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Papers by Linda Fried

Research paper thumbnail of Cortisol and Dehydroepiandrosterone Response to Adrenocorticotropic Hormone and Frailty in Older Women

The Journals of Gerontology: Series A, 2020

Background The response to adrenocorticotropic hormone (ACTH) is poorly characterized in old-old ... more Background The response to adrenocorticotropic hormone (ACTH) is poorly characterized in old-old adults and may provide insight into the physiologic response to stress. Method We performed a standard 250 µg ACTH stimulation test in a home-based substudy of 51 women aged 85–96 years enrolled in the Women’s Health and Aging Study II who were not taking corticosteroids. We examined the cortisol and dehydroepiandrosterone (DHEA) responses at 0, 30, 60, and 120 minutes, overall and by frailty status. Results The peak cortisol response to ACTH could not be determined, with the highest levels at the 120-minute time point. Pre- and post-ACTH stimulated cortisol levels did not differ by frailty status over this time frame, with no difference in the characteristics of the dose-response curves. Pre- and post-ACTH stimulated DHEA levels also did not differ by frailty status, though the dose-response curves suggested divergence after stimulation, with a more rapid DHEA response with increasing f...

Research paper thumbnail of The Association of Vitamin D Deficiency and Incident Frailty in Older Women: The Role of Cardiometabolic Diseases

Journal of the American Geriatrics Society, 2017

Evidence suggests vitamin D deficiency is associated with developing frailty. However, cardiometa... more 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. Prospective longitudinal cohort study (7 visits from 1994-2008). Baltimore, Maryland. Three hundred sixty-nine women from the Women's Health and Aging Study II aged 70-79 years, free of frailty at baseline. Serum circulating 25-hydroxyvitamin D (25[OH]D) concentration was assessed at baseline and categorized as: <10; 10-19.9; 20-29.9; and ≥30 ng/mL. Frailty incidence was determined based on presence of three or more criteria: weight loss, low physical activity, exhaustion, weakness, and slowness. Cardiometabolic diseases were ascertained at baseline. Anal...

Research paper thumbnail of Markers of B-vitamin deficiency and frailty in older women

The Journal of Nutrition Health and Aging, 2008

Research paper thumbnail of Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty

The journal of nutrition, health & aging, 2010

Research paper thumbnail of Analyzing feed-forward loop relationship in aging phenotypes: Physical activity and physical performance

Mechanisms of Ageing and Development, 2014

We present evidence of feed-forward loop relationships and positive association between physical ... more We present evidence of feed-forward loop relationships and positive association between physical activity and performance levels, which are components of frailty, using measures from 431 high functioning women initially aged 70-79 years followed over 7 visits. Physical activity levels were assessed using a questionnaire. Grip strength was measured using a handheld dynamometer and usual walking speed was measured over 4-meters. The results suggest that a reduction in physical activity would not only degrade physical performance, but it would further reduce physical activity through declines in physical performance. As both physical activity and physical performance impact frailty, improvement of physical activity could help reduce frailty directly as well as indirectly via improved physical performance. Our findings support a priori hypothesis that feed-forward loops are present in the phenotype of frailty, which is due to dysregulated energetics. A methodologically broader implication is that we introduce modeling and analysis of feed-forward loop data here. The feed-forward loop, as we define it, is different from the concept of feedback loops used in biochemical systems. Generalizing our model of two-variable feedforward loop, three, four or multivariable feed-forward loop can be applied to other biological systems.

Research paper thumbnail of Resting Metabolic Rate in Old‐Old Women with and without Frailty: Variability and Estimation of Energy Requirements

Journal of the American Geriatrics Society, 2012

ObjectivesTo measure resting metabolic rate (RMR) in old‐old adults living in the community and e... more ObjectivesTo measure resting metabolic rate (RMR) in old‐old adults living in the community and examine the association between measured RMR and frailty status and compare it with expected RMR generated by a predictive equation.DesignPhysiological substudy conducted as a home visit within an observational cohort study.SettingBaltimore City and County, Maryland.ParticipantsSeventy‐seven women aged 83 to 93 enrolled in the Women's Health and Aging Study II.MeasurementsResting metabolic rate with indirect calorimetry, frailty status, fat‐free mass, ambient and body temperature, expected RMR according to the Mifflin‐St. Jeor equation.ResultsAverage RMR was 1,119 ± 205 kcal/d (range 595–1,560 kcal/d). Agreement between observed and expected RMR was biased and poor (between‐subject coefficient of variation 38.0%, 95% confidence interval = 35.1–40.8). Variability of RMR was greater in frail individuals (heteroscedasticity F‐test P = .02). Low and high RMR were associated with being fra...

