Showing papers in "Journals of Gerontology Series A-biological Sciences and Medical Sciences in 2014"

Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases

Abstract: Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging." Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people. The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging. This article reports the main outcomes of this session.

The FNIH Sarcopenia Project: Rationale, Study Description, Conference Recommendations, and Final Estimates

Abstract: Background. Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.

Grip Strength Cutpoints for the Identification of Clinically Relevant Weakness

Abstract: Muscle weakness is related to poor physical performance and incident mobility limitations among older adults (1–6). Weakness is considered a key element of frailty (7) and, increasingly, of sarcopenia (8,9). Although the association between weakness and functional limitations is strong, there is no consensus regarding a cutpoint for identification of risk for functional problems. In order to identify population subgroups in whom weakness is a potential contributor to functional limitations, it is necessary to determine what constitutes a clinically relevant degree of weakness. This is the second in a series of reports from the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project, which pooled data from multiple studies to develop and evaluate clinically relevant criteria for weakness and low muscle mass (10). The purpose of the analysis presented here was to identify cutpoints that distinguish weakness (measured by grip strength) associated with mobility impairment (measured by gait speed) using cross-sectional data (ie, to maximize concurrent validity). This analysis builds on previous research on the association between strength and walking speed using a data-driven approach across multiple populations and an analytic technique (Classification and Regression Tree [CART] analysis) designed to optimize concurrent validity in the context of complex interactions. Findings were used to address subsequent Project goals reported separately (11–13).

Criteria for Clinically Relevant Weakness and Low Lean Mass and Their Longitudinal Association With Incident Mobility Impairment and Mortality: The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project

Abstract: Results. Low grip strength (men: odds ratio (OR) = 2.31, 95% confidence interval (CI) = 1.34-3.99; women: OR = 1.99, 95% CI 1.23-3.21), low grip strength-to-BMI ratio (men: OR = 3.28, 95% CI 1.92-5.59; women: OR = 2.54, 95% CI 1.10-5.83) and low ALM-to-BMI ratio (men: OR = 1.58, 95% CI 1.12-2.25; women: OR = 1.81, 95% CI 1.14-2.87), but not low ALM, were associated with increased likelihood for incident mobility impairment. Weakness increased likelihood of mobility impairment regardless of low lean mass. Mortality risk patterns were inconsistent. Conclusions. These findings support our cut-points for low grip strength and low ALM-to-BMI ratio as candidate criteria for clinically relevant weakness and low lean mass. Further validation in other populations and for alternate relevant outcomes is needed.

Is HIV a Model of Accelerated or Accentuated Aging

Abstract: Background Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging? Methods Extensive literature review. Results The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants. Conclusions There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases.

An Evidence-Based Comparison of Operational Criteria for the Presence of Sarcopenia

Abstract: Low muscle mass and weakness are potential contributors to disability in older persons. Although the term “sarcopenia” has become widespread, the criteria for an operational definition vary among studies and experts. Initial work on defining sarcopenia was based on measures of muscle mass alone, and the prevalence of sarcopenia when compared with a young reference population ranged between 13% and 24% among adults younger than 70 years to more than 50% among adults older than 80 years (1). However, a growing body of research suggests that there is a disconnect between muscle mass and strength. Thus, recent definitions of sarcopenia have incorporated elements of strength and physical performance in addition to muscle mass in the criteria for sarcopenia (2–5). However, these consensus statements were based on expert opinions and lacked access to large data sets to validate their recommendations. Thus, the goal of the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project was to create a data-driven set of criteria for clinically relevant weakness and low lean mass using pooled data from multiple studies. This is the fifth report of the FNIH Sarcopenia Project. The first manuscript describes the rationale for the FNIH Sarcopenia Project and characteristics of the participating studies. The second and third manuscripts describe in detail the development of cutpoints for weakness and low lean mass; and the fourth manuscript demonstrates the predictive validity of these cutpoints. The purpose of the analyses presented here is to compare the criteria developed by the FNIH project to other published criteria, in order to assess prevalence, agreement, and discrepancies between candidate criteria. Our goal is to provide data-driven evidence to the field in order to advance professional consensus regarding clinically relevant cutpoints and terminology.

