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Objectives frail older adults may be more vulnerable to stressors, resulting in steeper declines in cognitive function. Whether the frailty–cognition link differs by cognitive domain remains unclear; however, it could lend insight into underlying mechanisms. Methods we tested whether domain-specific cognitive trajectories (clock-drawing test, (CDT), immediate and delayed recall, orientation to date, time, president and vice-president naming) measured annually (2011–2016) differ by baseline frailty (physical frailty phenotype) in the National Health and Aging Trends Study (n = 7,439), a nationally representative sample of older adult U.S. Medicare beneficiaries, using mixed effects models to describe repeated measures of each cognitive outcome. To determine if the association between frailty and subsequent cognitive change differed by education, we tested for interaction using the Wald test. Results we observed steeper declines for frail compared to non-frail participants in each domain-specific outcome, except for immediate recall. Largest differences in slope were observed for CDT (difference = −0.12 (standard deviations) SD/year, 95%CI: −0.15, −0.08). By 2016, mean CDT scores for frail participants were 1.8 SD below the mean (95%CI: −1.99, −1.67); for non-frail participants, scores were 0.8 SD below the mean (95%CI: −0.89, −0.69). Associations differed by education for global cognitive function (Pinteraction Conclusion frailty is associated with lower levels and steeper declines in cognitive function, with strongest associations for executive function. These findings suggest that aetiologies are multifactorial, though primarily vascular related; further research into its association with dementia sub-types and related pathologies is critical.

The traditional disease-oriented model of healthcare is inadequate to address the needs of the older population. Greater attention should be given to strategies that promote healthy aging. Recently proposed constructs of intrinsic capacity (IC) and physical resilience (PR) hold great potential to reshape geriatric medicine and aging research. These constructs accentuate the positive health attributes of older people in contrast to the popular frailty construct that is centered on functional deficits. IC was introduced by the World Health Organization (WHO) as a composite of all the physical and mental capacities. WHO has emphasized enhancement of IC throughout the life course so as to maintain functional ability in old age. PR, recently highlighted by the National Institute on Aging, is the ability to successfully cope with stressors. High levels of resilience can result in desirable clinical and functional outcomes after stressors. Therefore, it is important to understand the underlying physiology of PR and the risk factors contributing to diminished PR. The main goal of this article is to explore the potential relationship between IC and PR. Based on a classical theory of aging, we postulate that IC is a determinant of PR and is also a high-level integrative measure of physiologic reserve which is the fundamental factor underlying one's ability to withstand stressors. A major implication of our postulates is that even though IC is only one of the many determinants of PR, it could serve as an important intervenable target for enhancing resilience in older adults.

Frailty in aging marks a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. This Perspective synthesizes the evidence on the aging-related pathophysiology underpinning the clinical presentation of physical frailty as a phenotype of a clinical syndrome that is distinct from the cumulative-deficit-based frailty index. We focus on integrating the converging evidence on the conceptualization of physical frailty as a state, largely independent of chronic diseases, that emerges when the dysregulation of multiple interconnected physiological and biological systems crosses a threshold to critical dysfunction, severely compromising homeostasis. Our exegesis posits that the physiology underlying frailty is a critically dysregulated complex dynamical system. This conceptual framework implies that interventions such as physical activity that have multisystem effects are more promising to remedy frailty than interventions targeted at replenishing single systems. We then consider how this framework can drive future research to further understanding, prevention and treatment of frailty, which will likely preserve health and resilience in aging populations. Linda Fried and colleagues argue that physical frailty reflects the dysregulation of a complex dynamical system underpinning health and resilience, and discuss the implications for new prevention and treatment approaches.

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.

Objectives To evaluate the effects of a home-based disability prevention program on life-space and falls efficacy among low-income older adults. Design Single-blind two-arm randomized controlled trial. Setting Participants' homes. Participants Participants were low-income cognitively intact older adults (≥65 years old) with restricted daily activities. Our analytic sample for life-space (n = 194) and falls efficacy (n = 233) varied as the life-space measure was introduced 4 months after the trial began. Intervention Up to six 1-hour home visits with an occupational therapist; up to four 1-hour home visits with a registered nurse; and up to $1,300 worth of home repairs, modifications, and assistive devices with a handyman, during a course of 4 months. Measurements Life-space was measured by the Homebound Mobility Assessment; falls efficacy was measured using the 10-item Tinetti Falls Efficacy Scale at baseline and 5 months. Results Participants were on average 75 years old, predominantly Black (86%) and female (85%-86%). Compared with participants in the control group, participants receiving the intervention were more likely to have improved versus decreased life-space in areas of bathroom (adjusted odds ratio (OR) = 3.95; 95% confidence interval (CI) = 1.20-12.97), front or back porch, patio, or deck (adjusted OR = 2.67; 95% CI = 1.05-6.79), stairs (adjusted OR = 4.09; 95% CI = 1.34-12.48), leaving the house for any reason other than for health care (adjusted OR = 2.40; 95% CI = 1.01-5.73), and overall life-space (adjusted OR = 2.15; 95% CI = 1.10-4.19). Participants who received the intervention also had an 11% improvement in falls efficacy in performing daily activities (exponentiated coefficient = 1.12; 95% CI = 1.04-1.21). Conclusion Life-space and falls efficacy were improved through a multicomponent, person-directed, home-based disability prevention intervention. Findings suggest that this intervention should be translated into different settings to promote independent aging.

Background/objectives To obtain national and regional estimates of prevalence of frailty with or without cognitive impairment, and cognitive impairment with or without frailty among older adults in the United States, and to identify profiles of characteristics that distinguish their joint versus separate occurrence. Design Cross-sectional. Setting Community or non-nursing home residential care settings. Participants A U.S. nationally representative sample of 7,497 older adults aged 65 and older from the National Health and Aging Trends Study. Measurements Frailty was measured by the physical frailty phenotype. Cognitive impairment was assessed by cognitive performance testing of executive function and memory or by proxy reports. Multinomial logistic regression was used to identify profiles of demographic, socioeconomic, health, behavioral, and psychosocial characteristics that distinguish four subgroups: not-frail and cognitively intact ("neither"), not-frail and cognitively impaired ("Cog. only"), frail and cognitively intact ("frailty only"), and frail and cognitively impaired ("both"). Results The prevalence of "Cog. only," "frailty only," and "both" was 25.5%, 5.6%, and 8.7%, respectively. Individuals with"frailty only" had the highest prevalence of obesity, current smoking, comorbidity, lung disease, and history of surgery. The "both" group had the highest prevalence of dementia, depression, cardiovascular diseases, and disability. No significant differences were found between the "Cog. only" group and the "neither" group with respect to history of surgery and comorbidity burden. The prevalence of dementia in the "Cog. only" was less than half of that in the "both" group. Conclusion The finding of sizable subgroups having physical frailty but not cognitive impairment, and vice versa, suggests that the two cannot be considered necessarily as antecedent or sequela of one another. The study provided empirical data supporting the prioritization of comorbidity, obesity, surgery history, and smoking status in clinical screening of frailty and cognitive impairment before formal diagnostic assessments.