Research paper thumbnail of Hyperglycemia and Incidence of Frailty and Lower Extremity Mobility Limitations in Older Women

Journal of the American Geriatrics Society, 2012

ObjectivesTo determine the degree to which hyperglycemia predicts the development of frailty and ... more ObjectivesTo determine the degree to which hyperglycemia predicts the development of frailty and lower extremity mobility limitations.DesignSecondary data analysis of longitudinal data collected in a prospective cohort study.SettingBaltimore, Maryland.ParticipantsThree hundred twenty‐nine women from the Women's Health and Aging Study II aged 70 to 79 at baseline who had all variables needed for analysis.MeasurementsGlycosylated hemoglobin (HbA1c) at baseline, categorized as less than 5.5%, 5.5% to 5.9%, 6.0% to 6.4%, 6.5% to 7.9%, and 8.0% and greater, was the independent variable. The incidence of frailty and lower extremity mobility limitations (based on self‐reported walking difficulty, walking speed, and Short Performance Physical Battery score) was determined (follow‐up ≈ 9 years). Frailty was assessed using the Cardiovascular Health Study criteria. Covariates included demographic characteristics, body mass index, interleukin‐6 level, and clinical history of comorbidities. ...

Research paper thumbnail of The Long-Term Relationship Between High-Intensity Volunteering and Physical Activity in Older African American Women

The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 2009

Research paper thumbnail of Measures of Physical Performance and Risk for Progressive and Catastrophic Disability: Results From the Women's Health and Aging Study

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2005

Background. Physical performance measures can predict incident disability, but little research ha... more Background. Physical performance measures can predict incident disability, but little research has assessed and compared how these measures predict progressive and rapid-onset (catastrophic) disability. The authors evaluated the ability of upper and lower extremity performance measures to predict progressive and catastrophic disability in activities of daily living (ADL), mobility, and upper extremity function. Methods. The incidence of progressive and catastrophic disability was assessed semiannually during a 3-year period in 884 women participating in the Women's Health and Aging Study I. Four-meter walking speed, balance, and chair stands tests were used to evaluate lower extremity function. The putting-on-blouse test, the Purdue pegboard test, and grip strength were used to assess upper extremity function. Summary performance scores (SPS) for the lower and upper extremities were calculated. Among participants in whom disability developed, those who reported no difficulty in the previous year were defined as cases of catastrophic disability, and those who previously reported little or some difficulty were considered to be cases of progressive disability. Cox proportional hazard regression analyses were used to evaluate the association of performance measures and time to incident disability. The predictive ability of performance measures was compared using receiver-operator characteristic curves. Results. All lower and upper extremity measures, with the exception of grip strength, significantly predicted the onset of progressive ADL disability, but only walking speed was significantly associated with the onset of catastrophic ADL disability. The chair stands test, walking speed, and the lower extremity SPS were significantly associated with the onset of both progressive and catastrophic mobility disability. Only lower extremity individual tests and SPS significantly predicted the onset of both progressive and catastrophic upper extremity disability. The receiver-operator characteristic curves for ADL and mobility disability showed that all performance measures evaluated had a greater predictive ability for progressive than for catastrophic incident disability. This finding was not consistent for upper extremity disability. The areas under the curve for walking speed and lower extremity SPS were very similar, ranging from 0.58 to 0.81 and from 0.57 to 0.85, and the predictive ability of these two measures was the greatest for all disability outcomes assessed. Conclusion. Physical performance measures of lower extremity and, in particular, walking speed and lower extremity SPS are valuable tools to predict different forms of disability, especially those with a progressive onset.

