured in 739 women, age ≥65 years, in the Women's Health and Aging Study I. Results. Geometric mean of protein carbonyls was 0.082 nmol/mg. After adjusting for age and smoking status, loge serum protein carbonyls were associated with loge IL-6 (β = 0.143, standard error [SE] = 0.048, p = .003) in linear regression analyses and with elevated IL-6 (≥2.5 pg/mL) (odds ratio = 1.38, 95% confidence interval, 1.02-1.86, p = .037) in logistic regression analyses. Conclusion. Oxidative damage to proteins is independently associated with serum IL-6 among older women living in the community. Increased oxidative stress may be a factor involved in the pathogenesis of the proinflammatory state that occurs in older adults. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress has been implicated in sarcopenia and the loss of muscle strength with aging, but the relationship between oxidative stress and decrease in muscle strength and physical performance has not been well characterized. Serum protein carbonyls are markers of oxidative damage to proteins and are caused by oxidative stress.Methods: Serum protein carbonyls were measured at baseline and compared with a decrease in walking speed and development of severe walking disability (inability to walk or walking speed <0.4 m/sec) over 36 months of follow-up in 545 moderately to severely disabled women, aged > or =65 years, living in the community in Baltimore, Maryland (the Women's Health and Aging Study I).Results: After adjusting for age, body mass index, smoking, and chronic diseases, log(e) protein carbonyls (nmol/mg) were associated with a decrease in walking speed over 36 months (P=.002). During follow-up, 154 women (28.2%) developed severe walking disability. After adjusting for the same potential confounders, log(e) protein carbonyls were associated with incident severe walking disability (hazards ratio 1.42, 95% confidence interval, 1.02-1.98, P=.037).Conclusion: High oxidative stress, as indicated by oxidative damage to proteins, is an independent predictor of decrease in walking speed and progression to severe walking disability among older women living in the community. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine whether oxidative stress, as implied by oxidative damage to proteins, is associated with greater mortality in older women living in the community. DESIGN: Longitudinal. SETTING: Women's Health and Aging Study I, Baltimore, Maryland. PARTICIPANTS: Seven hundred forty-six moderately to severely disabled women, aged 65 and older, with baseline measures of serum protein carbonyls. MEASUREMENTS: Serum protein carbonyls, which consist of chemically stable aldehyde and ketone groups produced on protein side chains when they are oxidized, were measured using enzyme-linked immunosorbent assay. Multivariate logistic regression was used to adjust for potential confounders. RESULTS: During 5 years of follow-up, 202 (27.1%) participants died. Geometric mean serum protein carbonyls were 0.091 nmol/mg in women who died and 0.083 nmol/mg in those who survived ( P=.02). Loge protein carbonyls (nmol/mg) were associated with greater risk of mortality (hazards ratio=1.34, 95% confidence interval=1.01–1.79, P=.04) in a multivariate Cox proportional hazards model adjusting for age, current smoking, and body mass index. CONCLUSION: Greater oxidative stress, as indicated by elevated serum protein carbonyl concentrations, was associated with greater risk of death in older women living in the community who were moderately to severely disabled. Prevention of oxidative stress may reduce the risk of mortality. [ABSTRACT FROM AUTHOR]