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1.  Patterns of 12-Year Change in Physical Activity Levels in Community-Dwelling Older Women: Can Modest Levels of Physical Activity Help Older Women Live Longer? 
American Journal of Epidemiology  2012;176(6):534-543.
Few studies have addressed changes in physical activity participation over time among the elderly. The authors hypothesized that there were distinct trajectories of physical activity level over time and identifiable predictors of such trajectories, as well as that the maintenance of regular physical activity, even below recommended levels, was associated with lower mortality risk. Using longitudinal data (1994–2009) from 433 initially high-functioning older women aged 70–79 years at baseline, a joint latent class and survival mixture model identified 4 activity trajectory classes: always active (16.6%), fast declining (19.2%), stable moderate (32.3%), and always sedentary (31.9%). Obesity, coronary artery disease, chronic obstructive pulmonary disease, depressive symptoms, low self-efficacy, mobility disability, and low energy were associated with sedentary behavior and/or a fast decline in activity. Women in the fast declining and always sedentary classes had hazard ratios for death of 2.34 (95% confidence interval: 1.20, 4.59) and 3.34 (95% confidence interval: 1.72, 6.47), respectively, compared with the always active class; no mortality difference was found between the stable moderate and always active groups (hazard ratio = 1.24, 95% confidence interval: 0.63, 2.47). Our findings suggest that physical activity does not have to be vigorous to be beneficial and that the gain may be the greatest among women who reported the lowest levels of activity.
PMCID: PMC3530350  PMID: 22935515
aging; exercise; healthy people programs; lifestyle; motor activity; risk factors; survival; walking
2.  Criteria for Clinically Relevant Weakness and Low Lean Mass and Their Longitudinal Association With Incident Mobility Impairment and Mortality: The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project 
This analysis sought to determine the associations of the Foundation for the National Institutes of Health Sarcopenia Project criteria for weakness and low lean mass with likelihood for mobility impairment (gait speed ≤ 0.8 m/s) and mortality. Providing validity for these criteria is essential for research and clinical evaluation.
Among 4,411 men and 1,869 women pooled from 6 cohort studies, 3-year likelihood for incident mobility impairment and mortality over 10 years were determined for individuals with weakness, low lean mass, and for those having both. Weakness was defined as low grip strength (<26kg men and <16kg women) and low grip strength-to-body mass index (BMI; kg/m2) ratio (<1.00 men and <0.56 women). Low lean mass (dual-energy x-ray absorptiometry) was categorized as low appendicular lean mass (ALM; <19.75kg men and <15.02kg women) and low ALM-to-BMI ratio (<0.789 men and <0.512 women).
Low grip strength (men: odds ratio [OR] = 2.31, 95% confidence interval [CI] = 1.34–3.99; women: OR = 1.99, 95% CI 1.23–3.21), low grip strength-to-BMI ratio (men: OR = 3.28, 95% CI 1.92–5.59; women: OR = 2.54, 95% CI 1.10–5.83) and low ALM-to-BMI ratio (men: OR = 1.58, 95% CI 1.12–2.25; women: OR = 1.81, 95% CI 1.14–2.87), but not low ALM, were associated with increased likelihood for incident mobility impairment. Weakness increased likelihood of mobility impairment regardless of low lean mass. Mortality risk patterns were inconsistent.
These findings support our cut-points for low grip strength and low ALM-to-BMI ratio as candidate criteria for clinically relevant weakness and low lean mass. Further validation in other populations and for alternate relevant outcomes is needed.
PMCID: PMC3991140  PMID: 24737560
Muscle; Sarcopenia; Mobility; Impairment.
3.  Hearing Loss and Cognitive Decline Among Older Adults 
JAMA internal medicine  2013;173(4):10.1001/jamainternmed.2013.1868.
Whether hearing loss is independently associated with accelerated cognitive decline in older adults is unknown.