Research paper thumbnail of Multiple Hormonal Deficiencies in Anabolic Hormones Are Found in Frail Older Women: The Women's Health and Aging Studies

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009

Background. Alterations in anabolic hormones are theorized to contribute to aging and frailty, wi... more Background. Alterations in anabolic hormones are theorized to contribute to aging and frailty, with most studies focusing on the relationship between individual hormones and specifi c age-associated diseases. We hypothesized that associations with frailty would most likely manifest in the presence of defi cits in multiple anabolic hormones. Methods. The relationships of serum levels of total IGF-1, DHEAS , and free testosterone (T) with frailty status (nonfrail, prefrail, or frail) were analyzed in 494 women aged 70-79 years enrolled in the Women's Health and Aging Studies I or II. Using multivariate polytomous regression, we calculated the odds of frailty for defi ciency in each hormone (defi ned as the bottom quartile of the hormone) individually, as well as for a count of the hormones. Results. For each hormone, in adjusted analyses, those with the defi ciency were more likely to be frail than those without the defi ciency, although this did not achieve statistical signifi cance (IGF-1: odds ratio [OR] 1.82, confi dence interval [CI] 0.81-4.08; DHEAS: OR 1.68, CI 0.77-3.69; free T: OR 2.03, CI 0.89-4.64). Compared with those with no hormonal defi ciencies, those with one defi ciency were not more likely to be frail (OR 1.15, CI 0.49-2.68), whereas those with two or three defi ciencies had a very high likelihood of being frail (OR 2.79, CI 1.06-7.32), in adjusted models. Conclusions. The absolute burden of anabolic hormonal defi ciencies is a stronger predictor of frailty status than the type of hormonal defi ciency, and the relationship is nonlinear. These analyses suggest generalized endocrine dysfunction in the frailty syndrome.

Research paper thumbnail of Associations of Subclinical Cardiovascular Disease With Frailty

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2001

Research paper thumbnail of Advancing the Taxonomy of Disability in Older Adults

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2004

Research paper thumbnail of Untangling the Concepts of Disability, Frailty, and Comorbidity: Implications for Improved Targeting and Care

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2004

Research paper thumbnail of Frailty and Impaired Cardiac Autonomic Control: New Insights From Principal Components Aggregation of Traditional Heart Rate Variability Indices

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009

Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased com... more Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased complexity in their output. For example, the degradation of cardiac autonomic control results in loss of complexity in the heart rate signal. Frailty is a state of critically impaired homeostasis that results in heightened vulnerability to stressors. We propose a new measure of heart rate variability (HRV) to capture the impairment in cardiac autonomic control associated with frailty. Methods. Traditional time and frequency domain indices of HRV were obtained from 2-hour ambulatory electrocardiograms (ECGs) of 276 women (65-101 years old) in the Women ' s Health and Aging Study-I. Principal components analysis was conducted on the correlation matrix of HRV indices. Frailty was defi ned using a validated instrument. Regression models were used to evaluate associations of HRV measures with age, frailty, and 5-year mortality. Results. The fi rst two principal components (PCs), PC1 and PC2, explained 90% of the variance in HRV indices. PC1 is the mean of log-transformed HRV indices. PC2 is a linear combination of log-transformed indices, with positive weights for very low frequency (VLF), low frequency (LF), and standard deviation of N-N intervals (SDNN), and negative weights for high frequency (HF), root-mean-squared differences of successive N-N intervals (RMSSD), and proportion of all N-N intervals that are larger than 50 ms (pNN50). Decreases in SDNN, VLF, LF, and LF/HF were associated with an increased risk of frailty. PC2 was more strongly associated with age (b = − .23, p < .001) and frailty (b = − .73, p < 10 − 5) than were the individual HRV indices and LF/HF. PC2 was also the best predictor of 5-year mortality (b = − .60, p < 10 − 6). Conclusions. Cardiac autonomic control, as refl ected by HRV, is impaired in frailty. A new measure derived from PC aggregation of traditional HRV indices provides a compact summary of this impairment.

