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1.  Subcellular characteristics of functional intracellular renin–angiotensin systems☆ 
Peptides  2012;38(2):437-445.
The renin–angio tensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems.
doi:10.1016/j.peptides.2012.09.016
PMCID: PMC3770295  PMID: 23032352
Renin-angiotensin system; Intracellular; Hypertension; Cardiovascular disease; Angiotensin peptides; Angiotensin receptors
2.  Decline in semicircular canal and otolith function with age 
Objective
To characterize the physiologic nature of the vestibular dysfunction that occurs with the normative aging process.
Study design
Cross-sectional study.
Setting
Tertiary care academic medical center.
Patients
Fifty individuals age 70 and above.
Interventions
Head thrust dynamic visual acuity testing (htDVA) and cervical and ocular vestibular-evoked myogenic potential (VEMP) testing.
Main Outcome Measures
Semicircular canal function measured by htDVA in each of the three semicircular canal planes, and saccular and utricular function measured by cVEMP and oVEMP testing, respectively.
Results
We observed significant declines in semicircular canal function in each of the canal planes as well as otolith function associated with aging. We found that individuals with impaired horizontal and superior semicircular canal function were likely to also have concomitant deficits in utricular but not saccular function. Overall, we noted that the prevalence of semicircular canal dysfunction was highest followed by saccular then utricular impairment, although we did observe individuals with isolated otolith deficits.
Conclusions
These data suggest an overall decline in semicircular canal as well as otolith function associated with aging, although the magnitude of impairment was greater for the semicircular canals than the otoliths in this elderly population. A better understanding of the specific vestibular deficits that occur with aging can inform the development of rational screening, vestibular rehabilitation and fall risk reduction strategies in older individuals.
doi:10.1097/MAO.0b013e3182545061
PMCID: PMC3376350  PMID: 22699991
3.  Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65495–503-specific CD8+ T cells in older adults 
Age  2011;33(4):607-614.
In immunocompetent individuals, cytomegalovirus (CMV) is thought to persist in a latent state in monocytes and myeloid progenitor cells, establishing a lifelong infection. In CMV-seropositive older adults, aging has been associated with both expansion of CMV pp65495–503-specific CD8+ T cell clones and shrinkage of the T cell repertoire that characterize T cell immunosenescence. In fact it has been suggested that chronic CMV infection is a driving force in age-related T cell immunosenescence. In older adults, chronic CMV infection is conventionally diagnosed by positive IgG serology which does not distinguish between past and persistent infections. To better define the relationship between chronic CMV infection and expansion of CMV pp65495–503-specific CD8+ T cells, we directly assessed CMV viral DNA in monocyte-enriched peripheral blood mononuclear cells in 16 HLA-A2-positive elderly volunteers (mean age = 83 years). While all participants had positive CMV IgG serology by enzyme-linked immunosorbent assays, only nine (56%) had detectable CMV DNA by nested polymerase chain reaction. These nine individuals had significantly higher percentages of CMV pp65495–503 tetramer-positive CD8+ T cells (median = 1.3%) than those without detectable CMV DNA (median = 0.1%; p < 0.001). Absolute CMV IgG antibody titers did not differ between these two groups (median = 54.6 vs 44.2 EU/ml, respectively, p = 0.4). CMV IgM titers were negative for all 16 participants, suggesting that recent primary CMV infection was unlikely. These results demonstrate a strong association between the presence of CMV DNA in peripheral monocytes and the expansion of CD8+ T cells specific for the CMV immunodominant epitope pp65495–503. Although the sample size in this study is relatively small, these findings provide initial evidence suggesting the heterogeneity of CMV IgG-seropositive older adult population and CMV viral DNA detection in peripheral monocytes as an informative tool to better understand the relationship between chronic CMV infection and T cell immunosenescence.
doi:10.1007/s11357-011-9205-9
PMCID: PMC3220402  PMID: 21274637
Monocytic CMV DNA; CMV pp65495–503-specific CD8+ T cells; CMV IgG serology; Older adults
4.  IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults 
Age and Ageing  2011;40(4):475-481.
Background: neopterin is a monocyte/macrophage-derived immune activation marker and its levels increase with age. Frailty is an important clinical syndrome of old age. Previous studies have shown significant association between elevated interleukin-6 (IL-6) levels and frailty. The objective of this study was to evaluate IL-6-independent association of serum neopterin levels with prevalent frailty.
Methods: this is a cross-sectional study in community-dwelling older adults recruited from residential and retirement communities in Baltimore, MD, USA. Frailty was determined using validated screening criteria. Serum neopterin and IL-6 levels were measured using standard enzyme-linked immunosorbent assay. Pearson correlation and multivariate linear regression analysis was performed to assess the relationship between log(neopterin) and log(IL-6). Odds ratios (ORs) for frailty were calculated using log(neopterin) and log(IL-6) as continuous measures and across tertiles of neopterin and IL-6 levels, adjusting for age, race, sex, education and body mass index.
