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PubMed2005

IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women.

Elevated levels of the inflammatory cytokine IL-6 are associated with the development of disability, frailty, and mortality in older adults. These outcomes are likely mediated through inflammatory activity that alters hormones, skeletal muscle, and the immune system. Polymorphic variants in the IL-6 gene influence IL-6 expression. We hypothesized that IL-6 alleles associate with increased serum of IL-6, decreased muscle strength, and frailty, and tested this in the Women's Health and Aging cohorts. We genotyped 463 participants age 70-79, and identified three common IL-6 haplotype blocks for the Caucasian (n=363) and African American (n=100) subsets. Using linear and logistic regression, and adjusting for age, BMI, race, and osteoarthritis, we identified no significant or clinically meaningful relationship between any single IL-6 single nucleotide polymorphism (SNP) or any IL-6 haplotype and serum IL-6 level, grip, knee, or hip strength, or frailty. Given that the promoter SNP (rs1800795) has been reported to influence IL-6 levels and health outcomes, we performed a similar association study in the In Chianti population (n=266) and confirmed lack of association. These results suggest that IL-6 gene variation may not be an important factor in the determination of elevated IL-6 levels and related phenotypes found in older women.

Aged↗

PubMed2005

Role of endocrine-immune dysregulation in osteoporosis, sarcopenia, frailty and fracture risk.

Osteoporosis, a key predictor of hip fractures can be treated using a variety of safe and effective interventions. Nevertheless, optimally effective strategies for the prevention of hip fractures must also incorporate efforts to address a broad range of other potentially reversible factors. Hyperthyroidism, anticonvulsants, caffeine and smoking may decrease bone mass and increase fracture risk at any age. In older individuals it is important to also consider additional risk factors, including long-acting benzodiazepines, poor vision and sarcopenia. The presence of sarcopenia, an age-related decline in muscle bulk and quality enhances the risk of frailty and possibly also hip fracture, particularly if associated with diminished functional mobility, lower quadriceps strength and poor balance or body sway. In this review we examine evidence which indicates the presence of endocrine-immune dysregulation in both osteoporosis and sarcopenia. Post-menopausal declines in serum estrogen and androgen levels contribute to increases in local bone levels of cytoclastic cytokines, followed by increased osteoclastogenesis and bone loss. Similarly, the presence of decreased gonadal hormones and IGF-1, combined with unusually high peripheral levels of cytokines, inflammatory mediators and coagulation markers all enhance the risk of sarcopenia and frailty. We propose that a translational research approach which emphasizes common pathophysiologic mechanisms in osteoporosis and sarcopenia could accelerate the speed of discovery of effective strategies for both frailty and hip fracture prevention.

Aged↗

PubMed2003

The frailty syndrome: a critical issue in geriatric oncology.

Evidence exists that the geriatric intervention guided by Comprehensive Geriatric Assessment (CGA) has positive effects on a number of important health outcomes in frail older patients. Although a number of observational studies, editorials, special articles and clinical reports, suggest that CGA should be used to guide the assessment and clinical decision-making in older cancer patients, there is limited support to this view in the literature. Older patients that are diagnosed with cancer are usually healthier and less problematic than persons of the same age who are randomly sampled from the general population. In these persons, the cancer dominates the clinical picture and, therefore, instruments especially tuned for the frail elderly may provide little information. The concept of the frailty syndrome, characterized by high susceptibility, low functional reserve and unstable homeostasis, has recently received a lot of attention by the geriatric community. A CGA approach, which also evaluates elements of the frailty syndrome, may be of great interest for those oncologists who want to identify older patients likely to develop severe toxicity and severe side effects in response to aggressive treatment. Improvements in the definition of the frailty syndrome may profit from the clinical experience of oncologists.

Adaptation, Physiological↗

PubMed2005

Caring the elderly diabetic patient with respect to concepts of successful aging and frailty.