BACKGROUND/OBJECTIVES: The extent to which the prevalence of muscle weakness in the US population varies by different putative grip strength constructs developed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) has not been described. DESIGN: Cross-sectional analysis. SETTING: Two nationally representative cohorts-2010 and 2012 waves of the Health and Retirement Survey and round 1 (2011) of the National Health and Aging Trends Survey. PARTICIPANTS: Adults aged 65 years and older (n = 12,984) were included in these analyses. MEASUREMENTS: We analyzed three constructs of muscle weakness developed by the SDOC, and found to be associated with mobility disability for men and women, respectively: absolute grip strength (

Background exposures in childhood and adolescence may impact the development of diseases and symptoms in late life. However, evidence from low- and middle-income countries is scarce. In this cross-sectional study, we examined the association of early life risk factors with frailty amongst older adults using a large, nationally representative cohort of community-dwelling Chinese sample. Methods we included 6,806 participants aged $\ge$60 years from the China Health and Retirement Longitudinal Study. We measured 13 risk factors in childhood or adolescence through self-reports, encompassing six dimensions (education, family economic status, nutritional status, domestic violence, neighbourhood and health). We used multinomial regression models to examine the association between risk factors and frailty. We further calculated the absolute risk difference for the statistically significant factors. Results persons with higher personal and paternal education attainment, better childhood neighbourhood quality and better childhood health status had lower risk of being frail in old age. Severe starvation in childhood was associated with higher risk of prefrailty. The risk differences of being frail were 5.6% lower for persons with a high school or above education, 1.5% lower for those whose fathers were literate, 4.8% lower for the highest neighbourhood quality and 2.9% higher for worse childhood health status compared to their counterparts. Conclusions unfavorable socioeconomic status and worse health condition in childhood and adolescence may increase the risk of late-life frailty amongst Chinese older adults.

Background/Aims:: Recent evidence has shown that Alzheimer’s Disease (AD) patients have reduced vestibular function relative to healthy controls. In this study, we evaluated whether patients with Mild Cognitive Impairment (MCI) also have reduced vestibular function relative to controls, and compared the level of vestibular impairment between MCI and AD patients. Methods:: Vestibular physiologic function was assessed in 77 patients (26 MCI, 51 AD) and 295 matched controls using 3 clinical vestibular tests. The association between vestibular loss and cognitive impairment was evaluated using conditional logistic regression models. Results:: Individuals with vestibular impairment had a 3 to 4-fold increased odds of being in the MCI vs. control group (p-values < 0.05). MCI patients had a level of vestibular impairment that was intermediate between controls and AD. Conclusion:: These findings suggest a dose-response relationship between vestibular loss and cognitive status, and support the hypothesis that vestibular loss contributes to cognitive decline.

Background: Frailty, originally characterized in community-dwelling older adults, is increasingly being studied and implemented for adult patients with end-stage kidney disease (ESKD) of all ages (>18 years). Frailty prevalence and manifestation are unclear in younger adults (18–64 years) with ESKD; differences likely exist based on whether the patients are treated with hemodialysis (HD) or kidney transplantation (KT). Methods: We leveraged 3 cohorts: 378 adults initiating HD (2008–2012), 4,304 adult KT candidates (2009–2019), and 1,396 KT recipients (2008–2019). The frailty phenotype was measured within 6 months of dialysis initiation, at KT evaluation, and KT admission. Prevalence of frailty and its components was estimated by age (≥65 vs. Results: In all 3 cohorts, frailty prevalence was higher among older than younger adults (HD: 71.4 vs. 47.3%; candidates: 25.4 vs. 18.8%; recipients: 20.8 vs. 14.3%). In all cohorts, older patients were more likely to have slowness and weakness but less likely to report exhaustion. Among candidates, older age (odds ratio [OR] = 1.79, 95% CI: 1.47–2.17), non-Hispanic black race (OR = 1.30, 95% CI: 1.08–1.57), and dialysis type (HD vs. no dialysis: OR = 2.06, 95% CI: 1.61–2.64; peritoneal dialysis vs. no dialysis: OR = 1.78, 95% CI: 1.28–2.48) were associated with frailty prevalence, but sex and Hispanic ethnicity were not. These associations did not differ by age (pinteractions > 0.1). Similar results were observed for recipients and HD patients. Conclusions: Although frailty prevalence increases with age, younger patients have a high burden. Clinicians caring for this vulnerable population should recognize that younger patients may experience frailty and screen all age groups.

There is an integral research gap regarding whether there is a relationship between pain levels and low physical activity among older women. This is a secondary analysis of a longitudinal cohort study, the Women’s Health and Aging Study (WHAS) II. Our analyses included 436 community-dwelling women between the ages of 70 and 79, who were followed for 10.5 years. We employed marginal structural modeling, which controls for time-dependent confounding, with the aim of assessing the potential direct association between pain levels and low physical activity and assess a graded relationship. Compared to women with no pain, those with widespread pain were nearly half as likely to be moderately active versus low active (aOR: 0.46, 95% confidence interval (CI): 0.22, 0.96). A graded association was observed across the four pain levels (no pain or mild pain, other pain, moderate or severe lower extremity pain, and widespread pain) on low physical activity. Our findings indicate that reducing chronic widespread pain in older women may increase moderate physical activity, and therefore reduce the downstream health risks of low physical activity, including morbidity and mortality risk.

Background Self-reported low physical activity is a defining feature of phenotypic frailty but does not adequately capture physical activity performed throughout the day. This study examined associations between accelerometer-derived patterns of routine daily physical activity and frailty. Methods Wrist accelerometer and frailty data from 638 participants (mean age 77 [SD = 5.5] years; 44% women) were used to derive 5 physical activity metrics: active minutes/day, sedentary minutes/day, total activity counts/day, activity fragmentation (reciprocal of the average active bout length), and sedentary fragmentation (reciprocal of the average sedentary bout length). Robust, prefrail, and frail statuses were identified using the physical frailty phenotype defined as having 0, 1–2, or ≥3 of the following criterion: weight loss, exhaustion, slowness, self-reported low activity, and weakness. Frailty was collapsed into not frail (robust and prefrail) and frail, and each frailty criteria was dichotomized. Multiple logistic regression was used to model each accelerometer metric. Separate frailty criteria and interactions with age and sex were also examined. Results With higher amounts and intensity of daily activity (more active minutes, fewer sedentary minutes, higher activity counts) and lower activity fragmentation, the odds of frailty were lower compared to robust/prefrail states (p < .02 for all). For interactions, only an age by sedentary fragmentation interaction on the odds of frailty was observed (p = .01). For each separate criteria, accelerometer metrics were associated with odds of slowness, low activity, and weakness. Conclusion Less favorable patterns of objectively measured daily physical activity are associated with frailty and the components of slowness, low self-reported activity, and weakness.