Results: one hundred and thirty-three individuals with a mean age of 84 years (range 72–97) completed the study. Neopterin levels were significantly higher in frail older adults than those in non-frail controls [median: 8.94 versus 8.35 nM, respectively, P < 0.001 t-test on log(neopterin)]. Log(neopterin) was significantly associated with prevalent frailty, adjusting for log(IL-6). Participants in the top tertile of neopterin had OR of 3.80 [95% confidence interval (CI) = 1.36–10.6, P < 0.01] for frailty. As expected, participants in the top tertile of IL-6 had OR of 3.29 (95% CI = 1.21–7.86, P < 0.05) for frailty. Log(neopterin) correlated with log(IL-6) (correlation coefficient = 0.19, P < 0.05). Moreover, OR for participants in the top neopterin tertile remained significant after adjusting for IL-6 (OR = 3.97, 95% CI = 1.15–13.72, P < 0.05).
Conclusion: elevated neopterin levels had IL-6-independent association with prevalent frailty, suggesting potential monocyte/macrophage-mediated immune activation in the frail elderly.
doi:10.1093/ageing/afr047
PMCID: PMC3114624  PMID: 21586579
frailty; neopterin; monocyte/macrophage-mediated immune activation; IL-6; elderly
5.  Angiotensin II Type-2 Receptors Modulate Inflammation Through Signal Transducer and Activator of Transcription Proteins 3 Phosphorylation and TNFα Production 
Angiotensin subtype-1 receptor (AT1R) influences inflammatory processes through enhancing signal transducer and activator of transcription proteins 3 (STAT3) signal transduction, resulting in increased tumor necrosis factor-α (TNF-α) production. Although angiotensin subtype-2 receptor (AT2R), in general, antagonizes AT1R-stimulated activity, it is not known if AT2R has any anti-inflammatory effects. In this study, we tested the hypothesis that AT2R activation plays an anti-inflammatory role by reducing STAT3 phosphorylation and TNF-α production. Changes in AT2R expression, TNF-α production, and STAT3 phosphorylation were quantified by Western blotting, Bio-Plex cytokine, and phosphoprotein cellular signaling assays in PC12W cells that express AT2R but not AT1R, in response to the AT2R agonist, CGP-42112 (CGP, 100 nm), or AT2R antagonist PD-123319 (PD, 1 μm). A 100% increase in AT2R expression in response to stimulation with its agonist CGP was observed. Further, AT2R activation reduced TNF-α production by 39% and STAT3 phosphorylation by 83%. In contrast, PD decreased AT2R expression by 76%, increased TNF-α production by 84%, and increased STAT3 phosphorylation by 67%. These findings suggest that increased AT2R expression may play a role in the observed decrease in inflammatory pathway activation through decreased TNF-α production and STAT3 signaling. Restoration of AT2R expression and/or its activation constitute a potentially novel therapeutic target for the management of inflammatory processes.
doi:10.1089/jir.2010.0043
PMCID: PMC3104285  PMID: 21288138
6.  Maximal Heart Rate Prediction in Adults that are Overweight or Obese 
An accurate predictor of maximal heart rate (MHR) is necessary to prescribe safe and effective exercise in those considered overweight and obese when actual measurement of MHR is unavailable or contraindicated. To date, accuracy of MHR prediction equations in individuals that are overweight or obese has not been well established. The purpose of this study was to examine the accuracy of three equations for predicting MHR in adults that are overweight or obese. One-hundred seventy three sedentary adults that were overweight or obese enrolled in weight loss study and performed a VO2peak treadmill test prior to the start of the weight loss treatment. A total of 132 of the 173 participants met conditions for achieving maximal exercise testing criteria and were included in this study. MHR values determined from VO2peak treadmill tests were compared across gender, age and weight status to the following prediction equations: 1) 220 − age, 2) 208 − 0.7 × age, and 3) 200 − 0.48 × age. Among 20-40 year old participants, actual MHR averaged 180 ± 9 beats per minute (BPM) and was overestimated (p < 0.001) at 186 ± 5 BPM with the 220 - age equation. Weight status did not affect predictive accuracy of any of the three equations. For all participants, the equation, 200 − 0.48 × age estimated MHR to be 178 ± 4 BPM, which was greater than the actual (175 ± 12, p = 0.005). Prediction equations showed close agreement to actual MHR, with 208 − 0.7 × age being the most accurate.
doi:10.1519/JSC.0b013e3181d682d2
PMCID: PMC3081386  PMID: 21116203
obesity; exercise prescription; exercise testing; accuracy; equations
7.  Measurement of Organ Structure and Function Enhances Understanding of the Physiological Basis of Frailty: The Cardiovascular Health Study 
Background
Chronic disease is a risk factor for frailty. Previous studies typically consider individual diagnosed diseases, but disease builds over time, possibly in several organs simultaneously.
Objective
We hypothesize that disease burden is associated with frailty independent of diagnosed chronic disease and that physiologic measurements provide greater understanding of the etiology of frailty.