Research paper thumbnail of Low Nutrient Intake Is an Essential Component of Frailty in Older Persons

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2006

Background. Poor nutrient intake is conceptualized to be a component of frailty, but this hypothe... more Background. Poor nutrient intake is conceptualized to be a component of frailty, but this hypothesis has been little investigated. We examined the association between low energy and nutrient intake and frailty. Methods. We used data from 802 persons aged 65 years or older participating to the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study. Frailty was defined by having at least two of the following criteria: low muscle strength, feeling of exhaustion, low walking speed, and reduced physical activity. The European Prospective Investigation into Cancer and nutrition (EPIC) questionnaire was used to estimate the daily intake of energy and nutrients. Low intake was defined using the value corresponding to the lowest sex-specific intake quintile of energy and specific nutrients. Adjusted logistic regression analyses were used to study the association of frailty and frailty criteria with low intakes of energy and nutrients.

Research paper thumbnail of Initial Manifestations of Frailty Criteria and the Development of Frailty Phenotype in the Women's Health and Aging Study II

The Journals of Gerontology: Series A, 2008

Research paper thumbnail of Oxidative Protein Damage Is Associated With Elevated Serum Interleukin-6 Levels Among Older Moderately to Severely Disabled Women Living in the Community

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2008

Background. Elevated interleukin (IL)-6 is associated with adverse outcomes. Our objective was to... more Background. Elevated interleukin (IL)-6 is associated with adverse outcomes. Our objective was to determine whether serum protein carbonyls, an indicator of oxidative protein damage and oxidative stress, were associated with IL-6. Methods. Serum protein carbonyls and IL-6 were measured in 739 women, age !65 years, in the Women's Health and Aging Study I. Results. Geometric mean of protein carbonyls was 0.082 nmol/mg. After adjusting for age and smoking status, log e serum protein carbonyls were associated with log e IL-6 (b ¼ 0.143, standard error [SE] ¼ 0.048, p ¼ .003) in linear regression analyses and with elevated IL-6 (!2.5 pg/mL) (odds ratio ¼ 1.38, 95% confidence interval, 1.02-1.86, p ¼ .037) in logistic regression analyses. Conclusion. Oxidative damage to proteins is independently associated with serum IL-6 among older women living in the community. Increased oxidative stress may be a factor involved in the pathogenesis of the proinflammatory state that occurs in older adults.

Research paper thumbnail of Exploring biologically relevant pathways in frailty

The journals of gerontology. Series A, Biological sciences and medical sciences, 2011

Frailty is a late-life syndrome of vulnerability to adverse health outcomes characterized by a ph... more Frailty is a late-life syndrome of vulnerability to adverse health outcomes characterized by a phenotype that includes muscle weakness, fatigue, and inflammatory pathway activation. The identification of biologically relevant pathways that influence frailty is challenged by its biological complexity and the necessity in separating disease states from the syndrome of frailty. As with longevity research, genetic analyses may help to provide insights into biologically relevant pathways that contribute to frailty.

Research paper thumbnail of Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults

Experimental Gerontology, 2011

In immunocompetent persons, cytomegalovirus (CMV) is thought to persist primarily in monocytes an... more In immunocompetent persons, cytomegalovirus (CMV) is thought to persist primarily in monocytes and myeloid progenitor cells, establishing a chronic infection. In older adults, chronic CMV infection is typically diagnosed by a positive IgG serology. While many studies have shown CMV-specific T-cell expansion in CMV seropositive older individuals, significant heterogeneity has also been observed in this elderly population. In a study of 71 community-dwelling older adults, we assessed CMV viral DNA in peripheral monocytes by nested PCR and compared the relationships of detectable CMV DNA and IgG serology with serum levels of neopterin, a marker for monocyte/macrophage-mediated immune activation. The results showed that 52 (73.2%) participants were CMV seropositive, of whom 30 (57.5%) had detectable CMV DNA. CMV seropositive and seronegative participants did not differ in their neopterin levels, but individuals with detectable CMV DNA had higher neopterin than those without (10.6±4.4 vs 8.0±1.9nM, respectively, p<.0001) adjusting for demographic and clinical covariates and interferon (IFN)-γ levels. In addition, there was no association between IgG titers and neopterin. These findings suggest that detection of CMV viral DNA in monocytes may be an informative tool to evaluate chronic CMV infection and its potential role in monocyte/macrophage-mediated immune activation in the elderly.