Background Cut-points to define slow walking speed have largely been derived from expert opinion. Methods Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4–6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not. Results Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as “fast”; 478 (9.5%) as “intermediate” (walking speed ≥0.62 m/s but Conclusions Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

Background Physical frailty is defined as a syndrome of decreased physiologic reserve conferring vulnerability to functional decline, mortality, and other adverse outcomes upon experiencing stressors. Self-efficacy, which is confidence in one's ability to perform well in a domain of life, is modifiable. Self-efficacy is associated with improved health behavior and decreased chronic disease burden. Its relationship to frailty is unknown. The purpose of this study was to evaluate whether a general self-efficacy proxy predicts incident frailty. Methods A nationally representative sample of 4825 U.S. older adults aged 65 and older living in the community or non-nursing home care setting enrolled in the National Health and Aging Trends Study from 2011 to 2018 was used. Self-efficacy was dichotomized into low and high groups using the one-item self-efficacy proxy measure. The Physical Frailty Phenotype was used to categorize participants as frail and non-frail. A discrete time hazard model using data from eight rounds was used to obtain incident hazard ratios of frailty in two models. Model 1 was adjusted for age, race, sex, education, and income. Model 2 contained Model 1 covariates and added disability and comorbidities. Results Among people without frailty at baseline, risk of developing frailty over 7 years was increased by 41% among those with low versus high self-efficacy after adjustment for sociodemographics (P = 0.002), and by 27% after further adjustment for disability and comorbidities (P = 0.032). Conclusion This study generates a rationale to further explore self-efficacy in frailty research. Self-efficacy may be a key modifiable element to incorporate into multimodal physical frailty interventions.

Background Programs to reduce disability are crucial to the quality of life for older adults with disabilities. Reducing disability is also important to avert unnecessary and costly hospitalizations, relocation, or nursing home placements. Few programs reduce disability and few have been replicated and scaled beyond initial research settings. CAPABLE is one such program initially tested in a randomized control trial and has now been tested and replicated in multiple settings. CAPABLE, a 10-session, home-based interprofessional program, provides an occupational therapist, nurse, and handyworker to address older adults' self-identified functional goals by enhancing individual capacity and home environmental supports. We examine evidence for the CAPABLE program from clinical trials embedded in different health systems on outcomes that matter most to older adults with disability. Methods Six trials with peer-reviewed publications or reports were identified and included in this review. Participants' outcomes included basic and instrumental activities of daily living (ADLs, IADLs), fall efficacy, depression, pain, and cost savings. Results A total of 1144 low-income, community-dwelling older adults with disabilities and 4236 matched comparators were included in the six trials. Participants were on average ≥74-79 years old, cognitively intact, and with self-reported difficulty with ≥1 ADLs. All six studies demonstrated improvements in ADLs and IADLs, with small to strong effect sizes (0.41-1.47). Outcomes for other factors were mixed. Studies implementing the full-tested dose of CAPABLE showed more improvement in ADLS and cost savings than studies implementing a decreased dose. Conclusions The CAPABLE program resulted in substantial improvements in ADLs and IADLs in all six trials with other outcomes varying across studies. A dose lower than the original protocol tested resulted in less benefit. The four studies examining cost showed that CAPABLE saved more than it costs to implement.

Key Points Question Is receipt of cancer screening independently associated with 10-year mortality after accounting for comorbidities and function in older adults? Findings In this cohort study of 5342 patients in the Health and Retirement Study, receipt of breast or prostate cancer screening was associated with a lower hazard of 10-year mortality after adjusting for all variables from a prognostic index that included age, comorbidities, and function. Meaning These findings suggest that screening decisions need to be individualized and not solely dependent on mortality prediction., This cohort study examines whether cancer screening is significantly associated with all-cause mortality in older adults after accounting for comorbidities and functional status., Importance Guidelines recommend against routine breast and prostate cancer screenings in older adults with less than 10 years’ life expectancy. One study using a claims-based prognostic index showed that receipt of cancer screening itself was associated with lower mortality, suggesting that the index may misclassify individuals when used to inform cancer screening, but this finding was attributed to residual confounding because the index did not account for functional status. Objective To examine whether cancer screening remains significantly associated with all-cause mortality in older adults after accounting for both comorbidities and functional status. Design, Setting, and Participants This cohort study included individuals older than 65 years who were eligible for breast or prostate cancer screening and who participated in the 2004 Health and Retirement Study. Data were linked to Medicare claims from 2001 to 2015. Data analysis was conducted from January to November 2020. Main Outcomes and Measures A Cox model was used to estimate the association between all-cause mortality over 10 years and receipt of screening mammogram or prostate-specific antigen (PSA) test, adjusting for variables in a prognostic index that included age, sex, comorbidities, and functional status. Potential confounders (ie, education, income, marital status, geographic region, cognition, self-reported health, self-care, and self-perceived mortality risk) of the association between cancer screening and mortality were also tested. Results The breast cancer screening cohort included 3257 women (mean [SD] age, 77.8 [7.5] years); the prostate cancer screening cohort included 2085 men (mean [SD] age, 76.1 [6.8] years). Receipt of screening mammogram was associated with lower hazard of all-cause mortality after accounting for all index variables (adjusted hazard ratio [aHR], 0.67; 95% CI, 0.60-0.74). A weaker, but still statistically significant, association was found for screening PSA (aHR 0.88; 95% CI, 0.78-0.99). None of the potential confounders attenuated the association between screening and mortality except for cognition, which attenuated the aHR for mammogram from 0.67 (95% CI, 0.60-0.74) to 0.73 (95% CI, 0.64-0.82) and the aHR for PSA from 0.88 (95% CI, 0.78-0.99) to 0.92 (95% CI, 0.80-1.05), making PSA screening no longer statistically significant. Conclusions and Relevance In this study, cognition attenuated the observed association between cancer screening and mortality among older adults. These findings suggest that existing mortality prediction algorithms may be missing important variables that are associated with receipt of cancer screening and long-term mortality. Relying solely on algorithms to determine cancer screening may misclassify individuals as having limited life expectancy and stop screening prematurely. Screening decisions need to be individualized and not solely dependent on life expectancy prediction.

Introduction “Frailty” has attracted attention for its promise of identifying vulnerable older adults, hence its potential use to better tailor geriatric health care. There remains substantial controversy, however, regarding its nature and ascertainment. Recent years have seen a proliferation of frailty assessment methods. We argue that the development of frailty assessments should be grounded in “validation”—the process of substantiating that a measurement accurately and precisely measures what it intends, identify unresolved measurement issues, and highlight measurement-related considerations for clinical practice. Methods Principles for validating frailty measures are elucidated. We follow principles—articulated, for example, by Borsboom—in which a construct must be clearly defined and then analyses undertaken to substantiate that a measurement accurately and precisely measures what it intends. Key elements are content validity, criterion validity, and construct validity, with an emphasis on the latter. Results We illustrate the principles for a physical frailty phenotype construct. Conclusions Unresolved conceptual issues include the roles of intersecting concepts such as cognition, disease severity, and disability in frailty measurement, conceptualization of frailty as a state versus a continuum, and the potential need for dynamic measures and systems concepts in furthering understanding of frailty. Clinical considerations include needs to distinguish interventions designed to address frailty “symptoms” versus underlying physiology, improve “prefrailty” measures intended to screen individuals early in their frailty progression, address feasibility demands, and further visioning followed by rigorous efficacy research to address the landscape of potential uses of frailty assessment in clinical practice.

