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Background Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty. Methods Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline. Results In the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk. Conclusion The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

Objectives Our primary objective was to examine the distribution of 3-m usual walk, five repeated chair stands, and three static balance stance performances among age and gender subgroups of adults at least 65 years in two national data sets. We secondarily determined whether demographic–function associations varied across data sets, birth cohorts, or models incorporating data from those “unable to do” tasks. Methods Two nationally representative data sets were used to generate survey weight-adjusted performance distributions: the 2015–2016 National Social Life Health and Aging Project and the 2016 National Health and Aging Trends Study. We then regressed walk and chair stand performance on age, gender, and race/ethnicity, examining differences across data sets, birth cohorts (1920–1947, 1948–1965), and before/after incorporating the “unable to do” performers. Results Findings confirmed the gradual decline in function with age and allowed estimation of “relative” performance within age/gender subgroups. Data set distribution differences were noted, possibly due to recruitment, eligibility, and protocol variations. Demographic associations were similar across data sets but generally weaker among the 1948–1965 cohort and in models including the sizable “unable to do” group. Discussion We present the largest, most current Short Physical Performance Battery reference data in U.S. adults aged 65 or older. Findings support standardization of administration protocols in research and clinical care and differentiating absolute from relative performance.

Low physical activity is a criterion of phenotypic frailty defined as an increased state of vulnerability to adverse health outcomes. Whether disengagement from daily all-purpose physical activity is prospectively associated with frailty, and possibly modified by chronic inflammation-a pathway often underlying frailty-remains unexplored.Using STURDY (Study to Understand Fall Reduction and Vitamin D in You) data from 477 robust/prefrail adults (mean age = 76 ± 5 years; 42% women), we examined whether accelerometer patterns (activity counts/day, active minutes/day, and activity fragmentation [broken accumulation]) were associated with incident frailty using Cox proportional-hazard regression. Baseline interactions between each accelerometer metric and markers of inflammation that include interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha receptor 1 (TNF-aR1) were also examined.Over an average of 1.3 years, 42 (9%) participants developed frailty. In Cox regression models adjusted for demographics, medical conditions, and device wear days, every 30 min/day higher baseline active time, 100,000 more activity counts/day, and 1% lower activity fragmentation was associated with a 16% (p = 0.003), 13% (p = 0.001), and 8% (p0.001) lower risk of frailty, respectively. No interactions between accelerometer metrics and either baseline IL-6, CRP, TNF-aR1 were detected (interaction p0.06 for all).Among older adults who are either robust or prefrail, constricted patterns of daily physical activity (i.e., lower total activity minutes and counts, and higher activity fragmentation) were prospectively associated with higher risk of frailty, but not modified by frailty-related chronic inflammation. Additional studies, particularly trials, are needed to understand if this association is causal.

Cell motility is essential to many biological processes as cells navigate and interact within their local microenvironments. Currently, most methods to quantify cell motility rely on the ability to follow and track individual cells. However, results from these approaches are typically reported as averaged values across cell populations. While these approaches offer biological simplicity, it limits the ability to assess cellular heterogeneity and infer generalizable patterns of single-cell behaviors at baseline or after perturbations. Here, we present CaMI, a computational framework that takes advantage of the single-cell nature of cell motility data to identify and classify distinct spatio-temporal behaviors of single cells. Using CaMI, we demonstrate the ability to robustly classify single-cell motility patterns in a large dataset (n=74,253 cells), quantify spatio-temporal heterogeneities, determine motility patterns in unclassified cells, and provide a visualization scheme for direct interpretation of dynamic cell behaviors. Furthermore, as a biological proof of concept, we investigate the biphasic spatial and temporal responses of T-cell lymphoma cells moving in Collagen-I gels of varying collagen concentrations and predict the dimensionality (2D vs. 3D) of matched cellular conditions based solely on spatio-temporal heterogeneities. Together, we present a multivariate framework to robustly classify emergent patterns of single-cell behaviors, highlighting cellular heterogeneity as a critical feature that establishes the behaviors of cellular populations.

