Progression of Physical Frailty and the Risk of All-Cause Mortality: Is There a Point of No Return?

OBJECTIVES: To investigate the rate and patterns of accumulation of frailty manifestations in relationship to all-cause mortality and whether there is a point in the progression of frailty beyond which the process becomes irreversible and death becomes imminent (a.k.a. point of no return). DESIGN: Longitudinal observational study. SETTING: Community or a non-nursing home residential care setting. PARTICIPANTS: Two thousand five hundred and fifty seven robust older adults identified at baseline in 2011 with follow-up for all-cause mortality between 2011 and 2018. MEASUREMENTS: Frailty was measured by the physical frailty phenotype. Cox models were used to study the relationships of the number of frailty criteria (0-5) at each point in time and its accumulation patterns with all-cause mortality. Markov state-transition models were used to study annual transitions between health states (i.e., frailty, recovery, and death) after becoming frail among those with frailty onset (n = 373). RESULTS: There was a nonlinear association between greater number of frailty criteria and increasing risk of mortality, with a notable risk acceleration after having accumulated all five criteria (hazard ratio (HR) = 32.6 vs none, 95% confidence interval (CI) = 15.7-67.5). In addition, the risk of one-year mortality tripled, and the likelihood of recovery (i.e., reverting to be robust or pre-frail) halved among those with five frailty criteria compared to those with three or four criteria. A 50% increase in mortality risk was also associated with frailty onset without (vs with) a prior history of pre-frailty (HR = 1.51, 95% CI = 1.20-1.90). CONCLUSION: Both the number and rate of accumulation of frailty criteria were associated with mortality risk. Although there was insufficient evidence to declare a point of no return, having all five-frailty criteria signals the beginning of a transition toward a point of no return. Ongoing monitoring of frailty progression could aid clinical and personal decision-making regarding timing of intervention and eventual transition from curative to palliative care.

The Current State of HIV and Aging: Findings Presented at the 10th International Workshop on HIV and Aging.

With increasing effectiveness of antiretroviral therapy, people with HIV (PWH) are living longer and the prevalence of older PWH continues to increase. Accordingly, PWH are experiencing an increased burden of age-related comorbidities. With this shifting demographics, clinicians and researchers face additional challenges in how to identify, address, and manage the complex intersections of HIV- and aging-related conditions. Established in 2009, the International Workshop on HIV and Aging brings together clinicians and researchers in cross-disciplinary fields along with community advocates and PWH to address the multidisciplinary nature of HIV and aging. This article summarizes plenary talks from the 10th Annual International Workshop on HIV and Aging, which took place in New York City on October 10 and 11, 2019. Presentation topics included the following: the burdens of HIV-associated comorbidities, aging phenotypes, community engagement, and loneliness; these issues are especially important for older PWH, considering the current COVID-19 pandemic. We also discuss broad questions and potential directions for future research necessary to better understand the interaction between HIV and aging.

Alcohol Consumption in Later Life and Mortality in the United States: Results from 9 Waves of the Health and Retirement Study.

BACKGROUND: Alcohol consumption in later life has increased in the past decade, and the relationship between alcohol consumption and mortality is controversial. Recent studies suggest little, if any, health benefit to alcohol. Yet most rely on single-time point consumption assessments and minimal confounder adjustments. METHODS: We report on 16 years of follow-up from the Health and Retirement Study (HRS) cohorts born 1931 to 1941 (N = 7,904, baseline mean age = 61, SD = 3.18). Respondents were queried about drinking frequency/quantity. Mortality was established via exit interviews and confirmed with the national death index. Time-varying confounders included but were not limited to household assets, smoking, body mass index, health/functioning, depression, chronic disease; time-invariant confounders included baseline age, education, sex, and race. RESULTS: After adjustment, current abstainers had the highest risk of subsequent mortality, consistent with sick quitters, and moderate (men: HR = 0.74, 95% CI: 0.60 to 0.91; women: HR = 0.82, 95% CI: 0.63 to 1.07) drinking was associated with a lower mortality rate compared with occasional drinking, though smokers and men evidenced less of an inverse association. Quantitative bias analyses indicated that omitted confounders would need to be associated with ~4-fold increases in mortality rates for men and ~9-fold increases for women to change the results. CONCLUSIONS: There are consistent associations between moderate/occasional drinking and lower mortality, though residual confounding remains a threat to validity. Continued efforts to conduct large-scale observational studies of alcohol consumption and mortality are needed to characterize the changing patterns of consumption in older age.

Men Sustain Higher Dysregulation Levels Than Women Without Becoming Frail.