Background Frailty and cognitive impairment (CI) are associated and often coexist in older adults. Whether temporal patterns of occurrence reflect different etiologies remain unknown. Methods Participants from the National Health and Aging Trends Study were assessed annually (2011–2016) for frailty (Fried’s criteria) and CI (bottom quintile of clock drawing test or immediate and delayed recall; proxy-report of dementia diagnosis or AD8 ≥ 2). We used the Fine & Gray model to identify correlates of frailty onset before CI, CI onset before frailty, and frailty-CI co-occurrence, accounting for death as a competing risk. Results Of 3,848 free of frailty, CI, and dementia at baseline, 2,183 (61.2%) developed neither frailty nor CI during the 5-year follow-up; 343 (8.3%) developed frailty first; 1,014 (24.4%) developed CI first; and 308 (6.0%) developed frailty-CI co-occurrence. Incident dementia, as a marker of underlying neuropathologies, was associated with greater likelihood of CI onset first (subdistribution hazard ratios [SHR] = 2.60, 95% confidence interval [ci] 2.09 to 3.24), and frailty-CI co-occurrence (SHR = 8.77, 95% ci 5.79 to 13.28), but lower likelihood of frailty onset first (SHR = 0.38, 95% ci 0.21 to 0.68). Number of comorbidities was only associated with frailty occurrence first (1 comorbidity: SHR = 2.51, 95% ci 1.15 to 5.47; 4+ comorbidities: SHR = 6.48, 95% ci 2.78 to 15.48). Conclusions Different patterns of frailty and CI occurrence exist, and dementia-related pathologies and comorbidities may be important correlates of order of emergence, potentially reflecting different etiologies. Future investigation into relationships between these patterns and dementia subtypes and related pathologies is needed to elucidate etiologic pathways and to provide new targets for prevention, intervention, and risk screening.

Background Restoration of kidney function after kidney transplant generally improves cognitive function. It is unclear whether frail recipients, with higher susceptibility to surgical stressors, achieve such post-transplant cognitive improvements or whether they experience subsequent cognitive decline as they age with a functioning graft. Methods In this two-center cohort study, we assessed pretransplant frailty (Fried physical frailty phenotype) and cognitive function (Modified Mini-Mental State Examination) in adult kidney transplant recipients. To investigate potential short- and medium-term effects of frailty on post-transplant cognitive trajectories, we measured cognitive function up to 4 years post-transplant. Using an adjusted mixed effects model with a random slope (time) and intercept (person), we characterized post-transplant cognitive trajectories by pretransplant frailty, accounting for nonlinear trajectories. Results Of 665 recipients (mean age 52.0 years) followed for a median of 1.5 years, 15.0% were frail. After adjustment, pretransplant cognitive scores were significantly lower among frail patients compared with nonfrail patients (89.0 versus 90.8 points). By 3 months post-transplant, cognitive performance improved for both frail (slope =0.22 points per week) and nonfrail (slope =0.14 points per week) recipients. Between 1 and 4 years post-transplant, improvements plateaued among nonfrail recipients (slope =0.005 points per week), whereas cognitive function declined among frail recipients (slope =−0.04 points per week). At 4 years post-transplant, cognitive scores were 5.8 points lower for frail recipients compared with nonfrail recipients. Conclusions On average, both frail and nonfrail recipients experience short-term cognitive improvement post-transplant. However, frailty is associated with medium-term cognitive decline post-transplant. Interventions to prevent cognitive decline among frail recipients should be identified.

OBJECTIVES: Cognitive frailty is a state at the lower end of the continuum of cognitive resilience in which one is at elevated risk for cognitive impairment and dementia. Metrics of a newly developed Cognitive Frailty Index (CFI) were examined for their association with objective functional limitations. METHODS: We used baseline data from 607 participants from the Baltimore Experience Corps Trial with measures on the CFI, a computerized Stroop test, and Short Physical Performance Battery (SPPB) score≤9. Multivariable log-binomial regression models were used to evaluate the associations of CFI metrics (mean reaction time (RT) for total, first-half and second-half trials per condition) with the SPPB. Latent growth models were used to create additional CFI metrics of initial level (intercept) and change (slope) in RT across accurate trials by easy (Color-X) and difficult (Color-Word) conditions. Models were adjusted for race, sex, age, income, major morbidities, depressive symptoms, self-reported health, and Stroop interference (for Color-Word condition only). RESULTS: All CFI RT metrics were associated with SPPB

Inflammation, particularly interleukin-6 (IL-6), is associated with chronic disease in older adults, but not all older adults have the same progression of poor health outcomes. Self-efficacy may play a role in buffering the inflammatory burden in chronic disease. To evaluate associations between self-efficacy and IL-6, 159 community-dwelling older adults ( N = 159, Mage = 82 years, SD = 6.3 years) with one or more chronic illnesses were recruited for this cross-sectional study. Sweat IL-6 was collected using a noninvasive sweat patch worn for 72 hrs. Multiple linear regression with bootstrapping showed a significant association between social coping self-efficacy and IL-6 (β = −0.534, p = .010) after adjustment for age, sex, race, body mass index, financial strain, chronic conditions, and social support. Although preliminary, this study creates a rationale to explore the self-efficacy inflammatory biomarker association further. Enhancing self-efficacy might be a viable nonpharmacological treatment to lower or slow the inflammatory burden in older adults.

BackgroundChronic inflammation (CI) is a common trait of aging associated with adverse outcomes including mortality. We hypothesized that recombinant human Lactoferrin (rhLf) would reduce chronic inflammation of aging.MethodsThirty-six community dwelling older adults were randomly assigned to rhLf or placebo treatment in 1:1 ratio for 3 months. IL-6, sTNFR1, Comprehensive Metabolic Panel (CMP), and Complete Blood Count (CBC) were measured at baseline, 1 month, 3 months, and 6 months. Physical and cognitive measures were completed at same timepoints, including 4-m walking speed (m/s), grip strength (kg), 6-min walking distance (m), home activity measured by accelerometer, trail making test – Part A (s) and – Part B (s), and Digit symbol substitution test (number correctly coded). Primary outcomes were differences in IL-6 and sTNFR1 concentrations evaluated by generalized linear model with log-link and gamma family distribution, controlling for baseline cytokine concentrations.ResultsrhLF was well-tolerated. There were a significant number of abdominal complaints and increased drop-out rate in placebo group. Participants in rhLf arm had non-significant lower mean percent increase in IL6 at 3 months (rhLf mean IL-6 6% lower than control, P = 0.843), and sTNFaR1 (rhLf mean 2% lower than control, P = 0.36). No significant changes were observed for the cognitive or physical measures.ConclusionTreatment with rhLf did not significantly alter serum IL6 or sTNFR1 concentrations of older adults. This study may have been underpowered to detect difference, but provided evidence that a larger sample-size could more definitively determine the effect of rhLF on age-associated CI.