Heterogeneity in Healthy Aging

Abstract: For a surprisingly large segment of the older population, chronological age is not a relevant marker for understanding, measuring, or experiencing healthy aging. Using the 2003 Medical Expenditure Panel Survey and the 2004 Health and Retirement Study to examine the proportion of Americans exhibiting five markers of health and the variation in health-related quality of life across each of eight age groups, we find that a significant proportion of older Americans is healthy within every age group beginning at age 51, including among those aged 85+. For example, 48% of those aged 51-54 and 28% of those aged 85+ have excellent or very good self-reported health status; similarly, 89% of those aged 51-54 and 56% of those aged 85+ report no health-based limitations in work or housework. Also, health-related quality of life ranges widely within every age group, yet there is only a comparatively small variation in median quality of life across age groups, suggesting that older Americans today may be experiencing substantially different age-health trajectories than their predecessors. Patterns are similar for medical expenditures. Several policy implications are explored.

Cutpoints for Low Appendicular Lean Mass That Identify Older Adults With Clinically Significant Weakness

Abstract: Early efforts to create an operational definition of sarcopenia (including the creation of cutpoints) have relied on distributional definitions of lean mass (1), with sarcopenia defined as a value of appendicular lean mass (ALM)/height2 (derived from whole-body dual-energy x-ray absorptiometry [DXA]) below the young adult mean level of lean mass or was based on definitions that further account for body size or fatness (2–4). More recent efforts have added functional and/or strength measures to lean mass to define sarcopenia (5,6), but no approaches thus far have proposed and validated cutpoints and definitions based on discriminative and predictive ability using a data-driven approach from a variety of cohort studies. The overarching goal of this set of concurrent reports from the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project was to determine preliminary data-driven criteria for clinically relevant weakness and low lean mass. The conceptual framework was based on a clinician making a “differential diagnosis” of mobility impairment, defined as slow gait speed. The clinician understands that there are many causes of slow walking, one of which is weakness. Similarly, low lean mass may be considered a potential contributing factor to the development of weakness (7). Data from multiple large cohort studies of aging were pooled for this effort (7). The first stage of analyses identified sex-specific cutpoints for weakness that discriminated slow participants (walking speed <0.8 m/s) from those who walked faster (8). In the second stage of the analyses, reported herein, we aimed to identify cutpoints in lean mass that discriminated those who were weak (grip strength <16kg in women or <26kg in men) from those who were stronger. The findings from this work were used to address subsequent goals of the Project, so it is important to consider these results within the context of all other articles in this series.

A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans

Abstract: We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5-28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight-item FI increased from 0.06 ± 0.01 at 5 months to 0.36 ± 0.06 at 19 months and 0.38 ± 0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02 ± 0.005 at 5 months; 0.12 ± 0.008 at 19 months; 0.33 ± 0.02 at 28 months; n = 14). FI scores calculated from 70 self-report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans.

Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point

Abstract: Background. The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear.