Design
Cross-sectional study.
Setting
Community.
Participants
Cardiovascular Health Study, 1992–93 examination (N=2437, mean (SD) age 74.8 (4.8) years, 43.4% male, 95.8% white).
Measurements
Disease burden and frailty were tabulated using 10-point scales (0=healthy, 10=unhealthy). Disease burden was the sum of measurements characterizing the vasculature, brain, kidneys, lungs, and glucose metabolism. Frailty was assessed with the frailty index reported by Fried. Multivariate linear models were used to determine the association of disease burden (predictor) to frailty (outcome).
Results
Unadjusted, 1 point higher disease burden was associated with a 0.28 point higher frailty score (p<0.0001). White matter grade, forced vital capacity, and cystatin-C were particularly strongly and significantly associated with frailty. Disease burden attenuated the association of frailty with age by 29%, and disease burden and age had similar associations with frailty. Disease burden attenuated the association of frailty with fibrinogen, Factor VIII, and CRP by 32%, 56%, and 83%. Frailty was associated with diagnosed depression, stroke, cognitive impairment, arthritis, and pulmonary disease but not coronary heart disease, diabetes, or kidney disease in the presence of a summary of disease burden. In the adjusted model disease burden remained significantly associated with frailty (β=0.11, p<0.0001).
Conclusion
Disease burden was independently and significantly associated with frailty. These results emphasize that typically unrecognized physiologic changes may importantly contribute to frailty.
doi:10.1111/j.1532-5415.2011.03557.x
PMCID: PMC3282048  PMID: 21883106
Frailty; etiology; disease burden
8.  Heritability Estimates of Endophenotypes of Long and Health Life: The Long Life Family Study 
Background.
Identification of gene variants that contribute to exceptional survival may provide critical biologic information that informs optimal health across the life span.
Methods.
As part of phenotype development efforts for the Long Life Family Study, endophenotypes that represent exceptional survival were identified and heritability estimates were calculated. Principal components (PCs) analysis was carried out using 28 physiologic measurements from five trait domains (cardiovascular, cognition, physical function, pulmonary, and metabolic).
Results.
The five most dominant PCs accounted for 50% of underlying trait variance. The first PC (PC1), which consisted primarily of poor pulmonary and physical function, represented 14.3% of the total variance and had an estimated heritability of 39%. PC2 consisted of measures of good metabolic and cardiovascular function with an estimated heritability of 27%. PC3 was made up of cognitive measures (h2 = 36%). PC4 and PC5 contained measures of blood pressure and cholesterol, respectively (h2 = 25% and 16%).
Conclusions.
These PCs analysis–derived endophenotypes may be used in genetic association studies to help identify underlying genetic mechanisms that drive exceptional survival in this and other populations.
doi:10.1093/gerona/glq154
PMCID: PMC2990267  PMID: 20813793
Heritability; Longevity; Endophenotypes
9.  Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty 
Cytokine  2009;46(3):319-324.
Frailty is an important geriatric syndrome that predicts disability and mortality. Substantial evidence suggests inflammation marked by elevated IL-6 levels as a key pathophysiologic factor that contributes to frailty. CXCL-10, a potent pro-inflammatory chemokine, has increased levels with age and is implicated in several inflammatory conditions. To better understand molecular mechanisms of inflammation activation in frailty, we evaluated monocytic expression of CXCL-10 and other inflammatory pathway genes by pathway-specific gene array analysis and quantitative RT-PCR. Frailty status was determined by the validated criteria. Sixteen pairs of community-dwelling frail and age-, race-, and sex-matched non-frail participants (mean age 83 years, range 72–94) completed the study. Here we report that frail participants had higher CXCL-10 expression levels than matched non-frail controls (1.05 ± 0.88 versus 0.53 ± 0.39, p = 0.04). CXCL-10 expression correlated with IL-6 levels only in frail participants (Spearman correlation coefficient r = 0.52, p = 0.03). Furthermore, frailty-associated CXCL-10 upregulation was highly correlated with IL-6 elevation, both measured by frail-over-non-frail ratios (r = 0.93, p < 0.0001). These findings suggest upregulated monocytic expression of CXCL-10 as an important molecular mechanism that contributes to inflammation activation in frail older adults. Therapeutic implications include potential development of CXCL-10-based interventional strategies for the prevention and treatment of frailty in older adults.
doi:10.1016/j.cyto.2009.02.015
PMCID: PMC3159181  PMID: 19342252
Frailty; CXCL-10; IL-6; Monocytic gene expression; Inflammation
10.  Serum Levels of the Immune Activation Marker Neopterin Change With Age and Gender and Are Modified by Race, BMI, and Percentage of Body Fat 
Background.
Neopterin, a GTP metabolite expressed by macrophages, is a marker of immune activation. We hypothesize that levels of this serum marker alter with donor age, reflecting increased chronic immune activation in normal aging. In addition to age, we assessed gender, race, body mass index (BMI), and percentage of body fat (%fat) as potential covariates.