BackgroundsCardiovascular disease (CVD) risk factors are individually associated with frailty. This study examined whether Framingham CVD risk score (FRS) as an aggregate measure of CVD risk is associated with incident frailty among Chinese older adults.MethodsThis study used data from the China Health and Retirement Longitudinal Study. A sample of 3,618 participants aged 60 to 95 years and without CVD at baseline were followed for four years. FRS was calculated at baseline. Frailty status was defined as not-frail (0–2 criteria) or frail (3–5 criteria) based on the physical frailty phenotype consisting of five binary criteria (weakness, slowness, exhaustion, low activity level, and weight loss). After excluding subjects who were frail (n = 248) at baseline, discrete-time Cox regression was used to evaluate the relationship between FRS and incident frailty.ResultsDuring a median follow-up of 4.0 years, 323 (8 %) participants developed CVD and 318 (11 %) subjects had frailty onset. Higher FRS was associated with greater risk of incident frailty (HR: 1.03, 95 % CI: 1.00 to 1.06) after adjusting for education, marital status, obesity, comorbidity burden, and cognitive function. This association however was no longer significant (HR: 1.00, 95 % CI: 0.97 to 1.03) after additionally adjusting for age. These findings remained essentially unchanged after excluding subjects with depression (n = 590) at baseline or incident CVD (n = 323) during the 4-year follow-up.ConclusionsThe FRS was not independently associated with incident frailty after adjusting for chronological age. More research is needed to assess the clinical utility of the FRS in predicting adverse health outcomes other than CVD in older adults.

Aims Physical frailty is a commonly encountered geriatric syndrome among older adults without coronary heart disease (CHD). The impact of frailty on the incidence of long-term cardiovascular outcomes is not known.We aimed to evaluate the long-term association of frailty, measured by the Fried frailty phenotype, with all-cause-mortality and MACE among older adults without a history of CHD at baseline in the National Health and Aging Trends Study. Methods and Results We used the National Health and Aging Trends Study, a prospective cohort study linked to a Medicare sample. Participants with a prior history of CHD were excluded. Frailty was measured during the baseline visit using the Fried physical frailty phenotype. Cardiovascular outcomes were assessed during a 6-year follow-up. Of the 4656 study participants, 3259 (70%) had no history of CHD 1 year prior to their baseline visit. Compared to those without frailty, subjects with frailty were older (mean age 82.1 vs. 75.1 years, P Conclusion In patients without CHD, frailty is a risk factor for the development of MACEs. Efforts to identify frailty in patients without CHD and interventions to limit or reverse frailty status are needed and, if successful, may limit subsequent adverse cardiovascular events.

The Community Aging in Place–Advancing Better Living for Elders (CAPABLE) program reduces disability in low-income older adults. In this study, we used CAPABLE baseline and 5-month data to examine whether its effects in reducing activities of daily living (ADLs) and instrumental ADLs (IADLs) difficulties differed by participants’ financial strain status. At baseline, participants with financial strain were more likely to report higher scores on depression ( p < .001), have low energy ( p < .001), and usually feel tired ( p = .004) compared with participants without financial strain, but did not differ in ADL/IADL scores. Participants with financial strain benefited from the program in reducing ADL (relative risk [RR]: 0.61, 95% confidence interval [CI]: 0.43, 0.86) and IADL disabilities (RR: 0.69, 95% CI: 0.54, 0.87), compared with those with financial strain receiving attention control. Individuals with financial strain benefited more from a home-based intervention on measures of disability than those without financial strain. Interventions that improve disability may be beneficial for financially strained older adults.

Background Increasingly, lifestyle factors in midlife are reported to impact health and functional status in old age. This work examines associations between dietary trajectories in middle age and subsequent impairments in physical function. Method Data are from 851 participants (61% men, mean age at first dietary assessment = 47 years, range 30–59 years) from the Baltimore Longitudinal Study of Aging. We used latent class analysis to derive dietary trajectories based on adherence to the Alternative Healthy Eating Index-2010 (AHEI), and further classified them based on tertiles, as poor (score 48.9). Physical function was assessed with the Short Physical Performance Battery (SPPB). Random effects tobit regression models were used to examine associations between dietary trajectories and later physical function. Results Two latent classes of AHEI scores were generated and labeled “greatly improved” or “moderately improved.” In the greatly improved class, participants showed a trend in overall AHEI score from poor/intermediate to good diet categories across dietary assessments with age, over time. In the moderately improved class, the overall AHEI score shifted from poor to intermediate diet categories over time, and the prevalence of the good diet category remained low. Mean AHEI score between ages 30 and 59 years was higher in the greatly, than moderately, improved class. The moderately improved class had 1.6 points lower SPPB score (indicating poorer physical function) at older age than the greatly improved class (p = .022). Conclusions Findings suggest that improving diet quality in middle age may contribute to better physical function in older age.

Emerging evidence suggests a relationship between impairments of the vestibular (inner ear balance) system and alterations in the function and the structure of the central nervous system in older adults. However, it is unclear whether age-related vestibular loss is associated with volume loss in brain regions known to receive vestibular input. To address this gap, we investigated the association between vestibular function and the volumes of four structures that process vestibular information (the hippocampus, entorhinal cortex, thalamus, and basal ganglia) in a longitudinal study of 97 healthy, older participants from the Baltimore Longitudinal Study of Aging. Vestibular testing included cervical vestibular-evoked myogenic potentials (cVEMP) to measure saccular function, ocular VEMP (oVEMP) to measure utricular function, and video head-impulse tests to measure the horizontal semi-circular canal vestibulo-ocular reflex (VOR). Participants in the sample had vestibular and brain MRI data for a total of 1 (18.6%), 2 (49.5%) and 3 (32.0%) visits. Linear mixed-effects regression was used to model regional volume over time as a function of vestibular physiological function, correcting for age, sex, intracranial volume, and inter-subject random variation in the baseline levels of and rates of change of volume over time. We found that poorer saccular function, characterized by lower cVEMP amplitude, is associated with reduced bilateral volumes of the basal ganglia and thalamus at each time point, demonstrated by a 0.0714 cm3 ± 0.0344 (unadjusted p=0.038; 95% CI: 0.00397-0.139) lower bilateral-mean volume of the basal ganglia and a 0.0440 cm3 ± 0.0221 (unadjusted p=0.046; 95% CI: 0.000727-0.0873) lower bilateral-mean volume of the thalamus for each 1-unit lower cVEMP amplitude. We also found a relationship between a lower mean VOR gain and lower left hippocampal volume (β=0.121, unadjusted p=0.018, 95% CI: 0.0212-0.222). There were no significant associations between volume and oVEMP. These findings provide insight into the specific brain structures that undergo atrophy in the context of age-related loss of peripheral vestibular function.Comprehensive SummaryHumans rely on their vestibular, or inner ear balance, system to manage everyday life. In addition to sensing head motion and head position with respect to gravity, the vestibular system helps to maintain balance and gaze stability. Furthermore, evidence is mounting that vestibular function is linked to structural changes in the central nervous system (CNS). Yet, the exact processes by which vestibular function alters brain structural integrity is unclear. One possible mechanism is that progressive vestibular deafferentation results in neurodegeneration of structures that receive vestibular input. In support of this putative mechanism, recent studies report the association of vestibular impairment with volume loss of brain areas that receive vestibular information, specifically the hippocampus and entorhinal cortex, in older adults. This present work investigates the extent over time to which age-related vestibular loss contributes to volume reduction of four brain regions that receive vestibular input: the hippocampus, entorhinal cortex, thalamus, and basal ganglia. Using data from a cohort of healthy, older adults between 2013 and 2017 from the Baltimore Longitudinal Study of Aging, we assessed regional brain volume as a function of vestibular function, while accounting for common confounds of brain volume change (e.g., age, sex, head size). We found that poor vestibular function is associated with significantly reduced volumes of the thalamus, basal ganglia, and left hippocampus. Notably, this study is one of the first to demonstrate relationships between age-related vestibular loss and gray matter loss in brain regions that receive vestibular input. Further research is needed to understand in greater detail the observed link between vestibular function and CNS structure. Which brain areas are impacted by age-related vestibular loss? How and in what sequence are they impacted? As the world’s aging population—and the prevalence of age-related vestibular impairment—increases, answering questions like these becomes increasingly important. One day, these answers will provide targets for preemptive interventions, like physical pre-habilitation, to stave off adverse changes in brain structure before they occur and progress towards clinical significance.