Glycans Are a Novel Biomarker of Chronological and Biological Ages

Abstract: Aging is a complex process of accumulation of molecular, cellular, and organ damage, leading to loss of function and increased vulnerability to disease and finally to death (1). It is well known that lifestyle choices such as smoking and physical activity can hasten or delay the aging process (2). Such observations have led to the search for molecular markers of age that can be used to predict, monitor, and provide insight into age-associated physiological decline and disease. Protein structure is defined by the sequence of nucleotides in the corresponding genes, thus the polypeptide sequence of a protein cannot change with age. However, an important structural and functional element of the majority of proteins are the glycans that participate in virtually all physiological processes (3). Glycans are product of a complex pathway that involves hundreds of different proteins and are encoded in a complex dynamic network of hundreds of genes (4). Epigenetic regulation of gene expression is expected to affect protein glycosylation and several publications recently reported this effect (5–8). Changes in glycosylation with age have been shown over 20 years ago (9) and have also replicated in recent large population studies (10–13). Immunoglobulin G (IgG) is an excellent model glycoprotein because its glycosylation has been well defined (Figure 1), and many important functional effects of alternative IgG glycosylation have been described (14). For example, glycosylation acts as a switch between pro- and anti-inflammatory IgG functionality. Most of the IgG molecules are not sialylated and are proinflammatory. Terminal α2,6-sialylation of IgG glycans decreases the ability of IgG to bind to activating FcγRs and promotes recognition by DC-SIGN, which increases expression of inhibitory FcγRIIB and is anti-inflammatory (15). Another fascinating example is the role of core fucose in the modulation of antibody-dependent cellular cytotoxicity: IgG-containing glycans that lack core fucose have 100-fold increased affinity for FcγRIIIA and are therefore much more efficient in activating antibody-dependent cellular cytotoxicity than fucosylated glycoforms of the same molecule (16). On average, 95% of the IgG population is core fucosylated (12); thus, most of the immunoglobulins have a “safety switch,” which prevents them from activating antibody-dependent cellular cytotoxicity. Malfunction of this system appears to be associated with autoimmune diseases as indicated by both pleiotropic effects of genes that associate with IgG glycosylation on different inflammatory and autoimmune diseases, and the observed alterations in IgG glycosylation in systemic lupus erythematous (17) and many inflammatory diseases (18). Figure 1. UPLC analysis of immunoglobulin G (IgG) glycosylation. Each IgG contains one conserved N-glycosylation site on Asn197 of its heavy chain. Different glycans can be attached to this site and the process seems to be highly regulated. UPLC analysis can reveal ... Interindividual variability of IgG glycosylation in a population is large (12) and it appears to be affected by both variation in DNA sequence (19) and environmental factors (11). Most of the studies that investigated glycosylation changes with age were either of limited size or were performed on the total plasma glycome; thus, in addition to changes in glycosylation, the observed differences reflected changes in the concentration of individual plasma proteins. In this study, we focused on glycosylation of IgG and analyzed more than 5,000 individuals from four different European populations to provide definitive data about changes in IgG glycosylation through the lifetime.

Obesity in Aging Exacerbates Blood–Brain Barrier Disruption, Neuroinflammation, and Oxidative Stress in the Mouse Hippocampus: Effects on Expression of Genes Involved in Beta-Amyloid Generation and Alzheimer’s Disease

Abstract: There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet–fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood–brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively. Obesity-induced blood–brain barrier damage was associated with microglia activation, upregulation of activating Fc-gamma receptors and proinflammatory cytokines, and increased oxidative stress. Treatment of cultured primary microglia with sera derived from aged obese mice resulted in significantly more pronounced microglia activation and oxidative stress, as compared with treatment with young sera. Serum-induced activation and oxidative stress were also exacerbated in primary microglia derived from aged animals. Hippocampal expression of genes involved in regulation of the cellular amyloid precursor protein–dependent signaling pathways, beta-amyloid generation, and the pathogenesis of tauopathy were largely unaffected by obesity in aged mice. Collectively, obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood–brain barrier disruption. The resulting neuroinflammation and oxidative stress in the mouse hippocampus likely contribute to the significant cognitive decline observed in aged obese animals.

Rapamycin extends life and health in C57BL/6 mice.

Abstract: Target of rapamycin inhibition by rapamycin feeding has previously been shown to extend life in genetically heterogeneous mice. To examine whether it similarly affected mouse health, we fed encapsulated rapamycin or a control diet to C57BL/6Nia mice of both sexes starting at 19 months of age. We performed a range of health assessments 6 and 12 months later. Rapamycin feeding significantly reduced mTOR activity in most but not all tissues. It also reduced total and resting metabolic rate during the light (inactive) phase of the light:dark cycle in females only but had no effect on spontaneous activity or metabolism during the dark (active) phase of either sex. Males only had less fragmented sleep when fed rapamycin, whereas stride length and rotarod performance were improved in both sexes. Survival was also improved by this late-life rapamycin feeding, and some pathological lesions were delayed. We found no adverse health consequences associated with rapamycin treatment.