We studied 1984 older adults (mean age 77.4 years) enrolled in the HealthABC study, a prospective observational study begun in 1997–98. Our baseline cohort consisted of participants without prevalent cognitive impairment (Modified Mini-Mental State [3MS] scores ≥ 80) who underwent audiometric testing in Year 5. Participants were followed for 6 years. Hearing was defined at baseline using a pure-tone average (PTA) of thresholds at 0.5 – 4 kHz in the better-hearing ear. Cognitive testing was performed in Years 5, 8, 10, and 11 and consisted of the 3MS (measuring global function) and the Digit Symbol Substitution test (DSS, measuring executive function). Incident cognitive impairment was defined as a 3MS score < 80 or a decline in 3MS > 5 points from baseline. Mixed-effects regression and Cox models were adjusted for demographic and cardiovascular risk factors.
Individuals with baseline hearing loss (PTA > 25 dB, n = 1162) had rates of decline in 3MS and DSS scores that were 41% and 32% greater, respectively, than those in normal hearing individuals (3MS: −0.65 points/year [95% CI: −0.73 – −0.56] vs. −0.46 points/year [95% CI: −0.55 – −0.36], p=.004; DSS: −0.83 points/year [95% CI: −0.94 – −0.73] vs. −0.63 points/year [95% CI: −0.75 – −0.51], p=.015). Compared to those with normal hearing, individuals with hearing loss had a 24% (Hazard ratio: 1.24 [95% CI: 1.05 – 1.48]) increased risk of incident cognitive impairment. Rates of cognitive decline and the risk of incident cognitive impairment were linearly associated with the severity of an individual’s baseline hearing loss.
Hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults. Further studies investigating the mechanistic basis of this association and whether hearing rehabilitative interventions could affect cognitive decline are needed.
PMCID: PMC3869227  PMID: 23337978
4.  Lifestyle Activities in Sociodemographically at-risk Urban, Older Adults Prior to Participation in the Baltimore Experience Corps® Trial 
Activities, adaptation & aging  2012;36(3):242-260.
Experience Corps® places teams of trained volunteers in elementary school classrooms to promote academic achievement in children, and serve as a health promotion intervention for older adults. Prior to randomization, individuals reported participation in several activities of varying cognitive, physical, and social demands. Maintaining an active lifestyle, particularly in intellectually demanding activities, was associated with physical, mental, and cognitive health in adulthood. Establishing how individuals allocated their time before randomization to this program provides insight to prevalent health behaviors for at-risk older adults, and can provide the basis for examining intervention-related changes in lifestyle as a result of volunteer participation
PMCID: PMC3490448  PMID: 23144524
Engagement; Activities; Intervention; Cognition; Aging; Volunteers
5.  Inflammation and mortality in a frail mouse model 
Age  2011;34(3):705-715.
Mice homozygous for targeted deletion of the interleukin 10 gene (Il-10) have been partially characterized as a model for human frailty. These mice have increased serum interleukin (IL)-6 in midlife, skeletal muscle weakness, and an altered skeletal muscle gene expression profile compared to age and sex-matched C57BL/6 (B6) control mice. In order to further characterize for use as a frailty model, we evaluated the evolution of inflammatory pathway activation, endocrine change, and mortality in these mice. Serum was collected in groups of age- and sex-matched B6.129P2-Il10tm1Cgn/J (IL-10tm/tm) mice and B6 control mice at age 12, 24, 48, 72, and 90 weeks. Cytokines including IL-6, interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), chemokine (C-X-C motif) ligand 1 (KC), IL-12, and IL-10 were measured using electro-chemiluminescent multiplex immunoassay and insulin-like growth factor 1 (IGF-1) was measured using solid-phase enzyme-linked immunosorbent assay. A separate longitudinal cohort was monitored from age 35 weeks to approximately 100 weeks. Survival was evaluated by Kaplan–Meier survival estimates and detailed necropsy information was gathered in a subset of mice that died or were sacrificed. In IL-10tm/tm mice compared to B6 controls, serum IL-6, IL-1β, TNF-α, IFN-γ, KC levels were significantly elevated across the age groups, serum mean IGF-1 levels were higher in the 48-week-old groups, and overall mortality rate was significantly higher. The quadratic relationship between IGF-1 and age was significantly different between the two strains of mice. Serum IL-6 was positively associated with IGF-1 but the effect was significantly larger in IL-10tm/tm mice. These findings provide additional rationale for the use of the IL-10tm/tm mouse as a model for frailty and for low-grade inflammatory pathway activation.