Angiotensin system, aging, and Alzheimer's disease are tightly linked. Of the brain angiotensin receptors, the subtype 2 receptor (AT2R) is relatively less studied. Canonically, the AT2R functions through nitric oxide release, and its activation has been linked to vasodilatation and neurite outgrowth as well as anti-inflammation. How AT2R signals is not known, however, an AT2R-binding protein (ATIP) has been recently described. Controversies exist on the link between ATIP and AT2R functions. Here, we describe the development of the first non-antibody based ultra-sensitive and specific quantitative mass spectrometry assay for ATIP. Using a technique that permits targeted analysis of multiple peptides across multiple samples in a single mass spectrometry run, known as TOMAHAQ, we have identified specific human tryptic peptides that permit quantification of ATIP abundance. We have used this method to quantify ATIP in postmortem frontal cortex samples of older adults (n= 60) with Alzheimer’s dementia (AD). We correlated levels of ATIP to brain RAS receptors, and biomarkers of AD pathogenesis including oxidative stress, inflammation, mitochondrial dysfunction as well as amyloid-β, and tau burden. Our results show that ATIP expression (ANLKNPQIMYLEQELESLK sequence of ATIP) is positively correlated with neuronal nitric oxide synthase (nNOS) (p = 0.009, r = 0.337). Furthermore, expression of ATIP is negatively correlated with amyloid-β load in several brain regions including hippocampus (p= 0.014, r= -0.317), entorhinal cortex (p= 0.010, r= -0.331), frontal cortex (p= 0.023, r= -0.294), and overall (p= 0.004, r= -0.365). These results highlight a potential protective role for ATIP in Alzheimer’s disease.

When confronted with a major physical stressor, some older adults are able to recover to baseline with minimal changes, while others undergo irreversible declines. The ability to adapt and recover well from physical stress is called physical resilience and may be impeded by altered glucose-insulin dynamics. Among 55 participants in the pilot phase of the Study of Physical Resilience IN Geriatrics(SPRING), we examined associations between metabolic syndrome and/or diabetes status to physical resiliency recovery parameters after the clinical stressors total knee replacement and bone marrow transplant. These parameters included health outcomes, functional recovery, and pain in the weeks after the intervention. Additionally, we hypothesized that less resilient individuals would have abnormal glucose and insulin responses to a 75-gram oral glucose tolerance test at 0, 30, 60, 120 minutes and tested this in a subset (n=40) without known diabetes. Exploratory analyses of this pilot study will be presented during this session.

Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease associated with reduced physical fitness, higher disease burden, and impaired cognitive functions in late life. Thus investigating antecedents, outcomes and correlates of metabolic health is a priority in order to promote healthier lifestyles and successful aging. This symposium compiles four empirical interdisciplinary studies that examine the role of metabolic health/risk on different timescales. Employing advanced modeling approaches to data obtained in large-scale studies, these reports will shed light on potential antecedents, correlates, and consequences thereof. First, Kalyani and colleagues will report data from the SPRING (Study of Physical Resilience IN Geriatrics) study on the interrelation between metabolic syndrome, glucose intolerance, and physical resilience.Second, Buchmann and colleagues examine the association of the metabolic syndrome and Lipoprotein(a) finding that hormonal aspects and in particular menopausal alterations seem to moderate theassociation between MetS and Lp(a). Third, Demuth and colleagues show how metabolic health is related to specific DNA methylation age acceleration as derived from five different epigenetic clocks, namely PhenoAge, and GrimAge.Fourth, Duezel and colleagues examine the neural correlates of metabolic risk in a sample of older adults finding that lower metabolic risk is linked to greater GMI in the prefrontal cortex. Conjointly, findings demonstrate the multifaceted nature of metabolic risk across adulthood and across different timescales. Walston will critically discuss the contributions from an aging perspective and discuss implications for future research.