Research paper thumbnail of Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: Results from the Women’s Health and Aging Studies I

Experimental Gerontology, 2009

This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright

Research paper thumbnail of Cortisol and Dehydroepiandrosterone Response to Adrenocorticotropic Hormone and Frailty in Older Women

The Journals of Gerontology: Series A, 2020

Background The response to adrenocorticotropic hormone (ACTH) is poorly characterized in old-old ... more Background The response to adrenocorticotropic hormone (ACTH) is poorly characterized in old-old adults and may provide insight into the physiologic response to stress. Method We performed a standard 250 µg ACTH stimulation test in a home-based substudy of 51 women aged 85–96 years enrolled in the Women’s Health and Aging Study II who were not taking corticosteroids. We examined the cortisol and dehydroepiandrosterone (DHEA) responses at 0, 30, 60, and 120 minutes, overall and by frailty status. Results The peak cortisol response to ACTH could not be determined, with the highest levels at the 120-minute time point. Pre- and post-ACTH stimulated cortisol levels did not differ by frailty status over this time frame, with no difference in the characteristics of the dose-response curves. Pre- and post-ACTH stimulated DHEA levels also did not differ by frailty status, though the dose-response curves suggested divergence after stimulation, with a more rapid DHEA response with increasing f...

Research paper thumbnail of The Association of Vitamin D Deficiency and Incident Frailty in Older Women: The Role of Cardiometabolic Diseases

Journal of the American Geriatrics Society, 2017

Evidence suggests vitamin D deficiency is associated with developing frailty. However, cardiometa... more 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. Prospective longitudinal cohort study (7 visits from 1994-2008). Baltimore, Maryland. Three hundred sixty-nine women from the Women's Health and Aging Study II aged 70-79 years, free of frailty at baseline. Serum circulating 25-hydroxyvitamin D (25[OH]D) concentration was assessed at baseline and categorized as: <10; 10-19.9; 20-29.9; and ≥30 ng/mL. Frailty incidence was determined based on presence of three or more criteria: weight loss, low physical activity, exhaustion, weakness, and slowness. Cardiometabolic diseases were ascertained at baseline. Anal...

Research paper thumbnail of Markers of B-vitamin deficiency and frailty in older women

The Journal of Nutrition Health and Aging, 2008

Research paper thumbnail of Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty

The journal of nutrition, health & aging, 2010

Research paper thumbnail of Analyzing feed-forward loop relationship in aging phenotypes: Physical activity and physical performance

Mechanisms of Ageing and Development, 2014

We present evidence of feed-forward loop relationships and positive association between physical ... more We present evidence of feed-forward loop relationships and positive association between physical activity and performance levels, which are components of frailty, using measures from 431 high functioning women initially aged 70-79 years followed over 7 visits. Physical activity levels were assessed using a questionnaire. Grip strength was measured using a handheld dynamometer and usual walking speed was measured over 4-meters. The results suggest that a reduction in physical activity would not only degrade physical performance, but it would further reduce physical activity through declines in physical performance. As both physical activity and physical performance impact frailty, improvement of physical activity could help reduce frailty directly as well as indirectly via improved physical performance. Our findings support a priori hypothesis that feed-forward loops are present in the phenotype of frailty, which is due to dysregulated energetics. A methodologically broader implication is that we introduce modeling and analysis of feed-forward loop data here. The feed-forward loop, as we define it, is different from the concept of feedback loops used in biochemical systems. Generalizing our model of two-variable feedforward loop, three, four or multivariable feed-forward loop can be applied to other biological systems.

Research paper thumbnail of Resting Metabolic Rate in Old‐Old Women with and without Frailty: Variability and Estimation of Energy Requirements

Journal of the American Geriatrics Society, 2012

ObjectivesTo measure resting metabolic rate (RMR) in old‐old adults living in the community and e... more ObjectivesTo measure resting metabolic rate (RMR) in old‐old adults living in the community and examine the association between measured RMR and frailty status and compare it with expected RMR generated by a predictive equation.DesignPhysiological substudy conducted as a home visit within an observational cohort study.SettingBaltimore City and County, Maryland.ParticipantsSeventy‐seven women aged 83 to 93 enrolled in the Women's Health and Aging Study II.MeasurementsResting metabolic rate with indirect calorimetry, frailty status, fat‐free mass, ambient and body temperature, expected RMR according to the Mifflin‐St. Jeor equation.ResultsAverage RMR was 1,119 ± 205 kcal/d (range 595–1,560 kcal/d). Agreement between observed and expected RMR was biased and poor (between‐subject coefficient of variation 38.0%, 95% confidence interval = 35.1–40.8). Variability of RMR was greater in frail individuals (heteroscedasticity F‐test P = .02). Low and high RMR were associated with being fra...