Successful aging and frailty are emerging constructs becoming necessary to define prevention and treatment goals in elderly subjects. Frailty corresponds to the stages between full autonomy or successful aging and irreversible functional dependency or pathological aging. However its definition is imprecise and potential clinical criteria are numerous and interrelated. Diabetes decreases the likelihood for successful aging and particularly increases the risk for functional dependency. One major end-point in the care of elderly diabetic subjects is to investigate the impact of blood glucose control on progression of disability. Geriatric intervention based on comprehensive geriatric assessment (CGA) in the frail elderly population has been shown effective to prevent the loss of autonomy and to improve quality of life, but seems ineffective on mortality. It is now recommended to screen elderly diabetic patients for frailty criteria. The effect of combined individualized diabetes care and CGA on the aging profile should be investigated.

Aged↗

PubMed2001

Contribution of self-reported health ratings to predicting frailty, institutionalization, and death over a 5-year period.

Cross-sectional data from Phase 1 of the Canadian Study of Health and Aging was used to examine the relationship between two self-report health measures: "How would you say your health is these days?"(HEALTH) and "How much do your health troubles stand in the way of your doing the things you want to do?"(TROUBLE). The contribution of these measures to predictive models for institutionalization and mortality is examined, using linked data from Phases 1 and 2. Their relationship to a proposed frailty measure is also examined. At CSHA-1, a majority of respondents perceived that they were in good health and did not feel that their health problems interfered with their preferred activities. At all frailty levels, a majority of both males and females rated their health as "very good" or "pretty good." As frailty increased, health problems increasingly interfered with normal activities. Logistic regression of the longitudinal data indicated that, despite their correlation, HEALTH and TROUBLE cannot act as proxies for each other. They appear to predict independently; adding one to the other significantly improved prediction of institutionalization and mortality.

Activities of Daily Living↗

PubMed1998

Frailty models and rank tests.

Connections are established between the theories of weighted logrank tests and of frailty models. These connections arise because omission of a balanced covariate from a proportional hazards model generally leads to a model with non-proportional hazards, for which the simple logrank test is no longer optimal. The optimal weighting function and the asymptotic relative efficiencies of the simple logrank test and of the optimally weighted logrank test relative to the adjusted test that would be used if the covariate values were known, are expressible in terms of the Laplace transform of the hazard ratio for the distribution of the omitted covariate. For example if this hazard ratio has a gamma distribution, the optimal test is a member of the "G rho" class introduced by Harrington and Fleming (1982). We also consider positive stable, inverse Gaussian, displaced Poisson and two-point frailty distribution. Results are obtained for parametric and nonparametric tests and are extended to include random censoring. We show that the loss of efficiency from omitting a covariate is generally more important than the additional loss due to misspecification of the resulting non-proportional hazards model as a proportional hazards model. However two-point frailty distributions can provide exceptions to this rule. Censoring generally increases the efficiency of the simple logrank test to the adjusted logrank test.

Biometry↗

PubMed2004

Ascertainment-adjusted maximum likelihood estimation for the additive genetic gamma frailty model.

The additive genetic gamma frailty model has been proposed for genetic linkage analysis for complex diseases to account for variable age of onset and possible covariates effects. To avoid ascertainment biases in parameter estimates, retrospective likelihood ratio tests are often used, which may result in loss of efficiency due to conditioning. This paper considers when the sibships are ascertained by having at least two affected sibs with the disease before a given age and provides two approaches for estimating the parameters in the additive gamma frailty model. One approach is based on the likelihood function conditioning on the ascertainment event, the other is based on maximizing a full ascertainment-adjusted likelihood. Explicit forms for these likelihood functions are derived. Simulation studies indicate that when the baseline hazard function can be correctly pre-specified, both approaches give accurate estimates of the model parameters. However, when the baseline hazard function has to be estimated simultaneously, only the ascertainment-adjusted likelihood method gives an unbiased estimate of the parameters. These results imply that the ascertainment-adjusted likelihood ratio test in the context of the additive genetic gamma frailty may be used for genetic linkage analysis.