Chronic inflammation, oxidative stress, and dysregulation of the renin–angiotensin system are closely linked, and their crosstalk commonly contributes to age-related physical and cognitive decline. The primary dementia-protective benefits of Angiotensin II type 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, there is an independently regulated brain-specific renin–angiotensin system. Here, we examined the impact of 4 weeks of oral Losartan treatment on the brains of aged (100 weeks old) IL-10−/− mice, an animal model of chronic inflammation and frailty. Our data show that aged IL-10−/− mice have higher AT1R and Nitrotyrosine (oxidative stress marker) levels in their frontal cortex tissue but not in cerebellar or hippocampal tissue compared to age- and sex-matched wild type mice. Losartan treatment for 4 weeks is associated with lower AT1R protein level, Nitrotyrosine, and Tau protein in the frontal cortex of aged IL-10−/− mice. Our results highlight the impact of Losartan, an AT1R blocker commonly prescribed for treating high blood pressure, on the brain-specific angiotensin system and AT1R-linked downstream effects such as brain oxidative stress damage and Tau burden in a frailty mouse model.

BACKGROUND: Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty. METHODS: Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline. RESULTS: In the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk. CONCLUSION: The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

Background/aim:Cost-efficient methods are essential for successful participant recruitment in clinical trials. Patient portal messages are an emerging means of recruiting potentially eligible patients into trials. We assessed the response rate and complaint rate from direct-to-patient, targeted recruitment through patient portals of an electronic medical record for a clinical trial, and compared response rates by differences in message content.Methods:The Study to Understand Fall Reduction and Vitamin D in You (STURDY) trial is a National Institutes of Health–sponsored, community-based study of vitamin D supplementation for fall prevention in older adults conducted at Johns Hopkins. Potential participants were identified using the Epic electronic medical record at the Johns Hopkins Health System based on age (≥70 years), ZIP code (30-mile radius of study site), and prior activation of a patient portal account. We prepared a shorter message and a longer message. Both had basic information about study participation, but the longer message also contained information about the significance of the study and a personal invitation from the STURDY principal investigator. The Hopkins Institutional Review Board did not require prior consent from the patient or their providers. We calculated the response rate and tracked the number of complaints and requests for removal from future messages. We also determined response rate according to message content.Results:Of the 5.5 million individuals receiving care at the Johns Hopkins Health System, a sample of 6896 met our inclusion criteria and were sent one patient portal recruitment message between 6 April 2017 and 3 August 2017. Assessment of enrollment by this method ended on 1 December 2017. There were 116 patients who expressed interest in the study (response rate: 1.7%). Twelve (0.2%) recipients were randomized. There were two complaints (0.03%) and one request to unsubscribe from future recruitment messages (0.01%). Response rate was higher with the longer message than the shorter message (2.1% vs 1.2%; p = 0.005).Conclusion:Patient portal messages inviting seniors to participate in a randomized controlled trial resulted in a response rate similar to commercial email marketing and resulted in very few complaints or opt-out requests. Furthermore, a longer message with more content enhanced response rate. Recruitment through patient portals might be an effective strategy to enroll trial participants.

End-stage renal disease (ESRD) causes age-accelerating disease and disproportionally affects older and minority patients; the preferred treatment is kidney transplantation (KT). Rates of KT have risen 5-fold for older adults since 1990 but there is great heterogeneity in KT outcomes by frailty and waitlist status. The person-environment fit theory posits that improving a person’s lived environment will facilitate optimal individual functioning. We recruited a balanced sample of 20 participants (mean age 60, range 35-82) with respect to their frail/ pre-frail and inactive/ active waitlist status to explore personal experience and the lived environment through the use of photovoice, gaining insight into the person-environment fit of those older adults awaiting KT. We will discuss IRB issues, recruitment and logistical tips with using Photovoice. This work will help to inform what vulnerable and marginalized older adults awaiting KT must be prepared for psychologically and physically, including modifications needed to their lived environments.

Dysregulation of energy producing metabolic pathways has been observed in older adults with frailty. In this study, we used liquid chromatography–mass spectrometry technology to identify aging- and frailty-related differences in metabolites involved in glycolysis, the tricarboxylic (TCA) cycle, and other energy metabolism-related pathways in the serum of a cohort of community-dwelling adults aged 20–97 (n = 146). We also examined the relationship between serum levels of metabolites and functional measures, physical frailty, and risk status for adverse health outcomes. We observed elevated levels of TCA cycle and glycolytic intermediates in frail subjects; however, the differences in the levels of ATP and other energy metabolites between young, nonfrail, and frail adults were not significant. Instead, we found that serum levels of neurotransmitters N-acetyl-aspartyl-glutamate, glutamate, and γ-aminobutyric acid were significantly elevated in older adults with frailty. These elevations of glycolytic and TCA cycle intermediates, and neurotransmitters may be part of the biological signature of frailty.