Introduction: Frailty, a clinical state of vulnerability, is associated with subsequent adverse geriatric syndromes in the general population. Hypothesis: We hypothesized that frailty influence health outcomes among older patients with coronary heart disease (CHD). Methods: We used the National Health and Aging Trends Study, a prospective cohort study linked to a Medicare sample. CHD was identified by self-report and/or ICD codes one-year prior to the baseline visit. Frailty was measured using the Fried physical frailty phenotype (PFP). Geriatric outcomes were assessed during five-year follow-up. Results: Of the 4,656 study participants, 1,395 (28%) had a history of CHD one-year prior to their baseline visit. Compared to those without frailty, subjects with frailty were older (Age ≥75: 69.9% vs. 57.1%, p Conclusion: Among patients with CHD, frailty is a risk factor for accelerated development of geriatric outcomes. Efforts to identify frailty in the context of CHD are needed, as well as interventions to limit or reverse frailty status in CHD patients.

BACKGROUND Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown. METHODS Here, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2). RESULTS During graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI. CONCLUSION Several-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations. FUNDING This work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins., Rapid exercise-induced skeletal muscle high-energy phosphate decline occurs in frail, older individuals and is closely linked to exercise intolerance and fatigue.

Adolescent girls and young women (AGYW) aged 15 to 24 years face disproportionately high risks of acquiring HIV and other sexually transmitted infections (STIs). A sexual health risk stratification tool can support the development and implementation of tailored HIV and STI prevention services for sub-groups of at-risk AGYW. Data were collected among sexually active AGYW aged 15 to 24 years in Tanzania between April 2015 and March 2017. Exploratory and confirmatory factor analyses were conducted to construct and assess the latent structure of a ten-item scale for rapid assessment of sexual health risks. Items with high factor loadings and minimal cross loadings were retained in the final scale. Scale performance was appraised against condomless sex (defined as unprotected vaginal or anal intercourse) reported by AGYW for construct validity. A three-factor structure of vulnerability to HIV among AGYW was supported with subscales for socioeconomic vulnerability; lack of adult support; and sexual behavioral risks. The chi-square goodness-of-fit test, root mean square error of approximation, comparative fit index, and Tucker-Lewis index indicated a strong goodness-of-fit of the three-factor scale. Cronbach alphas (0.55 for socioeconomic vulnerability, 0.55 for lack of support, and 0.48 for sexual risk) indicated sub-optimal internal consistency for all sub-scales. The factor-item and factor-factor correlations identified in these analyses were consistent with the conceptual framework of vulnerability of HIV infection in AGYW, suggesting good construct validity. The scale also demonstrated a statistically significant association with condomless sex and could be potentially used for sexual health risk stratification (OR = 1.17, 95% CI: 1.12, 1.23). The sexual health and HIV risk stratification scale demonstrated potential in identifying sexually active AGYW at high risk for HIV and other STIs. Ultimately, all AGYW in Tanzania are not at equal risk for HIV and this scale may support directing resources towards those at highest risk of HIV.

Background Physical frailty and cognitive impairment have been separately associated with falls. The purpose of the study is to examine the associations of physical frailty and cognitive impairment separately and jointly with incident recurrent falls among older adults. Methods The analysis included 6000 older adults in community or non-nursing home residential care settings who were at least 65 years old and participated in the National Health and Aging Trends Study. Frailty was assessed using the physical frailty phenotype; cognitive impairment was defined by bottom quintile of the clock-drawing test or immediate and delayed 10-word recall, or self/proxy-report of diagnosis of dementia, or AD8 score at least 2. The marginal means/rates models were used to analyze the associations of frailty and cognitive impairment with recurrent falls over 6 years of follow-up between 2011 and 2017. Results Of the 6000 older adults, 1787 (29.8%) had cognitive impairment only, 334 (5.6%) had frailty only, 615 (10.3%) had both, and 3264 (54.4%) had neither. After adjusting for age, sex, race, education, living alone, obesity, disease burden, and mobility disability, those with frailty (with or without cognitive impairment) at baseline had higher rates of recurrent falls than those without cognitive impairment and frailty (frailty only: rate ratio [RR] = 1.31, 95% confidence interval [CI] = 1.18–1.44; both: RR = 1.28, 95% CI = 1.17–1.40). The association was marginally significant for those with cognitive impairment only (RR = 1.07, 95% CI = 1.00–1.13). Conclusions Frailty and cognitive impairment were independently associated with recurrent falls in noninstitutionalized older adults. There was a lack of synergistic effect between frailty and cognitive impairment.

Resiliency is the ability to respond to, adapt to and recover from stressors. Deterioration of resiliency in older adults has been hypothesized to be regulated by age-related changes in stress response systems, including the Hypothalamic Pituitary Adrenal (HPA) axis and the innate immune system response. Although age-related chronic inflammation is strongly related to lack of resiliency, the impact of chronic inflammation on acute stress response is unclear. Here we describe the impact of a five-hour exposure to cold temperature acute stressor, on immune and corticosterone response using older and younger IL-10tm/tm mice, a mouse model with chronic inflammatory pathway activation, and age and gender matched C57/Bl6 background control (WT) mice. Overall, mice exposed to 4 °C for 5 h had significantly higher plasma corticosterone levels compared to those that remained at room temperature (25 °C), with the exception of the WT females. Cold stressed mice had lower plasma tumor necrosis factor receptor 1 (TNFR1) levels with varying significance, in all ages and phenotypes, with the exception of the old female WT mice. In contrast, the effects of cold stress on pro-inflammatory cytokine interleukin 6 (IL-6) levels were inconsistent and not significant, with the exception of the female IL-10tm/tm mice. In conclusion, these findings demonstrate that sex, age and chronic inflammatory pathway activation all influence corticosterone secretion and inflammatory processes in the face of acute cold stress.