The aging process differs in important ways between the sexes, with women living longer but at higher risk for frailty (the male-female health-survival paradox). The underlying biological mechanisms remain poorly understood, but may relate to sex differences in physiological dysregulation patterns. Here, using biomarkers from two longitudinal cohort studies (InCHIANTI and BLSA) and one cross-sectional survey (NHANES), we assess sex differences in trajectories of dysregulation globally and for five physiological systems: oxygen transport, electrolytes, hematopoiesis, lipids, and liver/kidney function. We found higher dysregulation levels in men, both globally and in the oxygen transport and hematopoietic systems (p < .001 for all), though differences for other systems were mixed (electrolytes) or absent (lipids and liver/kidney). There was no clear evidence for sex differences in rates of change in dysregulation with age. Although risk of frailty and mortality increase with dysregulation, there was no evidence for differences in these effects between sexes. These findings imply that the greater susceptibility of women to frailty is not simply due to a tolerance for higher dysregulation; rather, it may actually be men that have a greater tolerance for dysregulation, creating a male-female dysregulation-frailty paradox. However, the precise physiological mechanisms underlying the sex differences appear to be diffuse and hard to pin down.

Concordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults.

Reports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82, 95% confidence interval: 1.25, 2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors.

The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty.

OBJECTIVE: To develop Clinical Practice Guidelines for the screening, assessment and management of the geriatric condition of frailty. METHODS: An adapted Grading of Recommendations, Assessment, Development, and Evaluation approach was used to develop the guidelines. This process involved detailed evaluation of the current scientific evidence paired with expert panel interpretation. Three categories of Clinical Practice Guidelines recommendations were developed: strong, conditional, and no recommendation. RECOMMENDATIONS: Strong recommendations were (1) use a validated measurement tool to identify frailty; (2) prescribe physical activity with a resistance training component; and (3) address polypharmacy by reducing or deprescribing any inappropriate/superfluous medications. Conditional recommendations were (1) screen for, and address modifiable causes of fatigue; (2) for persons exhibiting unintentional weight loss, screen for reversible causes and consider food fortification and protein/caloric supplementation; and (3) prescribe vitamin D for individuals deficient in vitamin D. No recommendation was given regarding the provision of a patient support and education plan. CONCLUSIONS: The recommendations provided herein are intended for use by healthcare providers in their management of older adults with frailty in the Asia Pacific region. It is proposed that regional guideline support committees be formed to help provide regular updates to these evidence-based guidelines.

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

OBJECTIVES: Evidence suggests vitamin D deficiency is associated with developing frailty. However, cardiometabolic factors are related to both conditions and may confound and/or mediate the vitamin D-frailty association. We aimed to determine the association of vitamin D concentration with incidence of frailty, and the role of cardiometabolic diseases (cardiovascular disease, diabetes, hyperlipidemia, hypertension) in this relationship. DESIGN: Prospective longitudinal cohort study (7 visits from 1994-2008). SETTING: Baltimore, Maryland. PARTICIPANTS: Three hundred sixty-nine women from the Women's Health and Aging Study II aged 70-79 years, free of frailty at baseline. MEASUREMENTS: Serum circulating 25-hydroxyvitamin D (25[OH]D) concentration was assessed at baseline and categorized as: <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. Analyses included Cox regression models adjusted for key covariates. RESULTS: Incidence rate of frailty was 32.2 per 1,000 person-years in participants with 25(OH)D < 10 ng/mL, compared to 12.9 per 1,000 person-years in those with 25(OH)D ≥ 30 ng/mL (mean follow-up = 8.5 ± 3.7 years). In cumulative incidence analyses, those with lower 25(OH)D exhibited higher frailty incidence, though differences were non-significant (P = .057). In regression models adjusted for demographics, smoking, and season, 25(OH)D < 10 ng/mL (vs ≥30 ng/mL) was associated with nearly three-times greater frailty incidence (hazard ratio (HR) = 2.77, 95% CI = 1.14, 6.71, P = .02). After adjusting for BMI, the relationship of 25(OH)D < 10 ng/mL (vs ≥30 ng/mL) with incident frailty persisted, but was attenuated after further accounting for cardiometabolic diseases (HR = 2.29, 95% CI = 0.92, 5.69, P = .07). CONCLUSION: Low serum vitamin D concentration is associated with incident frailty in older women; interestingly, the relationship is no longer significant after accounting for the presence of cardiometabolic diseases. Future studies should explore mechanisms to explain this relationship.

Herpesvirus Infections and Risk of Frailty and Mortality in Older Women: Women's Health and Aging Studies.