Methods.
Serum was obtained from 426 healthy participants whose age ranged from 18 to 87 years. Anthropometric measures included %fat and BMI. Neopterin concentrations were measured by competitive ELISA. The paired associations between neopterin and age, BMI, or %fat were analyzed by Spearman's correlation or by linear regression of log-transformed neopterin, whereas overall associations were modeled by multiple regression of log-transformed neopterin as a function of age, gender, race, BMI, %fat, and interaction terms.
Results.
Across all participants, neopterin exhibited a positive association with age, BMI, and %fat. Multiple regression modeling of neopterin in women and men as a function of age, BMI, and race revealed that each covariate contributed significantly to neopterin values and that optimal modeling required an interaction term between race and BMI. The covariate %fat was highly correlated with BMI and could be substituted for BMI to yield similar regression coefficients.
Conclusion.
The association of age and gender with neopterin levels and their modification by race, BMI, or %fat reflect the biology underlying chronic immune activation and perhaps gender differences in disease incidence, morbidity, and mortality.
doi:10.1093/gerona/glq066
PMCID: PMC2903784  PMID: 20478905
Neopterin; Immune activation; Inflammation; BMI; Homeostasis
11.  Losartan Restores Skeletal Muscle Remodeling and Protects Against Disuse Atrophy in Sarcopenia 
Science translational medicine  2011;3(82):82ra37.
Sarcopenia, a critical loss of muscle mass and function because of the physiological process of aging, contributes to disability and mortality in older adults. It increases the incidence of pathologic fractures, causing prolonged periods of hospitalization and rehabilitation. The molecular mechanisms underlying sarcopenia are poorly understood, but recent evidence suggests that increased transforming growth factor–β (TGF-β) signaling contributes to impaired satellite cell function and muscle repair in aged skeletal muscle. We therefore evaluated whether antagonism of TGF-β signaling via losartan, an angiotensin II receptor antagonist commonly used to treat high blood pressure, had a beneficial impact on the muscle remodeling process of sarcopenic mice. We demonstrated that mice treated with losartan developed significantly less fibrosis and exhibited improved in vivo muscle function after cardiotoxin-induced injury. We found that losartan not only blunted the canonical TGF-β signaling cascade but also modulated the noncanonical TGF-β mitogen-activated protein kinase pathway. We next assessed whether losartan was able to combat disuse atrophy in aged mice that were subjected to hindlimb immobilization. We showed that immobilized mice treated with losartan were protected against loss of muscle mass. Unexpectedly, this protective mechanism was not mediated by TGF-β signaling but was due to an increased activation of the insulin-like growth factor 1 (IGF-1)/Akt/mammalian target of rapamycin (mTOR) pathway. Thus, blockade of the AT1 (angiotensin II type I) receptor improved muscle remodeling and protected against disuse atrophy by differentially regulating the TGF-β and IGF-1/Akt/mTOR signaling cascades, two pathways critical for skeletal muscle homeostasis. Thus, losartan, a Food and Drug Administration–approved drug, may prove to have clinical benefits to combat injury-related muscle remodeling and provide protection against disuse atrophy in humans with sarcopenia.
doi:10.1126/scitranslmed.3002227
PMCID: PMC3140459  PMID: 21562229
12.  Cytomegalovirus Infection and the Risk of Mortality and Frailty in Older Women: A Prospective Observational Cohort Study 
American Journal of Epidemiology  2010;171(10):1144-1152.
Cytomegalovirus (CMV), a prevalent pathogen, causes severe disease in immunocompromised humans. However, present understanding is limited regarding the long-term clinical effect of persistent CMV infection in immunocompetent adults. The authors conducted a prospective observational cohort study (1992–2002) of 635 community-dwelling women in Baltimore, Maryland, aged 70–79 years in the Women's Health and Aging Studies to examine the effect of CMV infection on the risk of frailty, a common geriatric syndrome, and mortality in older women. The effect of baseline serum CMV antibody (immunoglobulin G) concentration on the risk of 3-year incident frailty, defined by using a 5-component measure, and 5-year mortality was examined with Cox proportional hazards models. Compared with those who were CMV seronegative, women in the highest quartile of CMV antibody concentration had a greater incidence of frailty (hazard ratio = 3.46, 95% confidence interval: 1.45, 8.27) and mortality (hazard ratio = 3.81, 95% confidence interval: 1.64, 8.83). After adjustment for potential confounders, CMV antibody concentration in the highest quartile independently increased the risk of 5-year mortality (hazard ratio = 2.79, 95% confidence interval: 1.22, 6.40). Better understanding of the long-term clinical consequences of CMV infection in immunocompetent humans is needed to guide public health efforts for this widely prevalent infection.
doi:10.1093/aje/kwq062
PMCID: PMC2877470  PMID: 20400465
antibodies, viral; cytomegalovirus; frail elderly; immunoglobulin G; inflammation; interleukin-6; mortality; virus latency
13.  Health and function of participants in the Long Life Family Study: A comparison with other cohorts 
Aging (Albany NY)  2011;3(1):63-76.
Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.
PMCID: PMC3047140  PMID: 21258136
longevity; exceptional survival; family studies; genetics; healthy aging; genome wide association study; multicenter studies; aging phenotypes
14.  Measuring Systemic Inflammatory Regulation in Older Adults: Evidence and Utility 
Rejuvenation Research  2009;12(6):403-410.
Abstract
Aging is frequently accompanied by a proinflammatory state with adverse health consequences. This state is commonly assessed by markers in serum, either in isolation or ad hoc combination. We sought, alternatively, to develop scores summarizing multiple markers in accordance with biology on inflammatory regulation and evaluate their value added for discriminating functional outcomes in older adults. Data came from InCHIANTI (Invecchiare in Chianti; Aging in the Chianti Area) study participants age 65 years and older. Serum concentrations of seven inflammatory biomediators were subjected to latent variable analysis implementing a biological model of counterbalancing up- and down-regulation processes. Resulting process constructs were approximated by principal component scores; these, and individual markers, were evaluated as predictors of mobility impairment and frailty status in regression analyses, adjusting for key confounders. The biomediators' interrelationships were well predicted by the hypothesized biology. The up-regulation score was independently associated with worsened mobility functioning and frailty risk. For mobility, the association was stronger than, persisted independently of, and accounted for association with each biomediator. The down regulation score was associated with frailty outcomes. We conclude that systemic inflammation is relevant to the process that leads to functional loss in older persons and can be validly measured through biologically informed summary of inflammatory markers.
doi:10.1089/rej.2009.0883
PMCID: PMC2903341  PMID: 20041734
15.  Glutathione Peroxidase Enzyme Activity in Aging 
Background
It is hypothesized that free radical damage contributes to aging. Age-related decline in activity of the antioxidant enzyme glutathione peroxidase (GPx) may contribute to increased free radicals. We hypothesized that GPx activity decreases with age in a population of older women with disability.
Methods
Whole blood GPx activity was measured in baseline stored samples from participants in the Women's Health and Aging Study I, a cohort of disabled community-dwelling older women. Linear regression was used to determine cross-sectional associations between GPx activity and age, adjusting for hemoglobin, coronary disease, diabetes, selenium, and body mass index.
Results
Six hundred one participants had complete demographic, disease, and laboratory information. An inverse association was observed between GPx and age (regression coefficient = −2.9, p < .001), indicating that for each 1-year increase in age, GPx activity decreased by 2.9 μmol/min/L. This finding remained significant after adjustment for hemoglobin, coronary disease, diabetes, and selenium, but not after adjustment for body mass index and weight loss.
Conclusion
This is the first study to examine the association between age and GPx activity in an older adult cohort with disability and chronic disease. These findings suggest that, after age 65, GPx activity declines with age in older women with disability. This decline does not appear to be related to diseases that have been previously reported to alter GPx activity. Longitudinal examination of GPx activity and other antioxidant enzymes in diverse populations of older adults will provide additional insight into age- and disease-related changes in these systems.
PMCID: PMC2964084  PMID: 18511755
Glutathione peroxidase; Oxidative stress; Aging; Older adult
16.  Nonlinear Multisystem Physiological Dysregulation Associated With Frailty in Older Women: Implications for Etiology and Treatment 
Background
Frailty in older adults, defined as a constellation of signs and symptoms, is associated with abnormal levels in individual physiological systems. We tested the hypothesis that it is the critical mass of physiological systems abnormal that is associated with frailty, over and above the status of each individual system, and that the relationship is nonlinear.
Methods
Using data on women aged 70–79 years from the Women’s Health and Aging Studies I and II, multiple analytic approaches assessed the cross-sectional association of frailty with eight physiological measures.
Results
Abnormality in each system (anemia, inflammation, insulin-like growth factor-1, dehydroepiandrosterone-sulfate, hemoglobin A1c, micronutrients, adiposity, and fine motor speed) was significantly associated with frailty status. However, adjusting for the level of each system measure, the mean number of systems impaired significantly and nonlinearly predicted frailty. Those with three or more systems impaired were most likely to be frail, with odds of frailty increasing with number of systems at abnormal level, from odds ratios (ORs) of 4.8 to 11 to 26 for those with one to two, three to four, and five or more systems abnormal (p < .05 for all). Finally, two subgroups were identified, one with isolated or no systems abnormal and a second (in 30%) with multiple systems abnormal. The latter group was independently associated with being frail (OR = 2.6, p < .05), adjusting for confounders and chronic diseases and then controlling for individual systems.
