Comparative Analysis of Intrinsic Capacity Impairments, Determinants, and Clinical Consequences in Older Community-Dwellers in Japan and Taiwan: Longitudinal Studies Showing Shared Traits and Distinct Presentations.

OBJECTIVES: Despite the recognized impact of intrinsic capacity (IC) impairment on healthy aging, international comparisons in different sociocultural contexts are scarce. This study aimed to compare IC impairment among community-dwelling older adults in Japan and Taiwan to explore the context of healthy aging in different countries. DESIGN: Comparative observational study. SETTING: National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) in Japan and Longitudinal Aging Study of Taipei (LAST) in Taiwan. PARTICIPANTS: 794 individuals (age range, 60.0-86.5 years) from NILS-LSA and 1,358 (60.0-96.7 years) from LAST. MEASUREMENTS: IC impairment was evaluated across the domains of locomotion, cognition, vitality, sensory capacity, and psychological well-being. Participants were categorized as having impaired IC or healthy. We investigated associations between IC impairment, falls, and all-cause mortality. RESULTS: IC impairment was present in 54.9% and 37.3% of participants in the NILS-LSA and LAST cohorts, respectively. Male NILS-LSA participants with impaired IC (odds ratio [OR]:1.50, 95% confidence interval [CI]:1.03-2.20), with hearing loss (OR:1.98, 95% CI:1.00-3.90) were more likely to fall. In LAST, impaired locomotion (OR:2.14, 95% CI:1.46-3.14) increased the risk of falls. Men with impaired IC (hazard ratio [HR]; 2.14, 95% CI:1.10-4.15) and visual impairment (HR:2.21, 95% CI:1.15-4.25) and women with impaired psychological well-being (HR:4.94, 95% CI:1.28-18.97) in the NILS-LSA cohort had greater risk for all-cause mortality; however, this was not shown for LAST participants. CONCLUSION: The prevalence and distribution of IC impairment and associated biomarkers differed significantly between participants in Japan and Taiwan. However, the associations with adverse outcomes remained similar, emphasizing the need for tailored interventions for healthy aging.

Predictive Validity of Different Walking Measures to Identify the Incident Long-Term Care Needs in Older Adults.

OBJECTIVES: A comfortable walking speed is a suitable measurement of functional status in older adults. In addition to assessing their comfortable walking speed, two complex walking tests were administered to a cohort of older people, assuming that these tests would be a more sensitive predictor of the incident long-term care needs than comfortable walking speed. DESIGN: A prospective observational study was conducted to collect data. SETTING AND PARTICIPANTS: Among the initial 5,563 community-dwelling independent older adults (aged ≥ 65 years), 935 were excluded and the data of 4,628 (mean age, 73.9 ± 5.5 years, 65-94 years; 2,052 men, 2,576 women) older adults were finally analyzed. METHODS: Three walking tasks were administered: comfortable, complicated balance, and Go-stop walking. Complicated balance walking was measured under comfortable walking conditions, with participants having to walk with their hands crossed at the shoulder joint at 90°. For the Go-stop walking test, the time taken to walk 2 meters was measured using a stopwatch. For two years following baseline assessments, participants received monthly follow-ups for incident certification of the need for care under the long-term care insurance (LTCI) system. RESULTS: Low performance in comfortable, complicated balance, and Go-stop walking were 29.8%, 37.7%, and 35.1%, respectively. During the 24-month follow-up period, 246 participants (5.3%) required LTCI certification. The Youden Index was used to determine the cut-points of the incident long-term care needs in the comfortable, complicated balance, and Go-stop walking conditions, which were 1.055 m/s, 0.936 m/s, and 3.205 seconds, respectively. Participants classified as exhibiting low performance included 1,381 (29.8%) under comfortable walking, 1,746 (37.7%) under complicated balance walking, and 1,623 (35.1%) under the Go-stop walking tests. The C-indices of the comfortable, complicated balance, and Go-stop walking tests were 0.72 (95% confidence interval (CI) 0.69-0.76), 0.71 (95% CI 0.67-0.74), and 0.65 (95% CI 0.61-0.69), respectively. Cox proportional hazards regression model revealed significant relationships between the incident long-term care needs and the comfortable (hazard ratio (HR) 2.14, 95% CI 1.62-2.84), complicated balance (1.81, 1.36-2.41), and Go-stop (1.46, 1.12-1.91) walking conditions. CONCLUSIONS AND IMPLICATIONS: The findings suggest that slow walking speed has a considerably greater impact on the incident long-term care needs in older adults. However, the complex walking task did not improve the predictive performance. Comfortable walking speed tests, which can easily be measured to predict the future incident long-term care needs, are effective tools in community health promotion and primary care.