OBJECTIVES: To examine the relationship between herpesvirus infections and mortality and incident frailty risks in community-dwelling older women. DESIGN: Nested prospective cohort study. SETTING: Women's Health and Aging Studies I and II. PARTICIPANTS: Community-dwelling older women aged 70 to 79 (n = 633). MEASUREMENTS: Baseline serum antibody (immunoglobulin G) levels against four herpesviruses (herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), 7 Epstein-Barr virus (EBV)), 3-year incident frailty rates, and 5-year mortality. RESULTS: Women seropositive for HSV-1 and HSV-2, but not VZV and EBV, had higher risk of 3-year incident frailty (HSV-1: hazard ratio (HR) = 1.90, 95% confidence interval (CI) = 0.96-3.74; HSV-2: HR = 2.10, 95% CI = 1.05-4.37) and 5-year mortality (HR = 1.73, 95% CI = 0.93-3.20; HR = 1.80, 95% CI = 0.94-3.44, respectively) than seronegative women. Incremental increases in serum HSV-1 and HSV-2 antibody levels were associated with incrementally higher risks of incident frailty and mortality. After adjustment for potential confounders, only higher serum HSV-2 antibody level was independently predictive of higher risk of mortality in older women (for each unit increase in antibody index, HR = 1.47, 95% CI = 1.05-2.07). CONCLUSION: HSV-1 and HSV-2 antibody levels are not independently associated with risk of incident frailty in older women. Only HSV-2 antibody level is independently predictive of 5-year mortality risk, with each incremental increase in the antibody level adding further risk.

Physical Frailty Assessment in Older Women: Can Simplification Be Achieved Without Loss of Syndrome Measurement Validity?

Different phenotypes have increasingly been used as tools for clinical characterization of frailty among older adults. Although there have been studies about the comparability and effectiveness of various simplifications and approximations of existing frailty phenotypes for risk prediction, there have been no studies in which investigators evaluated the stability of the clinical characterization achieved. In the present study, we used baseline (1992-1996) data from 786 community-dwelling women who were 70-79 years of age in the Women's Health and Aging Study I and II to compare physical frailty phenotypes (PFPs). Using the 5 criteria set forth by Fried, we created 15 PFPs that were positive for various combinations of 3 or 4 of those criteria and compared them with the PFP that included all 5 criteria in order to assess construct validity with regard to frailty syndrome characterization and predictive validity for adverse outcomes of aging. All PFPs exhibited high specificity and negative predictive values for identifying frailty syndrome. Three-item PFPs were insensitive but were the best performers for positive predictive value, with the highest positive predictive value of 0.86 seen in the PFP characterized by the combination of weakness, exhaustion, and weight loss. In comparison, the 5-criterion PFP achieved a sensitivity of 0.82 but a positive predictive value of only 0.53. With regard to predictive validity, it was not merely the number of criteria used to characterize the PFPs but rather the specific criteria combinations that predicted the risk of adverse outcomes. Our findings show that there clinically important contexts in which simplified PFPs cannot be used interchangeably.

Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women's Health and Aging Study II.

BACKGROUND: Elevated inflammation is a proposed mechanism relating chronic diseases to cognitive dysfunction. The objective of this study was to test the hypothesis that greater levels of inflammation, as measured by the proinflammatory cytokine interleukin-6 (IL-6) and C-reactive protein, are associated with faster rates of cognitive decline among cognitively intact community-dwelling older women. METHODS: We analyzed 336 women from the Women's Health and Aging Study II. Cognitive assessments were performed at baseline and every 18-36 months, and included the following domains: immediate and delayed memory (Hopkins Verbal Learning Test), psychomotor speed (Trail Making Test, Part A), and executive function (Trail Making Test, Part B). Aggregate measures of IL-6 and C-reactive protein, based on the average from visits one and two, were analyzed categorically. Random effects models were employed to test the relationship between tertiles of each inflammatory marker and changes in cognitive domain scores over 9 years. RESULTS: Moderate and high levels of IL-6 predicted early declines in psychomotor speed by 1.0 connection/min per year. There were no differences in baseline scores or rates of change across tertiles of IL-6 in memory or executive function. No differences were observed across tertiles of C-reactive protein for all cognitive domains. CONCLUSIONS: Higher levels of serum IL-6 were associated with greater declines in psychomotor speed over 9 years. This finding could suggest that elevated IL-6 may result in microvascular changes that may lead to damage of myelin sheaths that line neuronal axons, leading to decreased neuron propagation and impaired processing speed; however, mechanistic studies are needed to evaluate these hypotheses.