Low physical activity (PA) is a common phenotype of frailty, but whether disengagement of daily lifestyle PA signals impending frailty remains unexplored. Using STURDY (Study to Understand Fall Reduction and Vitamin D in You) data from 499 robust/prefrail adults (mean age=76 + 5 years; 42% women), we examined whether accelerometer patterns (activity counts/day, active minutes/day, and activity fragmentation) were prospectively associated with incident frailty over 2 years of follow-up; 48 (10%) participants developed frailty. In Discrete-Cox hazard models adjusted for demographics, medical conditions, and device wear days, every 30 min/day higher baseline active time, 100,000 more activity counts/day, and 1% lower activity fragmentation was associated with a 13% (p=0.003), 10% (p=0.001), and 8% (p

An increase in life expectancy and an aging population has resulted in increased risks and prevalence of age-related diseases. Previous studies have shown that factors, such as chronic stress, are associated with shorter telomere length. When telomeres become critically short, cells enter a state of senescence, which is a hallmark of aging. Several prior studies examining the relationship between caregiving and telomere length have reported mixed results. The present study utilized data from the Caregiving Transitions Study, an ancillary study to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. The difference in telomere length across an average ~8.6 years was compared between 235 incident caregivers and 229 controls. Telomere length was determined using the qPCR telomere-to-single copy gene (IFNB1) ratio (T/S) for each participant at both baseline and follow-up timepoints. Regression models controlling for age, sex, race, and baseline telomere length examined the association between caregiving status (exposure) and the telomere length change (□T/S). Sensitivity models adjusted for potential lifestyle and socioeconomic factors, including income, education, BMI, cigarette smoking, and alcohol use. We did not observe a significant association between □T/S and caregiving (beta=0.041, p=0.615). Adding lifestyle and socioeconomic factors did not change the null relationship (beta=0.062, p=0.455). In conclusion, this study provides evidence against an association between caregiving and the change in telomere length. Ultimately, more research to address the complex relationship between caregiving and telomere attrition is needed in order to prevent or reduce adverse outcomes and improve the well-being of caregivers and care recipients.

The chronic activation of the immune system is commonly observed in older adults, and is highly associated with multiple chronic disease states and Geriatric syndromes including physical frailty, sarcopenia and mild cognitive impairment. Chronic inflammation is multifactorial, and the individual inflammatory mediators that drive the development and propagation of disease states impact normal tissue homeostasis as well as stem cell vitality. This session will discuss age-related etiologies of chronic inflammation and specific inflammatory mediators and their measurement, including Tumor Necrosis Factor (TNF) alpha and its receptors. Inflammation-driven molecular pathways that most impact relevant chronic disease states such as the tryptophan degradation pathway, and its relationship to pathophysiological changes, will also be considered. Finally, discussion of potential treatment modalities, including several emerging from Geroscience research, will be described as will their impact on chronic disease states.

The cytokine interleukin-6 (IL-6) has pleiotropic effects in aging and is elevated in frail older adults. We have developed a conditional mouse model to better characterize the role of IL-6 in promoting frailty and age-related mitochondrial dysregulation. The human IL-6 (hIL-6) knock-in mouse (TetO-hIL6) was developed utilizing CRISPR/Cas9 technology with transgene donor vector containing a tetracycline response element promoter driving expression of hIL-6 cDNA. Male TetO-hIL6 mice were treated with doxycycline-containing water for six weeks starting at 8 months old. RNAseq analysis of whole blood demonstrated significant upregulation of pro-inflammatory related markers at 6 weeks compared to baseline and upregulated cell proliferation and metabolism pathways. Physical testing of TetO-hIL6 mice before and after hIL-6 induction demonstrated decreased grip strength (p =0.003), decreased running capacity (p = 0.02), and 40% increase in falls off of the treadmill (p = 0.001). Induced mice also demonstrated decreased basal body temperature (p < 0.001). Given the significant dysregulation of metabolism-related genes in RNAseq analysis and changes in basal body temperature following hIL-6 induction, we next performed untargeted metabolomics on plasma from mice at baseline and 6 weeks post-induction to better evaluate metabolic changes associated with hIL-6 elevation. We found changes in key serum metabolites, including circulating adenosine triphosphate (56% reduction, p = 0.02), pyruvate (35% reduction, p = 0.0006), alpha-ketoglutarate (47% reduction, p = 0.04), and succinate (306% increase, p = 0.001). The TetO-hIL6 mouse model allows for induction of hIL-6 at various timepoints across the lifespan and demonstrates features of a frailty phenotype.