Research paper thumbnail of Hyperglycemia and Incidence of Frailty and Lower Extremity Mobility Limitations in Older Women

Journal of the American Geriatrics Society, 2012

ObjectivesTo determine the degree to which hyperglycemia predicts the development of frailty and ... more ObjectivesTo determine the degree to which hyperglycemia predicts the development of frailty and lower extremity mobility limitations.DesignSecondary data analysis of longitudinal data collected in a prospective cohort study.SettingBaltimore, Maryland.ParticipantsThree hundred twenty‐nine women from the Women's Health and Aging Study II aged 70 to 79 at baseline who had all variables needed for analysis.MeasurementsGlycosylated hemoglobin (HbA1c) at baseline, categorized as less than 5.5%, 5.5% to 5.9%, 6.0% to 6.4%, 6.5% to 7.9%, and 8.0% and greater, was the independent variable. The incidence of frailty and lower extremity mobility limitations (based on self‐reported walking difficulty, walking speed, and Short Performance Physical Battery score) was determined (follow‐up ≈ 9 years). Frailty was assessed using the Cardiovascular Health Study criteria. Covariates included demographic characteristics, body mass index, interleukin‐6 level, and clinical history of comorbidities. ...

Research paper thumbnail of The Long-Term Relationship Between High-Intensity Volunteering and Physical Activity in Older African American Women

The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 2009

Research paper thumbnail of Measures of Physical Performance and Risk for Progressive and Catastrophic Disability: Results From the Women's Health and Aging Study

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2005

Background. Physical performance measures can predict incident disability, but little research ha... more Background. Physical performance measures can predict incident disability, but little research has assessed and compared how these measures predict progressive and rapid-onset (catastrophic) disability. The authors evaluated the ability of upper and lower extremity performance measures to predict progressive and catastrophic disability in activities of daily living (ADL), mobility, and upper extremity function. Methods. The incidence of progressive and catastrophic disability was assessed semiannually during a 3-year period in 884 women participating in the Women's Health and Aging Study I. Four-meter walking speed, balance, and chair stands tests were used to evaluate lower extremity function. The putting-on-blouse test, the Purdue pegboard test, and grip strength were used to assess upper extremity function. Summary performance scores (SPS) for the lower and upper extremities were calculated. Among participants in whom disability developed, those who reported no difficulty in the previous year were defined as cases of catastrophic disability, and those who previously reported little or some difficulty were considered to be cases of progressive disability. Cox proportional hazard regression analyses were used to evaluate the association of performance measures and time to incident disability. The predictive ability of performance measures was compared using receiver-operator characteristic curves. Results. All lower and upper extremity measures, with the exception of grip strength, significantly predicted the onset of progressive ADL disability, but only walking speed was significantly associated with the onset of catastrophic ADL disability. The chair stands test, walking speed, and the lower extremity SPS were significantly associated with the onset of both progressive and catastrophic mobility disability. Only lower extremity individual tests and SPS significantly predicted the onset of both progressive and catastrophic upper extremity disability. The receiver-operator characteristic curves for ADL and mobility disability showed that all performance measures evaluated had a greater predictive ability for progressive than for catastrophic incident disability. This finding was not consistent for upper extremity disability. The areas under the curve for walking speed and lower extremity SPS were very similar, ranging from 0.58 to 0.81 and from 0.57 to 0.85, and the predictive ability of these two measures was the greatest for all disability outcomes assessed. Conclusion. Physical performance measures of lower extremity and, in particular, walking speed and lower extremity SPS are valuable tools to predict different forms of disability, especially those with a progressive onset.