Trajectories of physiological dysregulation predicts mortality and health outcomes in a consistent manner across three populations.

Mechanistic and evolutionary perspectives both agree that aging involves multiple integrated biochemical networks in the organism. In particular, the homeostatic physiological dysregulation (PD) hypothesis contends that aging is caused by the progressive breakdown of key regulatory processes. However, nothing is yet known about the specifics of how PD changes with age and affects health. Using a recently validated measure of PD involving the calculation of a multivariate distance (DM) from biomarker data, we show that PD trajectories predict mortality, frailty, and chronic diseases (cancer, cardiovascular diseases, and diabetes). Specifically, relative risks of outcomes associated with individual slopes in (i.e. rate of) dysregulation range 1.20-1.40 per unit slope. We confirm the results by replicating the analysis using two suites of biomarkers selected with markedly different criteria and, for mortality, in three longitudinal cohort-based studies. Overall, the consistence of effect sizes (direction and magnitude) across data sets, biomarker suites and outcomes suggests that the positive relationship between DM and health outcomes is a general phenomenon found across human populations. Therefore, the study of dysregulation trajectories should allow important insights into aging physiology and provide clinically meaningful predictors of outcomes.

Frailty consensus: a call to action.

Frailty is a clinical state in which there is an increase in an individual's vulnerability for developing increased dependency and/or mortality when exposed to a stressor. Frailty can occur as the result of a range of diseases and medical conditions. A consensus group consisting of delegates from 6 major international, European, and US societies created 4 major consensus points on a specific form of frailty: physical frailty. 1. Physical frailty is an important medical syndrome. The group defined physical frailty as "a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual's vulnerability for developing increased dependency and/or death." 2. Physical frailty can potentially be prevented or treated with specific modalities, such as exercise, protein-calorie supplementation, vitamin D, and reduction of polypharmacy. 3. Simple, rapid screening tests have been developed and validated, such as the simple FRAIL scale, to allow physicians to objectively recognize frail persons. 4. For the purposes of optimally managing individuals with physical frailty, all persons older than 70 years and all individuals with significant weight loss (>5%) due to chronic disease should be screened for frailty.

Adolescent risk-taking, cancer risk, and life course approaches to prevention.

Adolescent risk-taking may have long-term consequences for adult cancer risk. Behaviors such as smoking and sexual activity, commonly initiated during adolescence, may result--decades later--in cancer. Life course epidemiology focuses on unique vulnerabilities at specific development periods and their importance to later development of disease. A life course epidemiological perspective that integrates social and biological risk processes can help frame our understanding how specific adult cancers develop. Moreover, life course perspectives augment traditional public health approaches to prevention by emphasizing the importance of unique windows of opportunity for prevention.

Modification of the association between ambient air pollution and lung function by frailty status among older adults in the Cardiovascular Health Study.

The susceptibility of older adults to the health effects of air pollution is well-recognized. Advanced age may act as a partial surrogate for conditions associated with aging. The authors investigated whether gerontologic frailty (a clinical health status metric) modified the association between ambient level of ozone or particulate matter with an aerodynamic diameter less than 10 µm and lung function in 3,382 older adults using 7 years of follow-up data (1990-1997) from the Cardiovascular Health Study and its Environmental Factors Ancillary Study. Monthly average pollution and annual frailty assessments were related to up to 3 repeated measurements of lung function using cumulative summaries of pollution and frailty histories that accounted for duration as well as concentration. Frailty history was found to modify long-term associations of pollutants with forced vital capacity. For example, the decrease in forced vital capacity associated with a 70-ppb/month greater cumulative sum of monthly average ozone exposure was 12.3 mL (95% confidence interval: 10.4, 14.2) for a woman who had spent the prior 7 years prefrail or frail as compared with 4.7 mL (95% confidence interval: 3.8, 5.6) for a similar woman who was robust during all 7 years (interaction P < 0.001).

Fruit and vegetable intake, physical activity, and mortality in older community-dwelling women.