Frailty is most often conceptualized as an age-related medical syndrome with a biological basis that results in substantial vulnerability stressors and adverse health outcomes. It is increasingly thought of as the geriatric syndrome that underlies all other geriatric syndromes. Multiple measurement tools have been developed that have helped to differentiate frail from more robust or resilient older adults; and these tools enabling the characterization of and consequences of frailty, as well as its underlying biology. The recognition of frailty as a condition of advanced vulnerability has led to the development of interventions and novel approaches to integrate frailty into clinical practice. The following chapter describes the conceptualization of frailty, surveys the vast array of tools used to identify frailty, provides demographic information and epidemiological characterizations of causes and consequences of frailty, identifies important biological and environmental drivers of frailty, and describes the clinical efforts underway to better utilize frailty tools.

Objectives Evidence suggests vitamin D deficiency is associated with developing frailty. However, cardiometabolic factors are related to both conditions and may confound and/or mediate the vitamin D–frailty association. We aimed to determine the association of vitamin D concentration with incidence of frailty, and the role of cardiometabolic diseases (cardiovascular disease, diabetes, hyperlipidemia, hypertension) in this relationship. Design Prospective longitudinal cohort study (7 visits from 1994–2008). Setting Baltimore, Maryland. Participants Three hundred sixty-nine women from the Women's Health and Aging Study II aged 70–79 years, free of frailty at baseline. Measurements Serum circulating 25-hydroxyvitamin D (25[OH]D) concentration was assessed at baseline and categorized as

Aging and mitochondrial function have been closely linked. We recently reported the identification of a mitochondrial angiotensin system. We hypothesized that angiotensin AT1 receptor blockade would increase energy production and mitochondrial biogenesis and reduce oxidative stress in aging hearts. We used Magnetic resonance spectroscopy to measure cardiac energy metabolism and function in young (20 wks old), aged (150 wks old) mice at baseline and after 4 weeks of losartan (50 mg/kg/day). For mitobiogenesis, qPCR was used to calculate CytB (mitochondrial gene)/GAPDH (nuclear gene) ratio and to measure mito-survival genes Sirt1, Sirt3, Nampt, and PGC-1α. Cardiomyocyte mitochondria from young, aged and treated mice were examined with electron microscopy. The expression of nitrotyrosine was quantified by immunohistochemistry. Older animals hearts (n=9) exhibited increase in LV mass (103±9 mg versus 120±8 mg, young (n=8) versus old (n=9), P