Neuroimaging of Mobility in Aging: A Targeted Review

Abstract: Background The relationship between mobility and cognition in aging is well established, but the relationship between mobility and the structure and function of the aging brain is relatively unknown. This, in part, is attributed to the technological limitations of most neuroimaging procedures, which require the individual to be immobile or in a supine position. Herein, we provide a targeted review of neuroimaging studies of mobility in aging to promote (i) a better understanding of this relationship, (ii) future research in this area, and (iii) development of applications for improving mobility. Methods A systematic search of peer-reviewed studies was performed using PubMed. Search terms included (i) aging, older adults, or elderly; (ii) gait, walking, balance, or mobility; and (iii) magnetic resonance imaging, voxel-based morphometry, fluid-attenuated inversion recovery, diffusion tensor imaging, positron emission tomography, functional magnetic resonance imaging, electroencephalography, event-related potential, and functional near-infrared spectroscopy. Results Poor mobility outcomes were reliably associated with reduced gray and white matter volume. Fewer studies examined the relationship between changes in task-related brain activation and mobility performance. Extant findings, however, showed that activation patterns in the cerebellum, basal ganglia, parietal and frontal cortices were related to mobility. Increased involvement of the prefrontal cortex was evident in both imagined walking conditions and conditions where the cognitive demands of locomotion were increased. Conclusions Cortical control of gait in aging is bilateral, widespread, and dependent on the integrity of both gray and white matter.

Prevalence and Clinical Correlates of Sarcopenia in Community-Dwelling Older People: Application of the EWGSOP Definition and Diagnostic Algorithm

Abstract: Aging is accompanied by a change in body composition, including a loss of skeletal muscle mass, resulting in loss of strength and function that has been referred to as sarcopenia (1,2). Muscle impairment is associated with an increased risk of adverse outcomes including physical disability, poor quality of life, and death and thus may be an important and potentially reversible cause of morbidity and mortality in older persons. Since the coining of the term “sarcopenia” in 1989 by Rosenberg (1), many suggestions have been made to establish a clinically applicable definition. Recently, the European Working Group on Sarcopenia in Older People (EWGSOP) recommended using the presence of both low muscle mass and low muscle function (strength or performance) to define sarcopenia (3). This operational definition is based on the concept that defining sarcopenia only in terms of quantitative muscle mass amount would not capture other important age-related muscle changes that strongly affect muscle quality, strength, and muscle power, including but not limited to degeneration of motor neurons with intrinsic changes in muscle fibers and tissue structural organization, impairment in the neuromuscular junction, decrease of type II fibers proportion, impairment of sarcomeric or cytoskeletal signaling and structural protein, connective and fat muscle infiltration, and alteration of muscle metabolism (4,5). Accordingly, the International Working Group on Sarcopenia emphasizes that physical performance, as measured by gait speed, should be part for the diagnostic algorithm to identify people with reduced muscle mass and impaired physical function (1). According to published reports, prevalence of sarcopenia varies between 3% and 52% depending on the study population, definition criteria, and the instruments used to assess muscle mass. However, very few studies used the definition proposed by EWGSOP to define sarcopenia in the general population (6,7). Sarcopenia is a multifactorial process where nutritional, hormonal factors, lifestyle, and diseases exert an important role (8,9). Identification of potentially modifiable risk factors for sarcopenia is of pivotal importance for planning and implementing effective strategies to reduce sarcopenia-related adverse events, including falls, disability, institutionalization, and death. Using data from the population-based InCHIANTI study, we conducted an observational cross-sectional study to estimate prevalence (assessed according to the EWGSOP criteria) and clinical correlates of sarcopenia.

Proteostasis and the Aging Proteome in Health and Disease

Abstract: The maintenance of the proteome is essential to preserve cell functionality and the ability to respond and adapt to the changing environment. This is regulated by the proteostasis network, a dedicated set of molecular components comprised of molecular chaperones and protein clearance mechanisms, regulated by cell stress signaling pathways, that prevents the toxicity associated with protein misfolding and accumulation of toxic aggregates in different subcellular compartments and tissues. The efficiency of the proteostasis network declines with age and this failure in protein homeostasis has been proposed to underlie the basis of common age-related human disorders. The current advances in the understanding of the mechanisms and regulation of proteostasis and of the different types of digressions in this process in aging have turned the attention toward the therapeutic opportunities offered by the restoration of proteostasis in age-associated degenerative diseases. Here, we discuss some of the unresolved questions on proteostasis that need to be addressed to enhance healthspan and to diminish the pathology associated with persistent protein damage.