Conclusions
Overall, these findings indicate that the likelihood of frailty increases nonlinearly in relationship to the number of physiological systems abnormal, and the number of abnormal systems is more predictive than the individual abnormal system. These findings support theories that aggregate loss of complexity, with aging, in physiological systems is an important cause of frailty. Implications are that a threshold loss of complexity, as indicated by number of systems abnormal, may undermine homeostatic adaptive capacity, leading to the development of frailty and its associated risk for subsequent adverse outcomes. It further suggests that replacement of any one deficient system may not be sufficient to prevent or ameliorate frailty.
doi:10.1093/gerona/glp076
PMCID: PMC2737590  PMID: 19567825
Frailty etiology; Aging
17.  INFLAMMATION AND STRESS-RELATED CANDIDATE GENES, PLASMA INTERLEUKIN-6 LEVELS, AND LONGEVITY IN OLDER ADULTS 
Experimental gerontology  2009;44(5):350-355.
Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5,000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%-20% higher baseline IL-6 concentration per copy among CHS European-American (EA) participants (all p<10−4). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p=0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415 – longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all 3 studies, the “risk” of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62 – 1.02; p=0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.
doi:10.1016/j.exger.2009.02.004
PMCID: PMC2791897  PMID: 19249341
Inflammation; IL-6; PARP1; Longevity; Genetic Epidemiology
18.  Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14+ monocytes in frail older adults 
Frailty has been increasingly recognized as an important clinical syndrome in old age. The frailty syndrome is characterized by chronic inflammation, decreased functional and physiologic reserve, and increased vulnerability to stressors, leading to disability and mortality. However, molecular mechanisms that contribute to inflammation activation and regulation in frail older adults have not been investigated. To begin to address this, we conducted a pathway-specific gene array analysis of 367 inflammatory pathway genes by lipopolysaccharide (LPS)-challenged CD14+ monocytes from 32 community-dwelling frail and age-, race-, and sex-paired nonfrail older adults (mean age 83 years, range 72–94). The results showed that ex vivo LPS-challenge induced average 2.0-fold or higher upregulated expression of 116 genes in frail participants and 85 genes in paired nonfrail controls. In addition, frail participants had 2-fold or higher upregulation in LPS-induced expression of 7 stress-responsive genes than nonfrail controls with validation by quantitative real time RT-PCR. These findings suggest upregulated expression of specific stress-responsive genes in monocyte-mediated inflammatory pathway in the syndrome of frailty with potential mechanistic and interventional implications.
doi:10.1016/j.mad.2008.10.005
PMCID: PMC2673566  PMID: 19027777
Frailty; Monocyte-mediated inflammatory; pathways; Gene expression; Stress-responsive genes; Geriatrics; Aging
19.  Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation 
Background
Circulating levels of acute phase reactant proteins such as plasma C-reactive protein (CRP) are likely influenced by multiple genes regulating the innate immune response.
Methods
We screened a set of 16 inflammation-related genes for association with CRP in a large, population-based study of healthy young adults (n=1,627). Results were validated in two independent studies (n=1,208 and n=4,310), including a pooled analysis of all 3 studies.
Results
In the pooled analysis, the minor allele of IL1RN 1018 (rs4251961) within the gene encoding interleukin-1 receptor antagonist (IL-1RA) was significantly associated with higher mean plasma log(CRP) level (p < 1 × 10−4). The same IL1RN 1018 allele was associated with higher mean plasma log(IL-6) levels (p=0.004). In the pooled analysis, the minor allele of IL1RN 13888 (rs2232354) was associated with higher fibrinogen, (p = 0.001). The IL1RN 1018 and 13888 variant alleles tag a clade of IL1RN haplotypes linked to allele 1 of a 86 bp VNTR polymorphism. We confirmed that the IL1RN 1018 variant (rs4251961) was associated with decreased cellular IL-1RA production ex vivo.
Conclusions
Common functional polymorphisms of the IL1RN gene are associated with several markers of systemic inflammation.
doi:10.1161/ATVBAHA.108.167437
PMCID: PMC2748384  PMID: 18451331
IL-1receptor antagonist; C-reactive protein; inflammation; fibrinogen
20.  T-Lymphocytes Expressing CC Chemokine Receptor-5 Are Increased in Frail Older Adults 
OBJECTIVES
To evaluate the frequencies of T-lymphocytes expressing CC chemokine receptor-5 (CCR5+ T-cells) and their relationship with frailty in older adults.
DESIGN
Case-control study with an age-, race-, and sex-matched design.
SETTING
General Clinical Research Center.
PARTICIPANTS
Community-dwelling adults aged 72 and older from Baltimore, Maryland.
METHODS
Frailty was determined using five validated criteria: weakness, slow walking speed, fatigue, low physical activity, and weight loss. Those meeting three or more of these five criteria were defined as frail and those with none as nonfrail. Complete blood counts were performed to obtain peripheral lymphocyte counts using an automated (Coulter) counter. Peripheral blood was collected for surface immunofluorescent staining of CCR5 and other T-cell markers.