Relationships among Grip Strength Measurement, Response Time, and Frailty Criteria.

BACKGROUND: Muscle response in older adults is believed to decrease with maximal muscle strength, although it has not been adequately assessed; further, the relationship between frailty and muscle response remains unexamined. OBJECTIVES: This study aimed to develop a practical method for measuring muscle response using grip strength in older adults and to clarify the relationship between frailty and grip strength response. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional, clinical, observational study. A total of 248 patients (94 men and 154 women, mean age: 78.2 years) who visited the outpatient unit in the Integrated Healthy Aging Clinic of our Hospital for the first time were enrolled. MEASUREMENTS: Using a grip strength measuring device originally developed by us, we measured grip strength response indices, such as reaction time, time constant, rate of force development (response speed), and maximum grip strength. Grip strength response indices were compared among three groups (robust, pre-frail, and frail) according to the Fried and Kihon checklist assessments for frailty. RESULTS: Based on Fried's assessment, marked differences were found between groups not only in maximal grip strength but also in response time and response speed. Based on the Kihon checklist assessment, there was no significant difference in response time; however, a considerable difference in response speed for the left hand was observed. Moreover, according to the Kihon checklist assessment, some cases showed differences in muscle response although not in maximal muscle strength. CONCLUSIONS: The response speed of grip strength was suggested to decrease with frailty. The results suggest that measurement of grip strength response in both hands is useful to examine the relationship between frailty and grip strength response.

Prediction of Nursing Home Admission Using the FRAIL-NH Scale Among Older Adults in Post-Acute Care Settings.

OBJECTIVES: The FRAIL-NH scale was developed to identify frailty status in nursing home residents. The purpose of this study was to examine the utility of the FRAIL-NH scale for predicting nursing home admission among patients in post-acute care settings. Design/ Setting/ Participants: This single-center, prospective, observational cohort study included participants aged 65 years or older who were admitted to a community-based integrated care ward (CICW) between July 2015 and November 2020. MEASUREMENTS: Using the CICW database, we retrospectively classified participants as robust, prefrail, or frail based on the FRAIL-NH scale the score by identifying variables from our database that were most representative of each component. The following data were collected: examination findings, CICW admission and discharge information, length of CICW stay, and nursing home admission. The participants were divided into two groups based on whether or not they were admitted to a nursing home after CICW discharge. The hazard ratios (HRs) and 95% confidence intervals (CIs) for nursing home admission were calculated according to the FRAIL-NH categories using the Cox proportional hazards models with reference to the robust group. In the multivariate adjusted model, we adjusted for age, sex, nutritional status, cognitive function, living status, and economic status. RESULTS: Data of 550 older adults were analyzed, of which 118 were admitted and 432 were not admitted to a nursing home. The frail group had a higher risk of nursing home admission (HR, 2.22; 95% CI 1.32-3.76) than the robust group. CONCLUSIONS: This study showed that the FRAIL-NH scale was beneficial for predicting nursing home admission among older adults in the post-acute care setting. Thus, assessment using the FRAIL-NH scale may help to consider preparation and support for life after discharge.

Physical Frailty and Hemoglobin-to-Red Cell Distribution Width Ratio in Japanese Older Outpatients.