Epigenetics of Aging and Aging-related Disease

Abstract: Aging is associated with a wide range of human disorders, including cancer, diabetes, cardiovascular, and neurodegenerative diseases. Long thought to be an inexorable road toward decline and diseases, aging is in fact remarkably plastic. Such plasticity could be harnessed to approach age-related diseases from a novel perspective. Although many studies have focused on the genes that impact aging, the nongenetic regulation of aging is gaining increasing attention. Specifically, aging is associated with profound epigenetic changes, resulting in alterations of gene expression and disturbances in broad genome architecture and the epigenomic landscape. The potential reversibility of these epigenetic changes that occur as a hallmark of aging offers exciting opportunities to alter the trajectory of age-related diseases. This short review highlights key epigenetic players in the regulation of aging, as well as both future goals and challenges to the utilization of epigenetic strategies to delay and reverse the main diseases of aging.

The Motor Signature of Mild Cognitive Impairment: Results From the Gait and Brain Study

Abstract: BACKGROUND: Early motor changes associated with aging predict cognitive decline, which suggests that a "motor signature" can be detected in predementia states. In line with previous research, we aim to demonstrate that individuals with mild cognitive impairment (MCI) have a distinct motor signature, and specifically, that dual-task gait can be a tool to distinguish amnestic (a-MCI) from nonamnestic MCI. METHODS: Older adults with MCI and controls from the "Gait and Brain Study" were assessed with neurocognitive tests to assess cognitive performance and with an electronic gait mat to record temporal and spatial gait parameters. Mean gait velocity and stride time variability were evaluated under simple and three separate dual-task conditions. The relationship between cognitive groups (a-MCI vs nonamnestic MCI) and gait parameters was evaluated with linear regression models and adjusted for confounders. RESULTS: Ninety-nine older participants, 64 MCI (mean age 76.3±7.1 years; 50% female), and 35 controls (mean age 70.4±3.9 years; 82.9% female) were included. Forty-two participants were a-MCI and 22 were nonamnestic MCI. Multivariable linear regression (adjusted for age, sex, physical activity level, comorbidities, and executive function) showed that a-MCI was significantly associated with slower gait and higher dual-task cost under dual-task conditions. CONCLUSION: Participants with a-MCI, specifically with episodic memory impairment, had poor gait performance, particularly under dual tasking. Our findings suggest that dual-task assessment can help to differentiate MCI subtyping, revealing a motor signature in MCI. Language: en

Simple Biologically Informed Inflammatory Index of Two Serum Cytokines Predicts 10 Year All-Cause Mortality in Older Adults

Abstract: SERUM measures of inflammatory activation are among the most reliable markers of risk for adverse health outcomes in older persons (1). Interleukin-6 (IL-6) and other proinflammatory cytokines predict disability and mortality and have been correlated to many chronic diseases that are highly prevalent and frequently result in disability in older persons (1–3). Increasing evidence from basic biological studies suggest that inflammatory cytokines play a direct role in the development and clinical progression of chronic disease states, such as atherosclerosis, diabetes, and cancer, and the typical manifestations of aging, such as sarcopenia, anemia, and cognitive decline (4–9). Although the specific mechanisms that link inflammation to mortality and other adverse health outcomes have not been clarified, developing parsimonious and reliable measures of inflammation may be useful in clinical practice as risk assessment tools, as potential therapeutic targets, and to monitor clinical progression and effectiveness of interventions. In spite of this potential clinical utility, with the potential exception of C-reactive protein (CRP) in cardiovascular and inflammatory diseases (10), inflammatory markers have not yet been widely incorporated into clinical practice (11), partly because there is not yet a “gold standard” inflammatory measurement that best and most reliably predicts adverse outcomes in older adults. In fact, there have been few attempts to develop a comprehensive study of inflammatory markers for this purpose and to aggregate biologically informed measures to maximize predictive validity (11,12). As a result, most studies on the effect of proinflammatory state on health outcomes in older patients still consider cytokines separately. Previous research has suggested that the upregulation of the nuclear factor-kappa B (NFkB)-mediated innate immune system plays a key role in the progressive rise of serum inflammatory markers with aging (13). Building on this biological knowledge, we hypothesized that a simple aggregate measure whose expression is influenced by NFkB activation would be independently predictive of mortality and other adverse outcomes than any single inflammatory marker, after adjusting for age, sex, body mass index (BMI), education, smoking, and CVD status. We sought to evaluate this hypothesis and identify the subset of 15 NFkB-related inflammatory markers that were most predictive of mortality for 10 years in two large longitudinal cohort populations of older adults. As exploratory analyses, we also evaluated (a) whether the inflammatory phenotype for predicting mortality differed according to sex and CVD status and (b) whether the impact of inflammation on mortality changed with age.