Research paper thumbnail of Multiple Hormonal Deficiencies in Anabolic Hormones Are Found in Frail Older Women: The Women's Health and Aging Studies

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009

Background. Alterations in anabolic hormones are theorized to contribute to aging and frailty, wi... more Background. Alterations in anabolic hormones are theorized to contribute to aging and frailty, with most studies focusing on the relationship between individual hormones and specifi c age-associated diseases. We hypothesized that associations with frailty would most likely manifest in the presence of defi cits in multiple anabolic hormones. Methods. The relationships of serum levels of total IGF-1, DHEAS , and free testosterone (T) with frailty status (nonfrail, prefrail, or frail) were analyzed in 494 women aged 70-79 years enrolled in the Women's Health and Aging Studies I or II. Using multivariate polytomous regression, we calculated the odds of frailty for defi ciency in each hormone (defi ned as the bottom quartile of the hormone) individually, as well as for a count of the hormones. Results. For each hormone, in adjusted analyses, those with the defi ciency were more likely to be frail than those without the defi ciency, although this did not achieve statistical signifi cance (IGF-1: odds ratio [OR] 1.82, confi dence interval [CI] 0.81-4.08; DHEAS: OR 1.68, CI 0.77-3.69; free T: OR 2.03, CI 0.89-4.64). Compared with those with no hormonal defi ciencies, those with one defi ciency were not more likely to be frail (OR 1.15, CI 0.49-2.68), whereas those with two or three defi ciencies had a very high likelihood of being frail (OR 2.79, CI 1.06-7.32), in adjusted models. Conclusions. The absolute burden of anabolic hormonal defi ciencies is a stronger predictor of frailty status than the type of hormonal defi ciency, and the relationship is nonlinear. These analyses suggest generalized endocrine dysfunction in the frailty syndrome.

Research paper thumbnail of Associations of Subclinical Cardiovascular Disease With Frailty

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2001

Research paper thumbnail of Advancing the Taxonomy of Disability in Older Adults

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2004

Research paper thumbnail of Untangling the Concepts of Disability, Frailty, and Comorbidity: Implications for Improved Targeting and Care

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2004

Research paper thumbnail of Frailty and Impaired Cardiac Autonomic Control: New Insights From Principal Components Aggregation of Traditional Heart Rate Variability Indices

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009

Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased com... more Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased complexity in their output. For example, the degradation of cardiac autonomic control results in loss of complexity in the heart rate signal. Frailty is a state of critically impaired homeostasis that results in heightened vulnerability to stressors. We propose a new measure of heart rate variability (HRV) to capture the impairment in cardiac autonomic control associated with frailty. Methods. Traditional time and frequency domain indices of HRV were obtained from 2-hour ambulatory electrocardiograms (ECGs) of 276 women (65-101 years old) in the Women ' s Health and Aging Study-I. Principal components analysis was conducted on the correlation matrix of HRV indices. Frailty was defi ned using a validated instrument. Regression models were used to evaluate associations of HRV measures with age, frailty, and 5-year mortality. Results. The fi rst two principal components (PCs), PC1 and PC2, explained 90% of the variance in HRV indices. PC1 is the mean of log-transformed HRV indices. PC2 is a linear combination of log-transformed indices, with positive weights for very low frequency (VLF), low frequency (LF), and standard deviation of N-N intervals (SDNN), and negative weights for high frequency (HF), root-mean-squared differences of successive N-N intervals (RMSSD), and proportion of all N-N intervals that are larger than 50 ms (pNN50). Decreases in SDNN, VLF, LF, and LF/HF were associated with an increased risk of frailty. PC2 was more strongly associated with age (b = − .23, p < .001) and frailty (b = − .73, p < 10 − 5) than were the individual HRV indices and LF/HF. PC2 was also the best predictor of 5-year mortality (b = − .60, p < 10 − 6). Conclusions. Cardiac autonomic control, as refl ected by HRV, is impaired in frailty. A new measure derived from PC aggregation of traditional HRV indices provides a compact summary of this impairment.