Age of Onset↗

PubMed2001

Associations of demographic, functional, and behavioral characteristics with activity-related fear of falling among older adults transitioning to frailty.

OBJECTIVES: To determine, in a cohort of older individuals transitioning to frailty (defined by Speechley and Tinetti, 1991) who have previously fallen, whether there are significant associations between demographic, functional, and behavioral characteristics and activity-related fear of falling, using both the Falls Efficacy Scale (FES) and the Activities-Specific Balance Confidence Scale (ABC). DESIGN: Baseline cross-sectional analysis in a prospective cohort intervention study. SETTING: Twenty independent senior living facilities in Atlanta. PARTICIPANTS: Seventeen male and 270 female subjects (n = 287), age 70 and older (mean +/- standard deviation, 80.9 +/- 6.2), with Mini-Mental State Examination score > or = 24, transitioning to frailty, ambulatory (with or without assistive device), medically stable, and having fallen in the past year. MEASUREMENTS: Activity-related fear of falling was evaluated with the FES and ABC Scale. Because of the comparable data derived from each scale, associations with functional measures-related analyses were expressed using the latter. Depression was measured by Center for Epidemiological Studies Depression Scale. Functional measurements included timed 360 degrees turn, functional reach test, timed 10-meter walk test, single limb stands, picking up an object, and three chair stands. RESULTS: No statistically significant association was found between activity-related fear of falling and age. For the proposed activities, about half (ABC, 48.1%; FES, 50.1%) of the subjects were concerned about falling or showed lack of confidence in controlling their balance. A statistically significant inverse correlation was found between FES and ABC (r = -0.65; P < .001). African-American subjects showed more activity-related fear of falling than did Caucasians (odds ratio (OR): 2.7 for ABC; 2.1 for FES). Fearful individuals were more likely to be depressed and more likely to report the use of a walking aid than were nonfearful individuals. Fear of falling was significantly correlated to all of the functional measurements (P < .05). In a multivariable logistic regression model, depression, using a walking-aid, slow gait speed, and being an African-American were directly related to being more fearful of falling. CONCLUSIONS: Activity-related fear of falling was present in almost half of this sample of older adults transitioning to frailty. The significant association of activity-related fear of falling with demographic, functional, and behavioral characteristics emphasizes the need for multidimensional intervention strategies to lessen activity-related fear of falling in this population.

Accidental Falls↗

PubMed2002

Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study.

OBJECTIVES: To determine specific physiological correlates of the geriatric syndrome of frailty that warrant further investigation. DESIGN: Population-based case-control study. SETTING: General Clinical Research Center at Johns Hopkins Bayview Medical Center. PARTICIPANTS: Community-dwelling adults aged 74 and older from Baltimore, Maryland. MEASUREMENTS: Frailty status was determined using a recently validated screening tool that consists of weight loss, fatigue, low levels of physical activity, and measurements of grip strength and walking speed. Serum interleukin-6 (IL-6) was measured using enzyme-linked immunosorbent assay, and standard complete blood count was performed using a Coulter counter. RESULTS: Eleven frail and 19 nonfrail subjects with mean age +/- standard deviation of 84.9 +/- 6.7 vs 81.3 +/- 4.1 years, respectively, completed the study. The frail subjects had significantly higher serum IL-6 levels and significantly lower hemoglobin and hematocrit than the nonfrail subjects (4.4 +/-2.9 vs 2.8 +/- 1.6 pg/mL, 12.1 +/- 1.1 vs 13.9 +/- 1.0 g/dL, and 35.8% +/- 3.1% vs 40.6% +/- 2.8%, respectively). No significant difference was observed in mean corpuscular volume, red blood cell distribution width, or white blood cell and platelet counts between the frail and nonfrail groups. Furthermore, there was an inverse correlation between serum IL-6 level and hemoglobin (Pearson's correlation coefficient: -0.46) and hematocrit (-0.48) in the frail group but not in the nonfrail group. CONCLUSION: These results suggest that frail subjects have evidence of inflammation and lower hemoglobin and hematocrit levels. This subclinical anemia is normocytic and is hence unlikely due to myelosuppression or iron deficiency and is potentially related to the increased chronic inflammatory state marked by serum IL-6 elevation. Further studies are indicated to better characterize the immune and hematological changes that underlie frailty.