Age, Comorbidities, and AIDS Predict a Frailty Phenotype in Men Who Have Sex With Men

Abstract: Background. Adults aging with HIV infection are at risk for age-related comorbidities and syndromes, such as frailty. The objective of this study was to evaluate the expression and predictors of the frailty phenotype (FP) among HIV-infected (HIV+) and HIV-uninfected (HIV−) men who have sex with men.

Assessing the “Physical Cliff”: Detailed Quantification of Age-Related Differences in Daily Patterns of Physical Activity

Abstract: Background. In spite of evidence that physical activity has beneficial effects on health and age-related functional decline, there is a scarcity of detailed and accurate information on objectively measured daily activity and patterns of such activity in older adults.

Association of Sarcopenia With Short- and Long-term Mortality in Older Adults Admitted to Acute Care Wards: Results From the CRIME Study

Abstract: BACKGROUND Sarcopenia is a common condition in older and frail populations, and it has been associated with adverse health outcomes. However, impact of sarcopenia on mortality in hospitalized older adults has rarely been evaluated. Aim of the present study was to investigate the association between sarcopenia and mortality during hospital stay and at 1 year after discharge in older individuals admitted to acute care wards. METHODS This is a multicentre observational study involving 770 in-hospital patients. Muscle mass was quantified with the bioelectrical impedance analysis. The diagnosis of sarcopenia was based on the algorithm proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). After discharge, participants were followed for 1 year. Mortality was assessed during hospital stay and during 1-year follow-up. RESULTS Within the 770 participants (mean age: 81 ± 7 years, 56% women), sarcopenia was present in 214 (28%) of them, 22 participants died during hospital stay, and 113 in the year after discharge. Participants with sarcopenia had a significantly higher in-hospital (6% vs 2%; p = .007) and 1-year mortality (26% vs 14%; p < .001) as compared with participants without sarcopenia. After adjusting for potential confounders, sarcopenia resulted significantly associated with in-hospital (hazard ratio: 3.45; 95% CI: 1.35-8.86) and 1-year mortality (hazard ratio: 1.59; 95% CI: 1.10-2.41). CONCLUSIONS Sarcopenia is a prevalent condition among older adults admitted to acute care wards and it is associated with increased short- and long-term mortality in hospitalized older adults.

Stress Biology and Aging Mechanisms: Toward Understanding the Deep Connection Between Adaptation to Stress and Longevity

Abstract: The rate of biological aging is modulated in part by genes interacting with stressor exposures. Basic research has shown that exposure to short-term stress can strengthen cellular responses to stress ("hormetic stress"). Hormetic stress promotes longevity in part through enhanced activity of molecular chaperones and other defense mechanisms. In contrast, prolonged exposure to stress can overwhelm compensatory responses ("toxic stress") and shorten lifespan. One key question is whether the stressors that are well understood in basic models of aging can help us understand psychological stressors and human health. The psychological stress response promotes regulatory changes important in aging (e.g., increases in stress hormones, inflammation, oxidative stress, insulin). The negative effects of severe stress are well documented in humans. Potential positive effects of acute stress (stress resistance) are less studied, especially at the cellular level. Can stress resistance slow the rate of aging in humans, as it does in model organisms? If so, how can we promote stress resistance in humans? We urge a new research agenda embracing the continuum from cellular stress to psychological stress, using basic and human research in tandem. This will require interdisciplinary novel approaches that hold much promise for understanding and intervening in human chronic disease.

