Frailty Status and All-Cause Mortality in the Community-Dwelling Older People: An Umbrella Review

Abstract Frailty is increasingly recognised for its association with adverse health outcomes including mortality. However, various measures are used to assess frailty, and the strength of association could vary depending on the specific definition used. This umbrella review aimed to map which frailty scale could best predict the relationship between frailty and all-cause mortality among community-dwelling older people. According to the PRISMA guidelines, Medline, Embase, EBSCOhost and Web of Science databases were searched to identify eligible systematic reviews and meta-analyses which examined the association between frailty and all-cause mortality in the community-dwelling older people. Relevant data were extracted and summarised qualitatively. Methodological quality was assessed by AMSTAR-2 checklist. Five moderate-quality systematic reviews with a total of 374,529 participants were identified. Of these, two examined the frailty phenotype and its derivatives, two examined the cumulative deficit models and the other predominantly included studies assessing frailty with the FRAIL scale. All of the reviews found a significant association between frailty status and all-cause mortality. The magnitude of association varied between individual studies, with no consistent pattern related to the frailty measures that were used. In conclusion, regardless of the measure used to assess frailty status, it is associated with an increased risk of all-cause mortality.

Walking function is compromised with older age, particularly for cognitively demanding complex walking tasks. Frontal lobe brain networks are important to both complex walking and cognitive function. There is a need for interventions that target this brain region. This pilot study assessed a novel intervention to enhance both walking and executive function in older adults. The primary hypothesis was that eighteen sessions of frontal lobe tDCS combined with complex walking rehabilitation would be feasible, safe, and show preliminary efficacy for improvements in walking and cognition. Eighteen participants were randomized to one of three intervention groups: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Outcome measures included multiple tests of walking function, executive function, and prefrontal activity during walking measured by functional near infrared spectroscopy. For the walking tests, effect sizes for Active/Complex were generally higher than for Sham/ Complex. The Sham/Typical group exhibited walking test effect sizes that were often larger than either of the complex walking groups, possibly due to higher intervention step count. For the executive function tests, effect sizes were largest for the Active/Complex group. Improvements in prefrontal activity during walking were observed, as conceptualized by the Compensation Related Utilization of Neural Circuits Hypothesis. These preliminary findings support that tDCS combined with complex walking rehabilitation in older adults is feasible and may enhance both walking function and executive function.

CREATING A NOVEL PHYSICAL RESILIENCE MEASURE AMONG OLDER ADULTS: THE HEALTH, AGING, AND BODY COMPOSITION STUDY
Chenkai Wu, 1 Ya-Xi Li, 2 Michelle Odden, 3 and Megan Marron, 4 1. Duke Kunshan University, Kunshan,Jiangsu,China,2. Duke Kunshan University,Kunshan,China,3. Stanford University,STANFORD,California,United States,4. University of Pittsburgh,Pittsburgh,Pennsylvania,United States The concept of resilience has gained increasing attention in aging research; however, current literature lacks consensus on how to measure resilience. We constructed a novel resilience measure based on the degree of mismatch between persons' frailty level and disease burden and examined its predictive validity. We also sought to explore the physiological correlates of resilience. Participants were 2,457 older adults from the Health, Aging, and Body Composition Study. We constructed the resilience measure as the residual taken from the linear model regressing frailty on age, sex, race/ethnicity, 14 diseases, self-reported health, and number of medications. Participants were classified into three groups-adapters, expected agers, and premature frailers-based on residuals (less than, within, or above one standard deviation of the mean). Validation outcomes included years of able life (YAL), years of healthy life (YHL), years of healthy and able life (YHAL), disability, hospitalization, and survival. The average YHAL was 5.1, 7.7, and 9.1 years among premature frailers, expected agers, and adapters, respectively. Compared with premature frailers and expected agers, adapters had significantly lower rates of disability, hospitalization, and mortality and higher proportion surviving to 90 years. The likelihood of surviving to 90 years was 20.4%, 30.6%, and 39.7% among premature frailers, expected agers, and adapters. We developed and validated a novel approach for quantifying and classifying physical resilience in a cohort of well-functioning white and black older adults. Persons with high physical resilience level had longer healthy life span and lower rates of adverse outcomes. Frailty is gaining importance as a predictor of disability and mortality in older people, and becoming frail poses a challenge for healthy aging. We investigated the prevalence and factors associated with pre-frail and frail status in a large study cohort of community-dwelling healthy older adults from Australia and the United States. A total of 19,114 individuals (87% Australian and 56% women) aged 65 years or older enrolled in a primary prevention clinical trial were evaluated. Frailty status was classified using the modified Fried phenotype criteria comprising of exhaustion, body mass index, grip strength, gait speed and physical activity. Prevalence and factors associated with frailty status (e.g. demographic characteristics and lifestyle factors) were reported using descriptive statistics along with a logistic regression model. At baseline, 2.3 % (95% CI, 2.1-2.5) of older trial participants were frail and 39.2% (95% CI, 38.5-39.9) were pre-frail, respectively. Women were more likely to be frail (65.1% vs 36.9%) and prefrail (58.0% vs 42.0%) than men. Lower levels of education (<12 years), living alone, ethnic minorities, current smoking and past alcohol use were some of the factors which were common among frail or prefrail. Despite being a relatively healthy cohort, more than one-third of the older trial participants were prefrail, which was more prevalent among specific subgroups of individuals. This study emphasizes the high burden of the prefrailty status even among an apparently healthy cohort of community-dwelling older people.