Aged↗

PubMed2003

Selected as the best paper in the 1990s: Reducing frailty and falls in older persons: an investigation of tai chi and computerized balance training.

OBJECTIVES: To evaluate the effects of two exercise approaches, tai chi (TC) and computerized balance training (BT), on specified primary outcomes (biomedical, functional, and psychosocial indicators of frailty) and secondary outcomes (occurrences of fall). DESIGN: The Atlanta Frailty and Injuries: Cooperative Studies and Intervention Techniques, a prospective, randomized, controlled clinical trial with three arms (TC, BT, and education (ED)). Intervention length was 15 weeks, with primary outcomes measured before and after intervention and at 4-month follow-up. Falls were monitored continuously throughout the study. SETTING: Persons aged 70 and older living in the community. PARTICIPANTS: A total of 200 participants, 162 women and 38 men; mean age was 76.2. MEASUREMENTS: Biomedical (strength, flexibility, cardiovascular endurance, body composition), functional instrumental activities of daily living (IADL), and psychosocial well-being (Center for Epidemiological Studies for Depression scale, fear of falling questionnaire, self-perception of present and future health, mastery index, perceived quality of sleep, and intrusiveness) variables. RESULTS: Grip strength declined in all groups, and lower extremity range of motion showed limited but statistically significant changes. Lowered blood pressure before and after a 12-minute walk was seen following TC participation. Fear of falling responses and intrusiveness responses were reduced after the TC intervention compared with the ED group (P=.046 and P=.058, respectively). After adjusting for fall risk factors, TC was found to reduce the risk of multiple falls by 47.5%. CONCLUSION: A moderate TC intervention can impact favorably on defined biomedical and psychosocial indices of frailty. This intervention can also have favorable effects upon the occurrence of falls. TC warrants further study as an exercise treatment to improve the health of older people.

Accidental Falls↗

PubMed1994

Exercise training and nutritional supplementation for physical frailty in very elderly people.

BACKGROUND: Although disuse of skeletal muscle and undernutrition are often cited as potentially reversible causes of frailty in elderly people, the efficacy of interventions targeted specifically at these deficits has not been carefully studied. METHODS: We conducted a randomized, placebo-controlled trial comparing progressive resistance exercise training, multinutrient supplementation, both interventions, and neither in 100 frail nursing home residents over a 10-week period. RESULTS: The mean (+/- SE) age of the 63 women and 37 men enrolled in the study was 87.1 +/- 0.6 years (range, 72 to 98); 94 percent of the subjects completed the study. Muscle strength increased by 113 +/- 8 percent in the subjects who underwent exercise training, as compared with 3 +/- 9 percent in the nonexercising subjects (P < 0.001). Gait velocity increased by 11.8 +/- 3.8 percent in the exercisers but declined by 1.0 +/- 3.8 percent in the nonexercisers (P = 0.02). Stair-climbing power also improved in the exercisers as compared with the nonexercisers (by 28.4 +/- 6.6 percent vs. 3.6 +/- 6.7 percent, P = 0.01), as did the level of spontaneous physical activity. Cross-sectional thigh-muscle area increased by 2.7 +/- 1.8 percent in the exercisers but declined by 1.8 +/- 2.0 percent in the nonexercisers (P = 0.11). The nutritional supplement had no effect on any primary outcome measure. Total energy intake was significantly increased only in the exercising subjects who also received nutritional supplementation. CONCLUSIONS: High-intensity resistance exercise training is a feasible and effective means of counteracting muscle weakness and physical frailty in very elderly people. In contrast, multi-nutrient supplementation without concomitant exercise does not reduce muscle weakness or physical frailty.