PMCID: PMC3337927  PMID: 21633802
IGF-1; IL-6; IL-10; C57BL/6; Inflammation; Mortality; Frailty; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
6.  Anemia and 9-Year Domain-Specific Cognitive Decline in Community-Dwelling Older Women: The Women’s Health and Aging Study II 
To test the hypothesis that anemia (hemoglobin <12 g/dL) is associated with a faster rate of 9-year cognitive decline in a community-dwelling sample of women aged 70-80 years at baseline.
A population-based, prospective cohort study
East Baltimore, Maryland
436 women sampled to be representative of the 2/3 least disabled women in, aged 70-80 years at baseline (1994-1996).
9-year trajectories of cognitive decline, analyzed with linear random effects models, in the domains of immediate verbal recall, delayed verbal recall, psychomotor speed, and executive function.
At baseline and after adjustment for demographic and disease covariates, women with anemia were slower to complete a test of executive function than women without anemia by - 0.43 SD (95% CI: −0.74, −0.13) on the Trail Making Test, Part B (TMTB). During follow-up, anemia was associated with a faster rate of decline in memory. Between baseline and year 3, women with anemia declined at a rate of 0.18 more SD/year (95% CI: −0.29, −0.06) than women without anemia on the Hopkins Verbal Learning Test (HVLT) and by .0.15 more SD/year (95% CI: −0.26. −0.04) on the Hopkins Verbal Learning Test-Delayed (HVLT-Delayed).
Anemia was associated with poorer baseline performance on a test of executive function and with faster rates of decline on tests of immediate and delayed verbal recall. If this relationship is causal, it is possible that treatment of anemia could prevent or postpone cognitive decline.
PMCID: PMC3560911  PMID: 19682133
anemia; elderly; executive function; longitudinal study; memory
7.  Association Between Inflammatory-related Disease Burden and Frailty: Results From the Women’s Health and Aging Studies (WHAS) I and II 
Frailty is associated with a pro-inflammatory state, which has been characterized by elevated levels of systemic inflammatory biomarkers, but has not been related to the number of co-existing chronic diseases associated with inflammation. We sought to determine the extent to which a higher number of inflammatory-related diseases is associated with frailty and to identify the most common disease patterns associated with being frail in older adults. We performed binomial regression analyses to assess whether a higher count of inflammatory-related diseases increases the probability of frailty using data from the Women's Health and Aging Studies I and II, companion cohorts composed of 70–79-year-old community-dwelling older women in Baltimore, Maryland (n=620). An increase of one inflammatory-related disease was associated log-linearly with frailty (Prevalence Ratio (PR)=2.32, 95% Confidence Interval (CI)=1.85–2.92). After adjusting for age, race, education, and smoking status, the probability of frailty remained significant (PR=1.97, 95%CI=1.52–2.55). In the frail population, chronic kidney disease (CKD) and depressive symptoms (Prevalence=22.9%, 95%CI=14.2–34.8%); CVD and depressive symptoms (21.7%, 95%CI=13.2–33.5%); CKD and anemia (18.7%, 95%CI=11.1–29.7%); cardiovascular disease (CVD), CKD, and pulmonary disease (10.7%, 95%CI=5.2–21.0%); CKD, anemia, and depressive symptoms (8.7%, 95%CI=3.9–18.2%); and CVD, anemia, pulmonary disease, and depressive symptoms (5.0%, 95%CI=1.6–14.4%) were among the most frequent disease combinations. Their prevalence percentages were significantly higher in the frail versus non-frail women. A higher inflammatory-related disease count, perhaps reflecting a greater pro-inflammatory burden, increases the likelihood of frailty. Shared mechanisms among specific disease combinations may further contribute to this risk.
PMCID: PMC3197795  PMID: 21763008
comorbidity; inflammation; frailty
8.  Difficulty Assisting with Health Care Tasks Among Caregivers of Multimorbid Older Adults 
Family caregivers provide assistance with health care tasks for many older adults with chronic illnesses. The difficulty they experience in providing this assistance, and related implications for their well-being, have not been well described.