Our objectives were to evaluate: 1) the associations of cognitive frailty with various health outcomes including disability, hospitalization, and death; 2) whether the associations differed by multimorbidity. We included data of 5113 Chinese older adults (aged 60+ years) who had baseline cognition and physical frailty assessments (2011 wave) and follow-up for 4 years. About 16.0% (n=820) had cognitive impairment; 6.7% (n=342) had physical frailty; and 1.6% (n=82) met criteria for cognitive frailty. Both cognitive impairment (odds ratios (ORs) range: 1.41 to 2.11) and physical frailty (ORs range: 1.51 to 2.43) were independently associated with basic activities of daily living (BADL), instrumental ADL (IADL), mobility disability, hospitalization, and death among participants without that corresponding outcome at baseline, even after accounting for covariates. Relative to participants who had normal cognition and were nonfrail, those with cognitive frailty had the highest risk for IADL disability (OR=3.40, 95% CI, 1.23-9.40) and death (OR=3.89, 95% CI, 2.25-6.47). We did not find significant interaction effects between cognitive frailty and multimorbidity (Pinteractions>0.05). Overall, cognitive frailty was associated with disability and death, independent of multimorbidity. This highlights the importance of assessing cognitive frailty in the community to promote primary and secondary preventions for healthy aging.

Introduction Multifactorial biological processes underpin dysregulation over several individual physiological systems. However, it is challenging to characterize and model this multisystemic dysregulation and its relationship with individual physiologic systems. We operationalized a theory-driven measure of multisystem dysregulation and empirically tested for measurement differences by key characteristics. Methods We used the Women's Health and Aging Studies (WHAS) I and II (N = 649), and the Health ABC study (N = 1515). Twelve biomarkers representing multiple systems including stress response (e.g., inflammation), endocrine system, and energy regulation were identified. A series of confirmatory factor analyses (CFA) were conducted to evaluate the interplay between physiological systems and underlying multisystem dysregulation. We evaluated convergent criterion validity of a score for multisystem dysregulation against the physical frailty phenotype, and predictive criterion validity with incidence of walking difficulty and mortality. Results A bifactor CFA, a model in which dysregulation of individual systems proceeds independently of generalized dysregulation, fit data well in WHAS (RMSEA: 0.019; CFI: 0.977; TLI: 0.961) and Health ABC (RMSEA: 0.047; CFI: 0.874; TLI: 0.787). The general dysregulation factor was associated with frailty (OR: 2.2, 95 % CI: 1.4, 3.5), and elevated risk of incident walking difficulty and mortality. Findings were replicated in Health ABC. Discussion Biomarker data from two epidemiologic studies support the construct of multisystem physiological dysregulation. Results further suggest system-specific and system-wide processes have unique and non-overlapping contributions to dysregulation in biological markers.

Context Older adults have the greatest burden of diabetes; however, the contribution of age-related muscle loss to its development remains unclear. Objective We assessed the relationship of lean body mass with aging to incident diabetes in community-dwelling adults. Design and Setting We studied participants in the Baltimore Longitudinal Study of Aging with median follow-up of 7 years (range 1-16). Cox proportional hazard models with age as the time scale were used. Time-dependent lean body mass measures were updated at each follow-up visit available. Participants Participants included 871 men and 984 women without diabetes who had ≥ 1 assessment of body composition using dual x-ray absorptiometry. Main Outcomes Incident diabetes, defined as self-reported history and use of glucose-lowering medications; or fasting plasma glucose ≥ 126 mg/dL and 2-hour oral glucose tolerance test glucose ≥ 200 mg/dL either at the same visit or 2 consecutive visits. Results The baseline mean [standard deviation] age was 58.9 [17.3] years. Men and women with a higher percentage of total lean body mass had lower fasting and 2-hour glucose levels, and less prediabetes (all P Conclusions Relatively lower lean body mass with aging is associated with incident diabetes in men and partially related to anthropometrics, but not so in women.

Background Frailty (physical frailty phenotype [PFP]) and its criteria (slow gait, weakness, weight loss, low activity, and exhaustion) are each associated with cognitive dysfunction. The extent to which the PFP is associated with cognition beyond that expected from its component parts remains uncertain. Method We used the National Health and Aging Trends Study to quantify associations between PFP criteria and cognitive performance (level/change) using adjusted mixed effects models. We tested whether frailty was associated with excess cognitive vulnerability (synergistic/excess effects, Cohen’s d) beyond criteria contributions by assessing interactions between each criterion and frailty. Results Among 7439 community-dwelling older adults (mean age = 75.2 years) followed for a mean of 3.2 years (SE = 0.03), 14.1% were frail. The PFP and PFP criteria were all associated with lower baseline cognitive performance, among which slow gait (−0.31 SD, SE = 0.02) and frailty (−0.23 SD, SE = 0.02) were strongest. Only slow gait (−0.03 SD/year, SE = 0.01), frailty (−0.02 SD/year, SE = 0.01), weight loss (−0.02 SD/year, SE = 0.01), and weakness (−0.02 SD/year, SE = 0.01) were associated with cognitive decline. Frailty was associated with cognitive performance above and beyond each criterion (excess effects ranging from −0.07 SD [SE = −0.05] for slow gait to −0.23 SD [SE = 0.03] for weakness); the same was not true for cognitive decline. Slow gait was the only criterion associated with cognitive change among both frail and nonfrail participants (frail: Cohen’s d/year = −0.03, SE = 0.01; nonfrail: Cohen’s d/year = −0.02, SE = 0.01). Conclusions PFP is an important frailty measure that is cross-sectionally associated with lower cognitive performance, but not with subsequent cognitive decline, above and beyond its criteria contributions. Further research into the construct of frailty as a “syndrome” correlated with cognition and other adverse outcomes is needed.