Aged↗

PubMed1994

Frailty selection in bivariate survival models: a cautionary note.

"One problem that researchers face in analyzing the survival times of groups of related individuals is selecting how the distribution of frailty--an unobserved (or not adequately observed) random factor--should be specified. Several distributions have received attention--for instance, the gamma distribution and a nonparametric N-point, discrete probability distribution. Researchers have selected these distributions more for mathematical convenience than for their ability to represent biological, social, or economic reality, and the implications of choosing one functional representation of frailty over alternative choices have not been studied extensively.... This research paper explores the association among survival times under gamma, inverse Gaussian, nonparametric N-point, and Poisson distributions. It shows that the pattern and strength of this association depends on how the distribution of frailty is specified." (SUMMARY IN FRE)

Demography↗

PubMed2001

New-onset incontinence and markers of frailty: data from the Hispanic Established Populations for Epidemiologic Studies of the Elderly.

BACKGROUND: Urinary incontinence in older adults has many distinct etiologies and is associated with lower self-reported health. However, it is unclear whether the new onset of urinary incontinence marks newly emergent frailty. METHODS: Using a longitudinal population-based survey of older Mexican Americans (N = 2660) across five south-western states, this study compared the strength of association between markers of physical frailty such as activities of daily living (ADLs), instrumental activities of daily living (IADLs), and performance (timed walk, timed chair rise, and tandem balance) with baseline incontinence (prevalent disease) and new-onset incontinence (incident disease). RESULTS: We found that 14.1% of the participants (n = 329) were incontinent at baseline (prevalent cases) and 11.6% (n = 208) were newly incontinent 2 years later (incident cases). Controlling for other covariates, prevalent incontinence was only associated with a 60% increased risk of having difficulty walking 8 ft. Incident incontinence was associated with a twofold increased risk of impairment in ADLs and IADLs, and poor performance on all three physical measures. CONCLUSIONS: Incident incontinence is associated with an increased risk of more global functional impairment. Thus, incident disease may be an important early marker for signaling the onset of frailty among persons who become incontinent after the age of 65 years.

Age of Onset↗

PubMed2001

Instrumental activities of daily living as a potential marker of frailty: a study of 7364 community-dwelling elderly women (the EPIDOS study).

BACKGROUND: A number of clinical conditions have been shown to be associated with frailty in elderly people. We hypothesized that incapacities on the Instrumental Activities of Daily Living (IADLs) scale could make it possible to identify this population. We investigated the associations between IADL incapacities and the various known correlates of frailty in a cohort of community-dwelling elderly women. METHODS: Cross-sectional analysis was carried out on the data from 7364 women aged over 75 years (EPIDOS Study). The IADL was the dependent variable. Sociodemographic, medical, and psychological performance measures were obtained during an assessment visit. Falls in the previous 6 months and fear of falling were also ascertained. Body composition was measured by dual-energy x-ray absorptiometry. The factors associated with disability in at least one IADL were included in a logistic regression model. RESULTS: Thirty-two percent of the population studied had disability in at least one IADL item. This group was significantly older (81.7 +/- 4.1 yr vs 79.8 +/- 3.4 yr), had more frequent histories of heart disease, stroke, depression or diabetes, and was socially less active (p =.001). These associations persisted after multivariate analysis. Cognitive impairment as assessed by the Pfeiffer test (Pfeiffer score <8) was closely associated with disabilities on the IADL (OR 3.101, 95% confidence interval [CI] 2.19-4.38). Falls and fear of falling were also more frequent in the group of women with an abnormal IADL (p =.001) but only fear of falling remained significantly associated with incapacities on at least one IADL item after logistic regression (OR 1.47, 95% CI 1.28-1.69). Women with disability on at least one IADL item also had lower bone mineral density, this was independent of the other factors. CONCLUSION: Our results confirmed that women with disability on at least one IADL item are frailer because they had more associated disorders, poorer cognitive function and more frequent falls. Disabilities on this scale could be a good tool for identifying individuals at risk of frailty among elderly persons living at home and in apparent good health. This finding requires confirmation by longitudinal studies.