INTRODUCTION: C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Cigarette smoking is a major risk factor in the development of CVD and has been shown to affect circulating levels of CRP. Therefore, we sought to determine how this important environmental exposure may influence genetic associations with CRP in a multi-ethnic setting. METHODS: Using the ITMAT Broad-CARe (IBC) SNP array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate genes for CVD pathways, we performed a meta-analysis of up to 26,065 participants of European descent and 7,584 participants of African descent for association with log-CRP level within smoking status stratum. The 2 smoking strata were: never smokers and ever smokers (comprising of current and former smokers). We conducted IBC-wide association scans for CRP within cohort-, race- and smoking-stratum and meta-analyzed by race. Samples were from the Candidate gene Association Resource (CARe) cohorts (Atherosclerosis Risk in Communities Study, Framingham Heart Study, Cardiovascular Health Study, Cleveland Family Study , Coronary Artery Risk Development in Young Adults Study, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis Study). Results were considered to be panel wide statistically significant if p RESULTS: The overall sample size for ever smokers (never smokers) was 11,698 (10,344) in European Americans and 3,448 (4,330) in African Americans. The per-allele beta coefficients for genes previously established to be associated with CRP and present on the IBC chip ( CRP, APOE, GCKR, IL6R, LEPR, HNF1A, NLRP3 ) were very similar in magnitude between smoking strata in European Americans. However, in the African Americans, the estimated per-allele CRP and IL6R betas were 2-times larger for the ever smokers as compared to the never smokers. In the European American analysis, one gene not previously reported for association with CRP reached IBC-wide significance for a CRP-lowering effect in the never smokers ( GSTT1 , p=4.8E-07 for SNP rs405597 ), but not in the ever smokers (p=0.078). CONCLUSION: This large scale candidate gene based meta-analysis identified one novel locus for CRP ( GSTT1 ) associated with serum CRP levels in those reporting having never regularly smoked. Polymorphisms in GSTT1 , which plays a role in detoxification, have previously been reported to interact with smoking for other phenotypes including birth weight and colorectal cancer. We also observed evidence that smoking modifies the effects for previously established loci CRP and IL6R in African Americans. These results may identify important context genetic specific effects that influence chronic inflammation.

To determine whether hyperglycemia is related to prevalent frailty status in older women.Secondary data analysis of baseline data of a prospective cohort study.Baltimore, Maryland.Five hundred forty-three women aged 70 to 79.Research used baseline data from 543 participants in the Women's Health and Aging Studies I and II aged 70 to 79 who had all variables needed for analyses. The dependent variable was baseline frailty status (not frail, prefrail, frail), measured using an empirically derived model defining frailty according to weight loss, slow walking speed, weakness, exhaustion, and low activity (1-2 characteristics present=prefrail,OR =3 =frail). Covariates included body mass index (BMI), interleukin-6 (IL-6), age, race, and several chronic diseases. Analyses included descriptive methods and multinomial logistic regression to adjust for key covariates.A hemoglobin A1c (HbA1c) level of 6.5% or greater in older women was significantly associated with higher likelihood of prefrail and frail status (normal HbA1c6.0% was reference). The association between HbA1C levels of 6.0% to 6.5% and frailty status was not different from that of normal HbA1c, but HbA1c levels of 6.5% to 6.9% had nearly twice the likelihood of frailty (odds ratio (OR)=1.96, 95% confidence interval (CI)=1.47-2.59) as normal HbA1c. A HbA1c level of 9.0% or greater was also strongly associated (OR=2.57, 95% CI=1.99,3.32). Significant associations were also seen between baseline prefrail and frail status and low (18.5-20.0 kg/m2) and high (430.0 kg/m2) body mass index (BMI), interleukin-6, and all chronic diseases evaluated, but controlling for these covariates only minimally attenuated the independent association between HbA1c and frailty status.Hyperglycemia is associated with greater prevalence of prefrail and frail status; BMI, inflammation, and comorbidities do not explain the association. Longitudinal research and study of alternative pathways are needed.

To determine whether oxidative stress, as implied by oxidative damage to proteins, is associated with greater mortality in older women living in the community.Longitudinal.Women's Health and Aging Study I, Baltimore, Maryland.Seven hundred forty-six moderately to severely disabled women, aged 65 and older, with baseline measures of serum protein carbonyls.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.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). Log(e) 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.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.

Evolving definitions of frailty, and improved understanding of molecular and physiological declines in multiple systems that may increase vulnerability in frail, older adults has encouraged investigators from many disciplines to contribute to this emerging field of research. This article reports on the results of the 2004 American Geriatrics Society/National Institute on Aging conference on a Research Agenda on Frailty in Older Adults, which brought together a diverse group of clinical and basic scientists to encourage further investigation in this area. This conference was primarily focused on physical and physiological aspects of frailty. Although social and psychological aspects of frailty are critically important and merit future research, these topics were largely beyond the scope of this meeting. Included in this article are sections on the evolving conceptualization and definitions of frailty; physiological underpinnings of frailty, including the potential contributions of inflammatory, endocrine, skeletal muscle, and neurologic system changes; potential molecular and genetic contributors; proposed animal models; and integrative, system biology approaches that may help to facilitate future frailty research. In addition, several specific recommendations as to future directions were developed from suggestions put forth by participants, including recommendations on definition and phenotype development, methodological development to perform clinical studies of individual-system and multiple-system vulnerability to stressors, development of animal and cellular models, application of population-based studies to frailty research, and the development of large collaborative networks in which populations and resources can be shared. This meeting and subsequent article were not meant to be a comprehensive review of frailty research; instead, they were and are meant to provide a more-targeted research agenda-setting process.