The objectives of this study are: (1) to describe caregiver’s health care task difficulty (HCTD), (2) determine the characteristics associated with HCTD, and (3) explore the association between HCTD and caregiver well-being.
This is a cross-sectional study.
Baseline sample of caregivers to older (aged 65+ years) multimorbid adults enrolled in an ongoing cluster-randomized controlled trial (N = 308).
The HCTD scale (0–16) is comprised of questions measuring self-reported difficulty in assisting older adults with eight health care tasks, including taking medication, visiting health care providers, and managing medical bills. Caregivers were categorized using this scale into no, low, medium, and high HCTD groups. We used ordinal logistic regression and multivariate linear regression analyses to examine the relationships between HCTD, caregiver self-efficacy, caregiver strain (Caregiver Strain Index), and depression (Center for Epidemiological Studies Depression Scale), controlling for patient and caregiver socio-demographic and health factors.
Caregiver age and number of health care tasks performed were positively associated with increased HCTD. The quality of the caregiver’s relationship with the patient, and self-efficacy were inversely associated with increased HCTD. A one-point increase in self-efficacy was associated with a significant lower odds of reporting high HCTD (OR, 0.64; 95% CI, 0.54, 0.77).Adjusted linear regression models indicated that high HCTD was independently associated with significantly greater caregiver strain (B, 2.7; 95% CI, 1.12, 4.29) and depression (B, 3.01; 95% CI, 1.06, 4.96).
This study demonstrates that greater HCTD is associated with increased strain and depression among caregivers of multimorbid older adults. That caregiver self-efficacy was strongly associated with HCTD suggests health-system-based educational and empowering interventions might improve caregiver well-being.
PMCID: PMC3250537  PMID: 21874385
caregiver; chronic disease; self efficacy; psychology
9.  Community Aging in Place, Advancing Better Living for Elders (CAPABLE): A Bio-Behavioral-Environmental Intervention to Improve Function and Health-Related Quality of Life in Disabled, Older Adults 
To determine effect size and acceptability of a multi-component behavior and home repair intervention with low-income, disabled older adults
Prospective randomized controlled pilot trial
Participants’ homes
40 low income older adults with difficulties in at least 1 Activity of Daily Living (ADL) or 2 Instrumental Activities of Daily Living (IADL).
Coordinated occupational therapy (OT), nursing (RN), and handyman (HM) visits compared to attention-control visits. The intervention consisted of up to 6 visits with an OT, up to 4 visits with an RN and an average of $1,300 in HM repairs and modifications. Each intervention participant received all components of the intervention clinically tailored to risk profile and goals. Each attention-control participant received the same number of visits as the intervention participants, involving sedentary activities of their choice.
Primary Outcome: difficulty in performing ADL and IADLs. Secondary outcomes: Health related quality of life and falls–efficacy.
Thirty five of 40 adults (87%) completed the 6-month trial and 93% and 100% of the control and intervention group, respectively, stated the study benefited them. The intervention group improved on all outcomes. When comparing the mean change in the intervention group compared to the mean change in the control group from baseline to follow up, the CAPABLE intervention had an effect size of 0.63 for reducing difficulty in ADLs, 0.62 for reducing difficulty in IADLs, 0.89 for Quality of Life, and 0.55 for Falls-efficacy.
The multi-component CAPABLE intervention was acceptable to participants, feasible to provide, and showed promising results, suggesting that this multi-component intervention to reduce disability should be evaluated in a larger trial.
PMCID: PMC3245364  PMID: 22091738
disability; intervention; home-based
10.  Lifestyle Activities and Memory: Variety May Be the Spice of Life. The Women’s Health and Aging Study II 
This study examined whether participation in a variety of lifestyle activities was comparable to frequent participation in cognitively challenging activities in mitigating impairments in cognitive abilities susceptible to aging in healthy, community-dwelling older women. Frequencies of participation in various lifestyle activities on the Lifestyle Activities Questionnaire (LAQ) were divided according to high (e.g., reading), moderate (e.g., discussing politics), and low (e.g., watching television) cognitive demand. We also considered the utility of participation in a variety of lifestyle activities regardless of cognitive challenge. Immediate and delayed verbal recall, psychomotor speed, and executive function were each measured at baseline and at five successive exams, spanning a 9.5-year interval. Greater variety of participation in activities, regardless of cognitive challenge, was associated with an 8 to 11% reduction in the risk of impairment in verbal memory and global cognitive outcomes. Participation in a variety of lifestyle activities was more predictive than frequency or level of cognitive challenge for significant reductions in risk of incident impairment on measures sensitive to cognitive aging and risk for dementia. Our findings offer new perspectives in promoting a diverse repertoire of activities to mitigate age-related cognitive declines.