Markers of Human Skeletal Muscle Mitochondrial Biogenesis and Quality Control: Effects of Age and Aerobic Exercise Training

Abstract: Perturbations in mitochondrial health may foster age-related losses of aerobic capacity (VO2peak) and skeletal muscle size. However, limited data exist regarding mitochondrial dynamics in aging human skeletal muscle and the influence of exercise. The purpose of this study was to examine proteins regulating mitochondrial biogenesis and dynamics, VO2peak, and skeletal muscle size before and after aerobic exercise training in young men (20 ± 1 y) and older men (74 ± 3 y). Exercise-induced skeletal muscle hypertrophy occurred independent of age, whereas the improvement in VO2peak was more pronounced in young men. Aerobic exercise training increased proteins involved with mitochondrial biogenesis, fusion, and fission, independent of age. This is the first study to examine pathways of mitochondrial quality control in aging human skeletal muscle with aerobic exercise training. These data indicate normal aging does not influence proteins associated with mitochondrial health or the ability to respond to aerobic exercise training at the mitochondrial and skeletal muscle levels.

Advances in Geroscience: Impact on Healthspan and Chronic Disease

Abstract: Population aging is unprecedented, without parallel in human history, and the 21st century will witness even more rapid aging than did the century just past Improvements in public health and medicine are having a profound effect on population demographics worldwide By 2017, there will be more people over the age of 65 than under age 5, and by 2050, two billion of the estimated nine billion people on Earth will be older than 60 (http://unfpaorg/ageingreport/) Although we can reasonably expect to live longer today than past generations did, the age-related disease burden we will have to confront has not changed With the proportion of older people among the global population being now higher than at any time in history and still expanding, maintaining health into old age (or healthspan) has become a new and urgent frontier for modern medicine Geroscience is a cross-disciplinary field focused on understanding the relationships between the processes of aging and age-related chronic diseases On October 30-31, 2013, the trans-National Institutes of Health GeroScience Interest Group hosted a Summit to promote collaborations between the aging and chronic disease research communities with the goal of developing innovative strategies to improve healthspan and reduce the burden of chronic disease

Oropharyngeal dysphagia is a risk factor for readmission for pneumonia in the very elderly persons: observational prospective study.

Abstract: BACKGROUND To determine whether oropharyngeal dysphagia is a risk factor for readmission for pneumonia in elderly persons discharged from an acute geriatric unit. METHODS Observational prospective cohort study with data collection based on clinical databases and electronic clinical notes. All elderly individuals discharged from an acute geriatric unit from June 2002 to December 2009 were recruited and followed until death or December 31, 2010. All individuals were initially classified according to the presence of oropharyngeal dysphagia assessed by bedside clinical examination. Main outcome measure was readmission for pneumonia. Clinical notes were reviewed by an expert clinician to verify diagnosis and classify pneumonia as aspiration or nonaspiration pneumonia. RESULTS A total of 2,359 patients (61.9% women, mean age 84.9 y) were recruited and followed for a mean of 24 months. Dysphagia was diagnosed in 47.5% of cases. Overall, 7.9% of individuals were readmitted for pneumonia during follow-up, 24.2% of these had aspiration pneumonia. The incidence rate of hospital readmission for pneumonia was 3.67 readmissions per 100 person-years (95% CI 3.0-4.4) in individuals without dysphagia and 6.7 (5.5-7.8) in those with dysphagia, with an attributable risk of 3.02 readmissions per 100 person-years (1.66-4.38) and a rate ratio of 1.82 (1.41-2.36). Multivariate Cox regression showed an independent effect of oropharyngeal dysphagia, with a hazard ratio of 1.6 (1.15-2.2) for hospitalization for pneumonia, 4.48 (2.01-10.0) for aspiration pneumonia, and 1.44 (1.02-2.03) for nonaspiration pneumonia. CONCLUSION Oropharyngeal dysphagia is a very prevalent and relevant risk factor associated with hospital readmission for both aspiration and nonaspiration pneumonia in the very elderly persons.