Background Physical frailty phenotype is characterized by decreased physiologic reserve to stressors and associated with poor outcomes, such as delirium and mortality, that may result from post-kidney transplant (KT) inflammation. Despite a hypothesized underlying pro-inflammatory state, conventional measures of frailty typically do not incorporate inflammatory biomarkers directly. Among KT candidates and recipients, we evaluated the inclusion of inflammatory biomarkers with traditional physical frailty phenotype components. Methods Among 1154 KT candidates and recipients with measures of physical frailty phenotype and inflammation (interleukin 6 [IL6], tumor necrosis factor alpha [TNFα], C-reactive protein [CRP]) at 2 transplant centers (2009–2017), we evaluated construct validity of inflammatory-frailty using latent class analysis. Inflammatory-frailty measures combined 5 physical frailty phenotype components plus the addition of an individual inflammatory biomarkers, separately (highest tertiles) as a sixth component. We then used Kaplan–Meier methods and adjusted Cox proportional hazards to assess post-KT mortality risk by inflammatory-frailty (n = 378); Harrell’s C-statistics assessed risk prediction (discrimination). Results Based on fit criteria, a 2-class solution (frail vs nonfrail) for inflammatory-frailty was the best-fitting model. Five-year survival (frail vs nonfrail) was: 81% versus 93% (IL6-frailty), 87% versus 89% (CRP-frailty), and 83% versus 91% (TNFα-frailty). Mortality was 2.07-fold higher for IL6-frail recipients (95% CI: 1.03–4.19, p = .04); there were no associations between the mortality and the other inflammatory-frailty indices (TNFα-frail: 1.88, 95% CI: 0.95–3.74, p = .07; CRP-frail: 1.02, 95% CI: 0.52–2.03, p = .95). However, none of the frailty-inflammatory indices (all C-statistics = 0.71) improved post-KT mortality risk prediction over the physical frailty phenotype (C-statistics = 0.70). Conclusions Measurement of IL6-frailty at transplantation can inform which patients should be targeted for pre-KT interventions. However, the traditional physical frailty phenotype is sufficient for post-KT mortality risk prediction.

Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging., Tryptophan-related toxic metabolites known as kynurenines are altered with chronic inflammation, which damages nerves in aged and frail mice and humans.

PURPOSE Clinical practice guidelines recommend incorporating long-term life expectancy to inform a number of decisions in primary care. We aimed to examine older adults’ preferences for discussing life expectancy in a national sample. METHODS We invited 1,272 older adults (aged 65 or older) from a national, probability-based online panel to participate in 2016. We presented a hypothetical patient with limited life expectancy who was not imminently dying. We asked participants if they were that patient, whether they would like to talk with the doctor about how long they may live, whether it was acceptable for the doctor to offer this discussion, whether they want the doctor to discuss life expectancy with family or friends, and when it should be discussed. RESULTS The 878 participants (69.0% participation rate) had a mean age of 73.4 years. The majority, 59.4%, did not want to discuss how long they might live in the presented scenario. Within this group, 59.9% also did not think that the doctor should offer the discussion, and 87.7% also did not want the doctor to discuss life expectancy with family or friends. Fully 55.8% wanted to discuss life expectancy only if it were less than 2 years. Factors positively associated with wanting to have the discussion included higher educational level, believing that doctors can accurately predict life expectancy, and past experience with either a life-threatening illness or having discussed life expectancy of a loved one. Reporting that religion is important was negatively associated. CONCLUSIONS The majority of older adults did not wish to discuss life expectancy when we depicted a hypothetical patient with limited life expectancy. Many also did not want to be offered discussion, raising a dilemma for how clinicians may identify patients’ preferences regarding this sensitive topic.

Objectives The purpose of this study was to examine whether frailty could explain variability in healthcare expenditure beyond multimorbidity and disability among Chinese older adults. Design Cross-sectional. Setting and Participants Participants were 5300 community-dwelling adults age at least 60 years from the China Health and Retirement Longitudinal Study. Methods Frailty was identified by the physical frailty phenotype approach that has been created and validated among Chinese older adults. Five criteria were used: slowness, weakness, exhaustion, inactivity, and shrinking. Persons were classified as “nonfrail” (0 criteria), “prefrail” (1‒2 criteria), or “frail” (3‒5 criteria). Healthcare expenditure was measured based on participants’ self-report and was classified into 3 types: outpatient expenditure, inpatient expenditure, and self-treatment expenditure. The association of frailty and healthcare expenditure was analyzed using a 2-part regression model to account for excessive zero expenditures. Results Frailty was associated with higher odds of incurring outpatient, inpatient, and self-treatment expenditure. Among persons with non-zero expenditure, prefrail and frail persons, on average, had US $30.62 [95% confidence interval (CI) 8.41, 52.82] and US $60.60 (95% CI 5.84, 115.36) higher outpatient expenditure than the nonfrail, adjusting for sociodemographics, multimorbidity, and disability. After adjustment for all covariates, prefrail persons, on average, had US $3.34 (95% CI 0.54, 6.13) higher self-treatment expenditure than the nonfrail. Conclusions and Implications Frailty is an independent predictor of higher healthcare expenditure among older adults. These findings suggest that timely screening and recognition of frailty are important to reduce healthcare expenditure among older adults.

PURPOSE OF REVIEW: This review elucidates the concept of frailty in relationship to reserve and resilience, the relationships and shared pathophysiology between physical frailty and cognitive impairment, the theoretical underpinnings of three integrated phenotypes of physical and cognitive impairments, and the potential of incorporating biomarkers into phenotype refinement and validation. RECENT FINDINGS: The fact that frailty and cognitive impairment are associated and often coexist in older adults has led to the popular view of expanding the definition of frailty to include cognitive impairment. However, there is great variability in approaches to and assumptions regarding the integrated phenotypes of physical frailty and cognitive impairment. SUMMARY: The development of integrated frailty and cognitive phenotypes should explicate the types of frailty and cognitive impairment they intend to capture and prioritize the incorporation of biological theories that help determine shared and distinct pathways in the progression to physical and cognitive impairments.

Objective To study whether depression contributes to the association between subclinical cardiovascular disease (CVD) and dementia, and identify the contribution's magnitude. Methods Among participants from the Cardiovascular Health Study Cognition Study who did not have baseline CVD-related events (N = 2,450), causal mediation methodology was implemented to examine whether late-life depressive symptoms, defined as 10-item Center for Epidemiologic Studies-Depression (mCES-D) Scale scores ≥8 from 2 to 3 years after baseline, partially mediated the association of baseline subclinical CVD (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) with mild cognitive impairment (MCI)/dementia onset occurring between 5 and 10 years from baseline. The total effect was decomposed into direct and indirect effects (via late-life depressive symptoms), obtained from an accelerated failure time model with weights derived from multivariable logistic regression of late-life depressive symptoms on subclinical CVD. Analyses were adjusted by baseline covariates: age, race, sex, poverty status, marital status, body mass index, smoking status, ApoE4 status, and mCES-D. Results Participants contributed 20,994 person-years of follow-up with a median follow-up time of 9.4 years. Subclinical CVD was associated with 12% faster time to MCI/dementia (time ratio [TR]: 0.88; 95% CI: 0.83, 0.93). The total effect of subclinical CVD on MCI/dementia onset was decomposed into a direct effect (TR: 0.95, 95% CI: 0.92, 0.98) and indirect effect (TR: 0.92, 95% CI: 0.88, 0.97); 64.5% of the total effect was mediated by late-life depressive symptoms. Conclusions These data suggest late-life depressive symptoms partially mediate the association of subclinical CVD with MCI/dementia onset.