PMCID: PMC3508669  PMID: 22172155
Cognitive aging; Dementia; Intensity; Epidemiology; Longitudinal; Risk reduction behavior
11.  Exploring Biologically Relevant Pathways in Frailty 
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.
Based on current understanding of the physiological basis of frailty, we hypothesize that variation in genes related to inflammation and muscle maintenance would associate with frailty. One thousand three hundred and fifty-four single-nucleotide polymorphisms were genotyped across 134 candidate genes using the Illumina Genotyping platform, and the rank order by strength of association between frailty and genotype was determined in a cross-sectional study.
Although no single-nucleotide polymorphism reached study-wide significance after controlling family-wise false-discovery rate at 0.05, single-nucleotide polymorphisms within the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), Caspase 8 (CASP8), CREB-binding protein (CREBBP), lysine acetyltransferase 2B (KAT2B), and beta-transducin repeat containing (BTRC) loci were among those strongly associated with frailty.
The apoptosis– and transcription regulation–related pathways highlighted by this preliminary analysis were consistent with prior gene expression studies in a frail mouse model and provide useful etiological insights for future biological studies of frailty.
PMCID: PMC3156628  PMID: 21743092
Frailty; Candidate genes; Apoptosis
12.  The Role of Education and Intellectual Activity on Cognition 
Journal of Aging Research  2012;2012:416132.
Although educational attainment has been consistently related to cognition in adulthood, the mechanisms are still unclear. Early education, and other social learning experiences, may provide the skills, knowledge, and interest to pursue intellectual challenges across the life course. Therefore, cognition in adulthood might reflect continued engagement with cognitively complex environments. Using baseline data from the Baltimore Experience Corps Trial, multiple mediation models were applied to examine the combined and unique contributions of intellectual, social, physical, creative, and passive lifestyle activities on the relationship between education and cognition. Separate models were tested for each cognitive outcome (i.e., reading ability, processing speed, memory). With the exception of memory tasks, findings suggest that education-cognition relations are partially explained by frequent participation in intellectual activities. The association between education and cognition was not completely eliminated, however, suggesting that other factors may drive these associations.
PMCID: PMC3423895  PMID: 22928110
13.  Blunted Diurnal Decline of Cortisol among Older Adults with Low Socioeconomic Status 
Low socioeconomic status (SES) is associated with increased risk for adverse health outcomes; those with low SES are thought to experience more environmental disadvantage and exposure to chronic stress over the life course. The effects of chronic stress on health have been measured by cortisol levels and variations in their diurnal pattern. However, the patterns of association between SES and cortisol have been equivocal in older adults. This paper examined in 98 older adults participating in the Brain Health Substudy of the Baltimore Experience Corps Trial baseline patterns of diurnal variation in salivary cortisol associated with lower versus higher SES using total income and perceived SES relative to others. For each measure, participants stratified into lower vs. higher SES showed a more blunted rate of decline in diurnal salivary cortisol over the day in adjusted models (P values ≤ 0.05). There were no SES-related differences in awakening cortisol, cortisol awakening response, or area under the curve. These findings confirm prior evidence of a biologic pathway through which socioeconomic disadvantage is linked to biologic vulnerability, and through which the impact of volunteer service in Experience Corps may be measured.
PMCID: PMC3369216  PMID: 21884161
socioeconomic status; salivary cortisol; stress; diurnal pattern; HPA axis; resilience
14.  Education Predicts Incidence of Preclinical Mobility Disability in Initially High-Functioning Older Women. The Women’s Health and Aging Study II 
To examine the impact of educational attainment on the incidence of preclinical mobility disability (PCD).