RESULTS
Twenty-six frail and matched nonfrail participants (mean age ± standard deviation 83.8 ± 5.3, range 72–94) completed the study. Frail participants had higher CCR5+, CCR5+CD8+, and CCR5+CD45RO− T-cell counts than matched nonfrail controls (349 ± 160/mm3 vs 194 ± 168/mm3, P =.02; 208 ± 98/mm3 vs 105 ± 62/mm3, P =.02; and 189 ± 149/mm3 vs 52 ± 36/mm3, P =.01; respectively). Furthermore, there was a trend toward graded increase in these T-cell counts across the frailty scores in frail participants (e.g., CCR5+CD8+ counts of 123 ± 52/mm3, 248 ± 115/mm3, and 360 ± 215/mm3 for those with frailty scores of 3, 4, and 5, respectively).
CONCLUSION
These initial results suggest an expansion of the CCR5+ T-cell subpopulation in frailty. They provide a basis for further characterization of CCR5+ T-cells and their role in frailty, with potential therapeutic implications.
doi:10.1111/j.1532-5415.2008.01673.x
PMCID: PMC2662852  PMID: 18384587
frailty; inflammation; CCR5+ T-lymphocytes
21.  DHEAS Levels and Mortality in Disabled Older Women: The Women’s Health and Aging Study I 
Background
Dehydroepiandrosterone sulfate (DHEAS) is an endogenously produced sex steroid that has been hypothesized to have anti-aging effects. Low DHEAS levels are associated with mortality in older men, but the relationship between DHEAS levels and mortality in women is not clearly defined.
Methods
The relationship between serum DHEAS level and 5-year mortality was analyzed in a cohort of 539 disabled women aged 65–100 years enrolled in the Women’s Health and Aging Study I (WHAS I). Using Cox proportional hazard models, we calculated multivariate-adjusted mortality risks by DHEAS quartiles and by DHEAS continuously, allowing for a nonlinear relationship. We also examined cause-specific mortality.
Results
We found a U-shaped relationship between DHEAS level and mortality. After adjusting for multiple covariates, women in the top and bottom DHEAS quartiles had a more than 2-fold higher 5-year mortality than did those in the middle quartiles (hazard ratio, 2.15; 95% confidence interval [CI], 1.17–3.98 for the top quartile and 2.05; 95% CI, 1.27–3.32 for the bottom quartile, each compared to the third quartile). Women with higher DHEAS levels tended to have greater cancer mortality, whereas those with lower DHEAS tended to have greater cardiovascular mortality.
Conclusion
Disabled older women with either low or high levels of DHEAS are at greater risk for death than are those with intermediate levels. More research is needed to determine if targeted dehydroepiandrosterone supplementation would provide clinical benefit to disabled older women.
PMCID: PMC2645634  PMID: 16960027
22.  ELISA AND MULTIPLEX TECHNOLOGIES FOR CYTOKINE MEASUREMENT IN INFLAMMATION AND AGING RESEARCH 
Over the last decade there has been an enormous expansion of research focused on defining the role of inflammation in aging, age-related diseases, disability, and frailty. The availability of methods to measure cytokines and other inflammatory mediators or markers with high sensitivity and specificity is critically important. Enzyme-Linked Immuno-Sorbant Assay (ELISA), the most widely used and best validated method is limited by its ability to measure only a single protein in each sample. Recent developments in serum cytokine quantification technology include multiplex arrays. Multiplex Arrays offer the potential of better evaluating the complexity and dynamic nature of inflammatory responses and offer substantial cost and sample savings over traditional ELISA measurements. Despite potential advantages of this new technology, experience with these techniques is limited and it has not emerged to date as the gold standard in inflammatory mediator measurement. This article reviews ELISA and the emerging multiplex technologies, compares the cost and effectiveness of recently developed multiplex arrays with traditional ELISA technology, and provides specific recommendations for investigators interested in measuring serum inflammatory mediators in older adults.
PMCID: PMC2562869  PMID: 18772478
ELISA; Multiplex arrays; cytokines; inflammation; aging
23.  Development and Validation of a Falls Grading Scale 
Journal of geriatric physical therapy (2001)  2013;36(2):10.1519/JPT.0b013e31825f6777.
Background and Purpose
The recording of fall events is usually subjective and imprecise, which limits clinical practice and falls-related research. We sought to develop and validate a scale to grade near-fall and fall events based on their severity represented by the use of healthcare resources, with the goal of standardizing fall reporting in the clinical and research settings.
Methods
Qualitative instrument development was based on a literature review and semi-structured interviews to assess face and content validity. We queried older individuals and healthcare professionals with expertise in the care of patients at risk of falling about clinically important differences to detect and how to optimize the scale's ease of use. To assess the scale's inter-rater reliability, we created 30 video-vignettes of falls and compared how healthcare professionals and volunteers rated each of the falls according to our grading scale.
Results
We developed the illustrated 4-point Hopkins Falls Grading Scale (HFGS). The grades distinguish a near-fall (Grade 1) from a fall for which an individual did not receive medical attention (Grade 2), a fall associated with medical attention but not hospital admission (Grade 3), and a fall associated with hospital admission (Grade 4). Overall, the HFGS exhibited good face and content validity, and had an intraclass correlation coefficient of 0.998.