Research paper thumbnail of Low Nutrient Intake Is an Essential Component of Frailty in Older Persons

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2006

Background. Poor nutrient intake is conceptualized to be a component of frailty, but this hypothe... more Background. Poor nutrient intake is conceptualized to be a component of frailty, but this hypothesis has been little investigated. We examined the association between low energy and nutrient intake and frailty. Methods. We used data from 802 persons aged 65 years or older participating to the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study. Frailty was defined by having at least two of the following criteria: low muscle strength, feeling of exhaustion, low walking speed, and reduced physical activity. The European Prospective Investigation into Cancer and nutrition (EPIC) questionnaire was used to estimate the daily intake of energy and nutrients. Low intake was defined using the value corresponding to the lowest sex-specific intake quintile of energy and specific nutrients. Adjusted logistic regression analyses were used to study the association of frailty and frailty criteria with low intakes of energy and nutrients.

Research paper thumbnail of Initial Manifestations of Frailty Criteria and the Development of Frailty Phenotype in the Women's Health and Aging Study II

The Journals of Gerontology: Series A, 2008

Research paper thumbnail of Oxidative Protein Damage Is Associated With Elevated Serum Interleukin-6 Levels Among Older Moderately to Severely Disabled Women Living in the Community

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2008

Background. Elevated interleukin (IL)-6 is associated with adverse outcomes. Our objective was to... more Background. Elevated interleukin (IL)-6 is associated with adverse outcomes. Our objective was to determine whether serum protein carbonyls, an indicator of oxidative protein damage and oxidative stress, were associated with IL-6. Methods. Serum protein carbonyls and IL-6 were measured in 739 women, age !65 years, in the Women's Health and Aging Study I. Results. Geometric mean of protein carbonyls was 0.082 nmol/mg. After adjusting for age and smoking status, log e serum protein carbonyls were associated with log e IL-6 (b ¼ 0.143, standard error [SE] ¼ 0.048, p ¼ .003) in linear regression analyses and with elevated IL-6 (!2.5 pg/mL) (odds ratio ¼ 1.38, 95% confidence interval, 1.02-1.86, p ¼ .037) in logistic regression analyses. Conclusion. Oxidative damage to proteins is independently associated with serum IL-6 among older women living in the community. Increased oxidative stress may be a factor involved in the pathogenesis of the proinflammatory state that occurs in older adults.

Research paper thumbnail of Exploring biologically relevant pathways in frailty

The journals of gerontology. Series A, Biological sciences and medical sciences, 2011

Frailty is a late-life syndrome of vulnerability to adverse health outcomes characterized by a ph... more Frailty is a late-life syndrome of vulnerability to adverse health outcomes characterized by a phenotype that includes muscle weakness, fatigue, and inflammatory pathway activation. The identification of biologically relevant pathways that influence frailty is challenged by its biological complexity and the necessity in separating disease states from the syndrome of frailty. As with longevity research, genetic analyses may help to provide insights into biologically relevant pathways that contribute to frailty.

Research paper thumbnail of Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults

Experimental Gerontology, 2011

In immunocompetent persons, cytomegalovirus (CMV) is thought to persist primarily in monocytes an... more In immunocompetent persons, cytomegalovirus (CMV) is thought to persist primarily in monocytes and myeloid progenitor cells, establishing a chronic infection. In older adults, chronic CMV infection is typically diagnosed by a positive IgG serology. While many studies have shown CMV-specific T-cell expansion in CMV seropositive older individuals, significant heterogeneity has also been observed in this elderly population. In a study of 71 community-dwelling older adults, we assessed CMV viral DNA in peripheral monocytes by nested PCR and compared the relationships of detectable CMV DNA and IgG serology with serum levels of neopterin, a marker for monocyte/macrophage-mediated immune activation. The results showed that 52 (73.2%) participants were CMV seropositive, of whom 30 (57.5%) had detectable CMV DNA. CMV seropositive and seronegative participants did not differ in their neopterin levels, but individuals with detectable CMV DNA had higher neopterin than those without (10.6±4.4 vs 8.0±1.9nM, respectively, p<.0001) adjusting for demographic and clinical covariates and interferon (IFN)-γ levels. In addition, there was no association between IgG titers and neopterin. These findings suggest that detection of CMV viral DNA in monocytes may be an informative tool to evaluate chronic CMV infection and its potential role in monocyte/macrophage-mediated immune activation in the elderly.

Research paper thumbnail of Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: Results from the Women’s Health and Aging Studies I

Experimental Gerontology, 2009

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