To determine whether genetic variants in the ciliary neurotrophic factor (CNTF) gene are associated with muscle strength in older women.Cross-sectional analysis of baseline data from the Women's Health and Aging Studies I (1992) and II (1994), complementary population-based studies.Twelve contiguous ZIP code areas in Baltimore, Maryland.Three hundred sixty-three Caucasian, community-dwelling women aged 70 to 79.Participants were genotyped at the CNTF locus for eight single nucleotide polymorphisms (SNPs), including the null allele rs1800169. The dependent variables were grip strength and the frailty syndrome, identified as presence of three or more of five frailty indicators (weakness, slowness, weight loss, low physical activity, exhaustion). In addition to genotypes, independent variables of body mass index (BMI) and osteoarthritis of the hands were included.Using multivariate linear regression, single SNP analysis identified five SNPs significantly associated with grip strength (P.05), after adjusting for age, BMI, and osteoarthritis. Haplotype analysis was performed, and a single haplotype associated with grip strength was identified (P.01). The rs1800169 null allele fully explained the association between this haplotype and grip strength under a recessive model, with individuals homozygous for the null allele exhibiting a 3.80-kg lower (95% confidence interval=1.01-6.58) grip strength. No association was seen between the CNTF null allele and frailty.Individuals homozygous for the CNTF null allele had significantly lower grip strength but did not exhibit overt frailty. Larger prospective studies are needed to confirm this finding and extend it to additional populations.

To expand the ability to assess physical frailty by developing a Clinical Global Impression of Change in Physical Frailty (CGIC-PF) instrument.Qualitative and quantitative instrument development.Academic centers.s Six expert panel members, 46 clinicians, 24 patients, and 12 caregivers.Literature review and structured group processes with experts, clinicians, and consumers were used to generate an initial list of domains and indicators. Structured interviews with clinical experts in the area of frailty were used to establish relevance and feasibility of measurement of domains. Interrater reliability was assessed through a Web-based study. Geriatricians pilot tested the feasibility of the baseline CGIC-PF with 10 patients.The CGIC-PF includes six intrinsic domains (mobility, balance, strength, endurance, nutrition, and neuromotor performance) and seven consequences domains (medical complexity, healthcare utilization, appearance, self-perceived health, activities of daily living, emotional status, and social status). Each domain has two to four clinical indicators. Change is scored on a 7-point scale from markedly worse to markedly improved. Average interrater reliability of the CGIC-PF for the Web-based cases was 0.97. Geriatricians completed a baseline CGIC-PF on their own patients in 10 minutes or less.The CGIC-PF is a structured assessment of change in physical frailty with defined content and process. It has strong face validity, reliability, and feasibility for use in clinical research. It may be useful as one criterion of change and as an anchor for change in other measures.

The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness.To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus.Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures.Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (Por =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race.These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6% vs 127.2 +/- 1.3%; all p0.05). Exhaustion also was related to elevated inflammation and coagulation markers (p0.05). Exhausted men had markedly elevated CRP levels (6.82 +/- 2.10 mg/L) versus nonexhausted men (3.05 +/- 0.16: p = 0.007). After adjustment for control variables, exhaustion remained associated with albumin (p = 0.033), fibrinogen (p = 0.017), CRP (p = 0.066), and WBC (p = 0.060), whereas associations of depressive symptoms with biochemistry measures lost statistical significance. Thus, depression and exhaustion are associated with low-grade inflammation and elevated coagulation factors in persons aged65 years.