Conclusion
The 4-point HFGS demonstrates good face and content validity and high inter-rater reliability. We predict this tool will facilitate the standardization of falls reporting in both the clinical and research settings.
doi:10.1519/JPT.0b013e31825f6777
PMCID: PMC3867809  PMID: 22810170
Falls definition; falls classification; falls reporting
24.  Frailty and falls among adult patients undergoing chronic hemodialysis: a prospective cohort study 
BMC Nephrology  2013;14:224.
Background
Patients undergoing hemodialysis are at high risk of falls, with subsequent complications including fractures, loss of independence, hospitalization, and institutionalization. Factors associated with falls are poorly understood in this population. We hypothesized that insights derived from studies of the elderly might apply to adults of all ages undergoing hemodialysis; we focused on frailty, a phenotype of physiological decline strongly associated with falls in the elderly.
Methods
In this prospective, longitudinal study of 95 patients undergoing hemodialysis (1/2009-3/2010), the association of frailty with future falls was explored using adjusted Poisson regression. Frailty was classified using the criteria established by Fried et al., as a combination of five components: shrinking, weakness, exhaustion, low activity, and slowed walking speed.
Results
Over a median 6.7-month period of longitudinal follow-up, 28.3% of study participants (25.9% of those under 65, 29.3% of those 65 and older) experienced a fall. After adjusting for age, sex, race, comorbidity, disability, number of medications, marital status, and education, frailty independently predicted a 3.09-fold (95% CI: 1.38-6.90, P=0.006) higher number of falls. This relationship between frailty and falls did not differ for younger and older adults (P=0.57).
Conclusions
Frailty, a validated construct in the elderly, was a strong and independent predictor of falls in adults undergoing hemodialysis, regardless of age. Our results may aid in identifying frail hemodialysis patients who could be targeted for multidimensional fall prevention strategies.
doi:10.1186/1471-2369-14-224
PMCID: PMC3852906  PMID: 24131569
Hemodialysis; Falls; Frailty
25.  Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age☆ 
Experimental gerontology  2012;48(2):128-135.
Cardiovascular dysfunction is a primary independent predictor of age-related morbidity and mortality. Frailty is associated with activation of inflammatory pathways and fatigue that commonly presents and progresses with age. Interleukin 10 (IL-10), the cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine produced by immune and non-immune cells. Homozygous deletion of IL-10 in mice yields a phenotype that is consistent with human frailty, including age-related increases in serum inflammatory mediators, muscular weakness, higher levels of IGF-1 at midlife, and early mortality. While emerging evidence suggests a role for IL-10 in vascular protection, a clear mechanism has not yet been elucidated.
Methods
In order to evaluate the role of IL-10 in maintenance of vascular function, force tension myography was utilized to access ex-vivo endothelium dependent vasorelaxation in vessels isolated from IL-10 knockout IL-10(tm/tm) and control mice. Pulse wave velocity ((PWV), index of stiffness) of vasculature was measured using ultrasound and blood pressure was measured using the tail cuff method. Echocardiography was used to elucidated structure and functional changes in the heart.
Results
Mean arterial pressures were significantly higher in IL-10(tm/tm) mice as compared to C57BL6/wild type (WT) controls. PWV was increased in IL-10(tm/tm) indicating stiffer vasculature. Endothelial intact aortic rings isolated from IL-10(tm/tm) mice demonstrated impaired vasodilation at low acetylcholine doses and vasoconstriction at higher doses whereas vasorelaxation responses were preserved in rings from WT mice. Cyclo-oxygenase (COX-2)/thromboxane A2 inhibitors improved endothelial dependent vasorelaxation and reversed vasoconstriction. Left ventricular end systolic diameter, left ventricular mass, isovolumic relaxation time, fractional shortening and ejection fraction were all significantly different in the aged IL-10(tm/tm) mice compared to WT mice.
Conclusion
Aged IL-10(tm/tm) mice have stiffer vessels and decreased vascular relaxation due to an increase in eicosanoids, specifically COX-2 activity and resultant thromboxane A2 receptor activation. Our results also suggest that aging IL-10(tm/tm) mice have an increased heart size and impaired cardiac function compared to age-matched WT mice. While further studies will be necessary to determine if this age-related phenotype develops as a result of inflammatory pathway activation or lack of IL-10, it is essential for maintaining the vascular compliance and endothelial function during the aging process. Given that a similar cardiovascular phenotype is present in frail, older adults, these findings further support the utility of the IL-10(tm/tm) mouse as a model of frailty.
doi:10.1016/j.exger.2012.11.001
PMCID: PMC3744178  PMID: 23159957
Interleukin 10; Cyclo-oxygenase; Thromboxane; Endothelial dysfunction; Acetylcholine; Aorta; Frailty; Aging; Prostanoid; Cytokines

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