University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Frailty is increasingly recognised for its association with adverse health outcomes including mortality. However, various measures are used to assess frailty, and the strength of association could vary depending on the specific definition used. This umbrella review aimed to map which frailty scale could best predict the relationship between frailty and allcause mortality among community-dwelling older people. According to the PRISMA guidelines, Medline, Embase, EBSCOhost and Web of Science databases were searched to identify eligible systematic reviews and meta-analyses which examined the association between frailty and allcause mortality in the community-dwelling older people. Relevant data were extracted and summarised qualitatively. Methodological quality was assessed by AMSTAR-2 checklist. Five moderate-quality systematic reviews with a total of 374,529 participants were identified. Of these, two examined the frailty phenotype and its derivatives, two examined the cumulative deficit models and the other predominantly included studies assessing frailty with the FRAIL scale. All of the reviews found a significant association between frailty status and all-cause mortality. The magnitude of association varied between individual studies, with no consistent pattern related to the frailty measures that were used. In conclusion, regardless of the measure used to assess frailty status, it is associated with an increased risk of all-cause mortality.

FUNCTIONAL NEURAL UNDERPINNINGS OF INCREASED FALLS RISK
Meishan Ai, 1 Chun-Liang Hsu, 2 and Teresa Liu-Ambrose, 3 1. Northeastern University, Boston,Massachusetts,United States,2. Harvard Medical School,Roslindale,United States,3. University of British Columbia,Vancouver,British Columbia,Canada Impaired cognition, especially in the domain of executive functions, is a major risk factor for falls in older adults. However, the underlying neural mechanism of the association between cognitive function and falls risk remains unclear. The current study compared the performance on mobility and cognitive assessments, and brain activation under Stroop task between fallers (>=2 falls in the past year) and non-fallers (0 or 1 fall in the past year). We found that during the incongruent condition of Stroop task, higher activation in precuneous, frontal and temporal areas was observed in fallers, while they showed comparable task performance as non-fallers. In addition, the contrast between congruent and incongruent conditions showed fallers exhibited increased activation in middle frontal region (z>1.7, P<0.05). Further, through mediation analysis, our data revealed that brain activation in temporal and frontal-paracingulate regions mediated the relationship between Montreal Cognitive Assessment and number of falls (confidence interval = 95%), after controlling for age and sex. Overall, our findings suggested that lower neural efficiency may be an underlying mechanism by which cognitive function is associated with falls risk.

LOSS OF ARNT LIMITS IMPROVEMENT IN PHYSIOLOGICAL PERFORMANCE FOLLOWING AEROBIC EXERCISE IN AGING
Yori Endo, 1 Yuteng Zhang, 1 Bin Li, 1 Michael MacArthur, 2 and Indranil Sinha, 1 1. Harvard Medical School,Boston,Massachusetts,United States,2. Harvard T.H. Chan School of Public Health,Boston,Massachusetts,United States Hypoxia signaling is essential for angiogenesis and metabolic regulation during exercise. Our previous study has demonstrated an age-related loss of ARNT resulting in limited muscle regeneration. To explore the role of hypoxia signaling in physiological performance in relation to aging, we generated a mouse model with skeletal muscle-specific knockout of ARNT (ARNT mKO). ARNT mKO and ARNT WT mice were subjected to a sedentary activity or treadmill running exercise regime at an increasing speed of 8-12 m/ min for 40 minutes, three times weekly over the course of 8 weeks. ARNT levels was 3-fold lower in old mice compared to young. The exercised WT mice exhibited 52% greater increase over the sedentary group in exercise endurance as measured by the maximum running distance (490.92±154.28 vs 237.76±135.19m, p＜0.01 Diet may influence the risk for cognitive decline and neurodegenerative disorders, including Alzheimer's disease (AD), but these relationships are difficult to study in humans. Cynomolgus macaques (Macaca fascicularis) are appropriate models for investigations of diet effects on the brain because, like humans, they are omnivorous, have complex central nervous systems, are susceptible to diet-induced diseases, and accumulate amyloid and tauopathies with age. Using structural magnetic resonance imaging, we examined diet effects on brain anatomy by measuring thickness and volume of several areas relevant to AD in 38 middle-aged females, at baseline and after Mediterranean or Western diet consumption for 36 months (equivalent to a 9-year follow-up in humans). Using repeated measures analysis, cortical thicknesses generally increased in the Western diet group. Western diets also resulted in increases in total brain volume and cortical gray matter and decreases in cerebrospinal fluid, white matter, and deep gray matter (striatum and thalamus) (all p's≤0.05). In contrast, thicknesses and volumes generally remained