The Women's Health and Aging II Study is a prospective observational cohort study of 436 initially high-functioning community-dwelling women aged 70–79 years at baseline in Baltimore, Maryland. We measured the association of highest attained education level with preclinical mobility disability (PCD) over an 11-year period. PCD is defined as self-reported modification in any of four tasks without reporting difficulty in those tasks. The tasks were walking ½ mile, climbing up steps, doing heavy housework, and getting in/out of bed or chair.
Participants with less than 9 years of education were more likely to acquire incident PCD (hazard ratio: 3.1, 95% confidence interval = 1.2–7.7) than their counterparts with more education after adjusting for income, marital status, number of diseases, and high self-efficacy.
Lower education level is an independent predictor of incident preclinical mobility disability. This association has important implications for primary and secondary prevention and can be easily assessed in clinical encounters.
PMCID: PMC3074962  PMID: 21382883
Health disparities; Mobility; Preclinical disability
15.  The Frailty Syndrome: Definition and Natural History 
Clinics in geriatric medicine  2011;27(1):1-15.
PMCID: PMC3028599  PMID: 21093718
16.  Patterns of Comorbid Inflammatory Diseases in Frail Older Women: The Women’s Health and Aging Studies I and II 
Developing interventions to prevent frailty in older adults is a priority as it increases the risk for disability, institutionalization, and death. Single chronic inflammatory diseases are known to increase the risk of frailty. Identification of comorbid inflammatory diseases that synergistically might heighten this risk would provide further insight into therapeutic approaches to prevent frailty. The study aims were to characterize whether there are specific inflammatory disease pairs that are associated with frailty and to determine whether the risk of frailty is affected by synergistic interactions between these inflammatory diseases.
Data were from the Women's Health and Aging Studies I and II and complementary cohorts of community-dwelling women aged 70–79 years from Baltimore, Maryland (n = 620). Multivariable logistic regression analyses were performed to evaluate the relationships between these diseases and frailty.
Among the frail (11.3%), 15.2% had both depressive symptoms and anemia and 14.5% had pulmonary disease and anemia. The risk of frailty was synergistically increased in those with depressive symptoms and anemia (adjusted risk ratios = 11.93, 95% confidence interval [CI] 4.10–34.76) and those with pulmonary disease and anemia (risk ratios = 5.57, 95% CI 2.14–14.48), compared with those without either disease in each pair. The attributable proportions of frail cases due to interaction between the diseases of each pair were 0.56 (95% CI 0.07–1.05) and 0.61 (95% CI 0.18–1.05), respectively.
Synergistic interactions between specific inflammatory diseases may heighten the risk of frailty. These findings suggest that a common etiologic pathway may exist among co-occurring inflammatory diseases and that their improved comanagement may be an approach to reducing frailty.
PMCID: PMC3004772  PMID: 19933749
Frailty; Comorbidity; Inflammation
17.  Depressive symptoms predict incident cognitive impairment in cognitive healthy older women 
There is increasing evidence that depressive symptoms are associated with the development of cognitive impairment and dementia in late life. We sought to examine whether depression increased the risk of incident cognitive impairment in a longitudinal study of older women.
observational study, up to 6 examinations spanning up to 9 years.
university-based Division of Geriatric Medicine
community-based sample of 436 older, non-demented women
Participants were followed with regular medical and neuropsychiatric evaluations. Cognitive assessment included episodic immediate and delayed memory, psychomotor speed, and executive functioning. Participants were characterized as having incident impairment on a cognitive test when scores fell below the tenth percentile on age-adjusted norms. Baseline depressive symptoms were measured using the Geriatric Depression Scale (GDS) (30-item). Discrete-time Cox Proportional hazards regression with generalized linear models were used to determine whether baseline risk factors predicted incident impairment on each cognitive test, defined as performance below the tenth percentile on age-adjusted norms.
Baseline GDS was highly associated with incident impairment on all cognitive tests (p <.03). These associations were unaffected by vascular conditions except diabetes, which was associated with incident impairment in delayed recall and psychomotor speed.