OBJECTIVES: To examine the relationship between fruit and vegetable intake, physical activity, and all-cause mortality in older women. DESIGN: Six Cox proportional hazards models examined independent and additive relationships between physical activity, carotenoids, and all-cause mortality. Additional models tested whether physical activity and carotenoids were conjointly related to mortality. Models were adjusted for age, education, and race and ethnicity. SETTING: Baltimore, Maryland. PARTICIPANTS: Seven hundred thirteen women aged 70 to 79 participating in the Women's Health and Aging Studies. MEASUREMENTS: Total serum carotenoids, a marker of fruit and vegetable intake, and physical activity were measured at baseline. Physical activity was measured according to kilocalorie expenditure. RESULTS: During 5 years of follow-up, 82 (11.5%) participants died. Measured continuously, physical activity improved survival (HR = 0.52, 95% CI = 0.41-0.66, P < .001). The most active women were more likely to survive than the least physically active women (HR = 0.28, 95% CI = 0.13-0.59, P < .001). Continuous measures of carotenoids improved survival (HR = 0.67, 95% CI = 0.51-0.89, P = .01). Women in the highest tertile of total carotenoids were more likely to survive those in the lowest (HR = 0.50, 95% CI = 0.27-0.91, P = .03). When examined in the same model, continuous measures of physical activity (HR = 0.54, 95% CI = 0.42-0.68, P < .001) and carotenoids (HR = 0.76, 95% CI = 0.59-0.98, P = .04) predicted survival during follow-up. CONCLUSION: The combination of low total serum carotenoids and low physical activity, both modifiable risk factors, strongly predicted earlier mortality. These findings provide preliminary support that higher fruit and vegetable intake and exercise improve survival.

Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars.

BACKGROUND: Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging. METHODS: We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996-1997 and 2005-2006. RESULTS: In 2005-2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996-1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005-2006 level, only level was associated with CVD events and mortality. CONCLUSIONS: Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.

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 WHAS 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)=2.28, 95% Confidence Interval (CI)=1.81-2.87). 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.

Serum 25-hydroxyvitamin D and pulmonary function in older disabled community-dwelling women.

BACKGROUND: Recent studies have expanded the functions of vitamin D to a possible role in pulmonary function. Our objective was to examine the relationship between serum 25-hydroxyvitamin D (25[OH]D), serum parathyroid hormone, and pulmonary function in older women. METHODS: We examined the relationship of serum 25(OH)D and parathyroid hormone with pulmonary function (forced expiratory volume in one second [FEV(1)], forced vital capacity [FVC], and FEV(1)/FVC ratio) in a cross-sectional study of 646 moderately to severely disabled women, 65 years or more, living in the community in Baltimore, Maryland, who participated in the Women's Health and Aging Study I. RESULTS: Overall, median (25th, 75th percentile) serum 25-hydroxyvitamin D concentrations were 19.9 (14.7, 26.7) ng/mL. Serum 25(OH)D was positively associated with FEV(1) (p = .03), FVC (p = .18), and FEV(1)/FVC (p = .04) in multivariable linear regression models adjusting for age, race, education, smoking, height, physical activity, cognition, interleukin-6, chronic diseases, and other potential confounders. In the same models, serum parathyroid hormone was not significantly associated with FEV(1), FVC, or FEV(1)/FVC. CONCLUSIONS: These findings support the idea that vitamin D deficiency is independently associated with poor pulmonary function in older disabled women.

Measurement of organ structure and function enhances understanding of the physiological basis of frailty: the Cardiovascular Health Study.

OBJECTIVES: To determine whether disease burden is associated with frailty independent of diagnosed chronic disease and whether physiological measurements provide greater understanding of the etiology of frailty. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: Two thousand four hundred thirty-seven participants in the Cardiovascular Health Study, 1992/93 examination (mean age 74.8 ± 4.8, 43.4% male, 95.8% white). MEASUREMENTS: Disease burden and frailty were tabulated using 10-point scales (0 = healthy, 10 = unhealthy). Disease burden was the sum of measurements characterizing the vasculature, brain, kidneys, lungs, and glucose metabolism. Frailty was assessed using the frailty index reported by Fried. Multivariate linear models were used to determine the association between disease burden (predictor) and frailty (outcome). RESULTS: Unadjusted, 1-point-higher disease burden was associated with a 0.28-point-higher frailty score (P < .001). White matter grade, forced vital capacity, and cystatin-C were particularly strongly and significantly associated with frailty. Disease burden attenuated the association between frailty and age by 29%, and disease burden and age had similar associations with frailty. Disease burden attenuated the association between frailty and fibrinogen, Factor VIII, and C-reactive protein by 32%, 56%, and 83%, respectively. Frailty was associated with diagnosed depression, stroke, cognitive impairment, arthritis, and pulmonary disease but not coronary heart disease, diabetes mellitus, or kidney disease in the presence of a summary of disease burden. In the adjusted model, disease burden remained significantly associated with frailty (ß = 0.11, P < .001). CONCLUSION: Disease burden was independently and significantly associated with frailty. These results emphasize that typically unrecognized physiological changes may contribute significantly to frailty.