Accidental Falls↗

PubMed2002

A conceptual framework of frailty: a review.

This article presents an overview of the increasingly common condition of frailty, which by and large lacks clarity of definition. A variety of sources provide this statement regarding definition, incidence, causation, rate, and time of appearance. Utilizing the newly elaborated process of symmorphosis, which explains the coadaptation of structure and function secondary to altered energy loads, I propose that frailty is a body-wide set of linked deteriorations including, but not confined to, musculoskeletal, cardiovascular, metabolic, and immunologic systems. The common final pathway that leads to this constellation of findings is usually keyed to a decline in physical activity either as a result of habit or disease inputs. As such, the state of frailty is largely separable from the process of aging and should thereby be susceptible to active intervention and reversal.

Aged↗

PubMed2006

Lower plasma vitamin E levels are associated with the frailty syndrome: the InCHIANTI study.

BACKGROUND: The primary biologic mechanism that causes frailty in older persons has never been adequately explained. According to recent views, oxidative stress may be the driving force of this condition. We tested the hypothesis that, independent of confounders, low plasma levels of vitamin E (alpha-tocopherol), the main fat-soluble human antioxidant, are associated with the frailty syndrome in older persons free from dementia and disability. METHODS: The study sample included 827 older (> or =65 years) persons (women, 54%) who participated in a population-based epidemiological study. Frail participants were identified based on the presence of at least three of five of the following features: self-reported weight loss, low energy, slow gait speed, low grip strength, and low physical activity. Participants with none of these features were considered nonfrail, while participants with one or two were considered intermediate frail. Plasma vitamin E levels were determined using reverse-phase high-performance liquid chromatography. Measured confounders included lower extremity muscle strength, cognitive function, diseases, and factors related to vitamin E metabolism. RESULTS: Age- and gender-adjusted levels of vitamin E decreased gradually from the nonfrail to the frail group (p for trend =.015). In the logistic model adjusted for multiple potential confounders, participants in the highest vitamin E tertile were less likely to be frail than were participants in the lowest vitamin E tertile (odds ratio, 0.30; 95% confidence interval, 0.10-0.91). CONCLUSIONS: Our findings show an association between low circulating levels of one of the most important components of the human antioxidant system and the presence of frailty.

Aged↗

PubMed2006

Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and D-dimer.

BACKGROUND: Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the "frailty syndrome," defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. METHODS: Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 +/- 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. RESULTS: Caregivers had higher mean levels of IL-6 (1.38 +/- 1.42 vs 1.00 +/- 0.92 pg/mL, p =.032) and of D-dimer (723 +/- 530 vs 471 +/- 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (beta =.20, p =.029) and of borderline significance for IL-6 (beta =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (beta =.50, p <.001) and IL-6 (beta =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. CONCLUSIONS: The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Age Factors↗

PubMed1998

Antecedents of frailty over three decades in an older cohort.

Studies of disability in old age have focused on gross measures of physical functioning. More useful results for prevention might be gleaned from examining risk factors associated with frailty, a concept implying a broader range of more subtle problems in multiple domains. This study conceptualized frailty as involving problems or difficulties in two or more functional domains (physical, nutritive, cognitive, and sensory) and analyzed prospective predictors. Subjects were 574 Alameda County Study respondents age 65-102. One-fourth scored as frail; there was no gender difference. Frail persons reported reduced activities, poorer mental health, and lower life satisfaction. Cumulative predictors over the previous three decades included heavy drinking, cigarette smoking, physical inactivity, depression, social isolation, fair or poor perceived health, prevalence of chronic symptoms, and prevalence of chronic conditions. By modifying these risk factors, it may be possible to postpone the onset of frailty or ameliorate its further development.

Age Distribution↗