These data suggest that depression may be risk factors for cognitive decline, and thus a potential target for diagnostic and therapeutic interventions.
PMCID: PMC2838202  PMID: 20224517
cognitive decline; depression; cognitive impairment; Mild Cognitive Impairment
18.  Glutathione Peroxidase Enzyme Activity in Aging 
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.
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.
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.
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
19.  Nonlinear Multisystem Physiological Dysregulation Associated With Frailty in Older Women: Implications for Etiology and Treatment 
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.
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.
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.
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.
PMCID: PMC2737590  PMID: 19567825
Frailty etiology; Aging
20.  Transitions Among Disability Levels or Death in African American and White Older Women 
This study examined the racial differences in probabilities of transitioning across three disability levels of walking ½ mile in a community-dwelling population of older women.
The sample comprised 436 community-dwelling older women who were among the two-third least disabled women in Baltimore, Maryland. The levels of disability status of walking ½ mile included high functioning defined as reporting no difficulty, preclinical disability defined as reports of task modification but no reported difficulty, and disability defined as reported difficulty. First-order Markov transition models were specified to determine whether race influences the types of individual-level transitions between difficulty levels of walking ½ mile.
Among high-functioning women, African Americans were more likely to be disabled at the next round than their White counterparts. African American women who began with preclinical disability were more likely to die before the next round. After adjusting for age, education, and perceived income inadequacy, African American women tended to have an increased risk of becoming disabled if preclinically disabled than White women.
Prevention through identification of individuals at an early phase of decline appears to be key to addressing racial disparities in physical disability even in later life.
PMCID: PMC2800803  PMID: 19228790
Racial disparities; Preclinical disability; Mobility disability; Walking
21.  Functional Decline and Recovery of Activities of Daily Living among Hospitalized, Disabled Older Women: The Women’s Health and Aging Study I 
Among community-dwelling, disabled older women who were hospitalized, to determine: 1) the rates and predictors of functional decline, 2) the probability and time course of subsequent functional recovery, and 3) predictors of functional recovery.
Population-based observational cohort study.
Woman’s Health and Aging Study
A subset of the 1002 moderately to severely disabled community-dwelling older women who were hospitalized over 3 years(n=457).
Functional decline and complete and partial recovery were defined using a 0-6 scale of dependencies in Activities of Daily Living(ADL), evaluated every six months over 3 years. Complete recovery was defined as returning to baseline function after functional decline; partial recovery was defined as any improvement in the ADL scale after functional decline. Multiple logistic regression analysis was used to determine predictors of functional decline. Kaplan-Meier curves were produced to estimate the proportions recovering as a function of time since hospitalization. Discrete-time proportional hazards models were used to regress the time-to-recovery hazards on the predictor variables.
33% of hospitalized women experienced functional decline. Older age, frailty, length of stay and higher education were associated with functional decline. 50% fully recover over the subsequent 30 months, with 33% recovering within 6 months, and an additional 14% over the next 6 months. Younger women were more likely to recover (80 to 70 year old women,Hazard Ratio=0.39, 95%CI 0.24,0.64).
While most recovery of function occurs by 6 months after the first visit after a hospitalization, a significant proportion of women recover over the next 2 years.
PMCID: PMC2805561  PMID: 19694869
Hospitalization; Activities of Daily Living; Disability; Recovery
22.  White Blood Cell Counts, Insulinlike Growth Factor-1 Levels, and Frailty in Community-Dwelling Older Women 
Elevated white blood cell (WBC) counts and decreased insulin-like growth factor-1 (IGF-1) levels are individually associated with frailty in older adults. WBC subpopulations are known to produce IGF-1 and express IGF-1 receptors in vitro. However, in vivo relationships between WBC and IGF-1 and their joint contribution to frailty have not been investigated.
Baseline data from 696 community-dwelling older women in the Women’s Health and Aging Study I were included in this cross-sectional analysis. Multivariate linear regression analysis was performed to assess the relationship between WBC counts and IGF-1 levels. Odds ratios (ORs) for frailty were evaluated across tertiles of WBC counts and IGF-1 levels, adjusting for age, race, education, body mass index, and smoking.