Sarcopenia: An Independent Predictor of Mortality in Community-Dwelling Older Korean Men

Abstract: BACKGROUND The concept of sarcopenia has expanded recently to include muscle strength or physical performance. We investigated whether the Europe Working Group on Sarcopenia in Older People (EWGSOP) definition of sarcopenia predicts the risk of all-cause mortality in community-dwelling older adults. METHODS This study included 284 men and 272 women aged 65 and older. The outcome was all-cause mortality during the 6-year follow-up period. We defined sarcopenia based on the EWGSOP definitions of sarcopenia: height (ht)- or weight (wt)-adjusted appendicular skeletal muscle mass (ASM/ht(2) or ASM/wt) assessed by dual-energy x-ray absorptiometry, leg muscle strength, and short physical performance battery test score. RESULTS During the 6-year follow-up, 40 men and 19 women died. The risk of death was 2.99 times and 3.22 times higher in men with sarcopenia identified by ASM/ht(2) and ASM/wt, respectively, compared with nonsarcopenic men. The hazard ratio for death was 5.37 for men with weak leg muscle strength. Men with a low short physical performance battery score had a 3.15 times higher risk of death compared with those with high short physical performance battery scores, even after adjusting for all covariates. The adjusted hazard ratios for EWGSOP-defined sarcopenia were 4.00 for ASM/ht(2) and 6.89 for ASM/wt in men. By contrast, sarcopenia defined by these criteria was not associated with a higher risk of death in women. CONCLUSIONS Our data suggest that, in older men, EWGSOP-defined sarcopenia is related to higher mortality compared with nonsarcopenia regardless of the ASM/ht(2) or ASM/wt index. In older women, further studies with large sample sizes are needed to assess whether EWGSOP-defined sarcopenia increases the mortality risk.

Brain Pathology Contributes to Simultaneous Change in Physical Frailty and Cognition in Old Age

Abstract: Objective. First, we tested the hypothesis that the rate of change of physical frailty and cognitive function in older adults are correlated. Next, we examined if their rates of change are associated with the same brain pathologies. Methods. About 2,167 older adults participating in the Religious Orders Study and the Rush Memory and Aging Project had annual clinical evaluations. Bivariate random coefficient models were used to estimate simultaneously the rates of change in both frailty and cognition, and the correlation of change was characterized by a joint distribution of the random effects. Then, we examined whether postmortem indices from deceased were associated with the rate of change of frailty and cognition. Results. During an a verage follow-up of 6 years, frailty worsened by 0.09 unit/y and cognition declined by 0.08 unit/y. Most individuals showed worsening frailty and cognition (82.8%); 17% showed progressive frailty alone and <1% showed only cognitive decline. The rates of change of frailty and cognition were strongly correlated (ρ = −0.73, p < .001). Among deceased (N = 828), Alzheimer’s disease pathology, macroinfarcts, and nigral neuronal loss showed independent associations with the rate of change in both frailty and cognition (all ps < .001). In these models, demographics explained about 9% of the variation in individual rate of change in frailty, and neuropathologies explained about 8%. In contrast, demographics and neuropathologies accounted for 2% and 30%, respectively, of the variance in the cognitive decline. Conclusion. The rates of change in frailty and cognition are strongly correlated and this may be due in part because

Type 2 Diabetes and Antidiabetic Medications in Relation to Dementia Diagnosis

Abstract: Background Type 2 diabetes (T2D) has been shown to increase dementia risk, but few studies evaluated the relationship between antidiabetic treatment and dementia. Methods We followed up 67,731 participants who were nondemented, nondiabetic, aged 65 or over at baseline from January 2004 to December 2009, to observe the onset of T2D (median follow-up 2.4 years), and to compare the risk of the development of dementia associated with particular types of antidiabetic medication among participants with T2D who had solely one type of antidiabetic agents throughout the follow-up period (median follow-up for participants with T2D 3.1 years). Results The hazard ratio for dementia diagnosis in the new-onset T2D participants compared with the non-T2D participants was 1.56 (95%CI: 1.39-2.18). The relative rate of dementia was 5.31 (95% CI: 1.89-14.96) for participants taking thiazolidinediones (n = 28) and 1.22 (95% CI: 0.78-1.91) for those taking sulfonylureas (n = 796) compared to those taking metformin (n = 1,033). The risk of dementia was higher in ever (n = 841) versus never users (n = 4,579) of thiazolidinediones: 1.44 (95% CI: 1.12-1.86). Conclusions Diabetes is associated with an increased risk of dementia. The risk effect becomes weaker provided that participants take sulfonylureas or metformin rather than thiazolidinediones for a longer period.

Aging Exacerbates Obesity-induced Cerebromicrovascular Rarefaction, Neurovascular Uncoupling, and Cognitive Decline in Mice

Abstract: Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet–fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood–brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood–brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.