WBC counts correlated with IGF-1 levels (Spearman coefficient: .10, p < .01). Compared with participants in the low WBC and high IGF-1 tertiles (reference group), those in the low WBC and low IGF-1 tertiles had OR of 2.33 for frailty (95% confidence interval [CI]: 1.04–3.65, p < .05), those in the high WBC and high IGF-1 tertiles had OR of 3.86 (95% CI: 1.13–4.07, p < .01), and those in the high WBC and low IGF-1 tertiles had OR of 3.61 (95% CI: 1.64–4.97, p < .01), adjusting for covariates.
These findings demonstrate in vivo correlation between WBC and IGF-1. They suggest U-shaped joint associations of WBC and IGF-1 with frailty, with the strongest association at adverse levels of both. They also provide a basis for further investigation into the complex immune–endocrine dysregulations in frailty.
PMCID: PMC2657176  PMID: 19251912
Frailty; WBC; IGF-1
23.  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.
PMCID: PMC2673566  PMID: 19027777
Frailty; Monocyte-mediated inflammatory; pathways; Gene expression; Stress-responsive genes; Geriatrics; Aging
24.  Multiple Hormonal Deficiencies in Anabolic Hormones Are Found in Frail Older Women: The Women's Health and Aging Studies 
Alterations in anabolic hormones are theorized to contribute to aging and frailty, with most studies focusing on the relationship between individual hormones and specific age-associated diseases. We hypothesized that associations with frailty would most likely manifest in the presence of deficits in multiple anabolic hormones.
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 deficiency in each hormone (defined as the bottom quartile of the hormone) individually, as well as for a count of the hormones.
For each hormone, in adjusted analyses, those with the deficiency were more likely to be frail than those without the deficiency, although this did not achieve statistical significance (IGF-1: odds ratio [OR] 1.82, confidence 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 deficiencies, those with one deficiency were not more likely to be frail (OR 1.15, CI 0.49–2.68), whereas those with two or three deficiencies had a very high likelihood of being frail (OR 2.79, CI 1.06–7.32), in adjusted models.
The absolute burden of anabolic hormonal deficiencies is a stronger predictor of frailty status than the type of hormonal deficiency, and the relationship is nonlinear. These analyses suggest generalized endocrine dysfunction in the frailty syndrome.
PMCID: PMC2655016  PMID: 19182229
Hormones; Aging; Elderly; Women; Frailty; IGF-1; DHEAS; Testosterone
25.  Executive Decline and Dysfunction Precedes Declines in Memory: The Women's Health and Aging Study II 
Understanding preclinical transitions to impairment in cognitive abilities associated with risks for functional difficulty and dementia. This study characterized in the Women's Health and Aging Study (WHAS) II 9-year declines and transitions to impairment across domains of cognition.
The WHAS II is an observational study of initially high-functioning, community-dwelling women aged 70–80 years at baseline. Random-effects models jointly compared rates of decline, and discrete-time Cox models estimated hierarchies of incident clinical impairment on measures of psychomotor speed and executive function (EF) using the Trail Making Test and in immediate and delayed verbal recall using the Hopkins Verbal Learning Test. Patterns of transition were related to incidence of global cognitive impairment on the Mini-Mental State Exam (MMSE).
Mean decline and impairment occurred first in EF and preceded declines in memory by about 3 years. Thereafter, memory decline was equivalent to that for EF. Over 9 years, 49% developed domain-specific impairments. Risk of incident EF impairment occurred in 37% of the sample and was often the first impairment observed (23.7%), at triple the rate for psychomotor speed (p < .01). Risk of immediate and delayed recall impairments was nearly double that for psychomotor speed (p values <.01). Incident impairment in EF and delayed recall was associated with greater risk for MMSE impairment.
Executive dysfunction developed first among nearly one quarter of older women and was associated with elevated risk for global cognitive impairment. Because EF declines preceded memory declines and are important to efficient storage and retrieval EF represents an important target for interventions to prevent declines in memory and MMSE both of which are associated with progression to dementia.
PMCID: PMC2691188  PMID: 19182230
Cognitive decline; Executive dysfunction; Memory; Cognitive impairment; Mild cognitive impairment

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