The Frailty screening should be widely performed; however, simple and inexpensive biomarkers are missing. Biomarkers that can be routinely assessed in many patients are desirable. Recently, the hemoglobin-to-red cell distribution width ratio (Hb/RDW, HRR) has been suggested as a new prognostic marker and has been reported to be associated with inflammation, one of the factors contributing to frailty. Therefore, we aimed to address the role of HRR in frailty among 557 older outpatients (aged 65-96 years). Frailty was assessed using the Japanese version of the Cardiovascular Health Study criteria, and HRR was calculated from clinical records. Participants were classified into five groups based on a sex-stratified quintile of HRR (Q1-Q5). Of the participants, 20.3% were frail. Using multiple logistic regression models with the Q5 group as a reference, after adjusting for sex, age, body mass index, polypharmacy, pre-orthopedic surgery, and the use of iron medications, the multivariable-adjusted odds ratios (95% confidence intervals) of the Q4 to Q1 groups were 0.92 (0.58-1.47), 1.04 (0.67-1.61), 1.29 (0.84-1.96), and 1.85 (1.22-2.82), respectively, indicating that a lower HRR was significantly associated with frailty. The robustness of these results was also shown in the multiple imputation analysis. The results suggest that HRR measurement may be one of the indicators to identify frail older adults in routine practice.

Study Protocol of a Comprehensive Activity Promotion Program for the Prevention of Dementia: A Randomized Controlled Trial Protocol.

BACKGROUND: Several technical devices are available to monitor and promote changes in behavior toward higher activity. In particular, smartphones are becoming the primary platform for recognizing human activity. However, the effects of behavior change techniques that promote physical, cognitive, and social activities on incident dementia in older adults remain unknown. OBJECTIVES: This randomized controlled trial aims to examine the effects of behavior change techniques on the prevention of dementia among community-dwelling older adults using a smartphone as a behavior change tool. DESIGN: A randomized controlled trial. SETTING: Community in Japan. PARTICIPANTS: The study cohort comprises 3,498 individuals, aged ≥60 years, randomized into two groups: the smartphone group (n = 1,749) and the control group (n = 1,749). INTERVENTION: The smartphone group will be asked to use smartphone applications for at least 30 minutes daily to self-manage and improve their physical, cognitive, and social activities. The smartphone group will perform 60-minute group walking sessions using application-linked Nordic walking poles with cognitive stimulation twice a week during the intervention period. The walking poles are a dual-task exercise tool that works with a smartphone to perform cognitive tasks while walking, and the poles are equipped with switches to answer questions for simple calculation and memory tasks. The smartphone and control groups will receive lectures about general health that will be provided during the baseline and follow-up assessments. MEASUREMENTS: Incident dementia will be detected using cognitive tests (at baseline, after 15 months, and after 30 months) and by preparing diagnostic monthly reports based on data from the Japanese Health Insurance System. Participants without dementia at baseline who will be diagnosed with dementia over the 30-month follow-up period will be considered to have incident dementia. CONCLUSIONS: This study has the potential to provide the first evidence of the effectiveness of information communication technology and Internet of Things in incident dementia. If our trial results show a delayed dementia onset for self-determination interventions, the study protocol will provide a cost-effective and safe method for maintaining healthy cognitive aging.

The Design and Rationale of a Phase 2b, Randomized, Double-Blinded, and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B in Older Adults with Frailty.

BACKGROUND: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes. OBJECTIVES: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty. DESIGN: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers. SETTING: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center. PARTICIPANTS: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 ("mild") or 6 ("moderate"), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL. INTERVENTION: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days. MEASUREMENTS: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial. RESULTS: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board. CONCLUSION: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty.

Association of Dietary Intake with the Transitions of Frailty among JapaneseCommunity-Dwelling Older Adults.

BACKGROUND: Frailty is a dynamic process, with frequent transitions between frailty, prefrailty, and robust statuses over time. The effect of dietary intake on frailty transitions is unknown. OBJECTIVE: To examine the association between dietary intake and frailty transitions. DESIGN: Survey-based retrospective analysis of the National Institute for Longevity Sciences-Longitudinal Study of Aging data. SETTING: Areas neighboring the National Center for Geriatrics and Gerontology in Aichi Prefecture, Japan. PARTICIPANTS: We included 469 prefrail community dwellers aged 60-87 years who participated both in the baseline (2008-2010) and 2-year follow-up (2010-2012) surveys of the National Institute for Longevity Sciences-Longitudinal Study of Aging. MEASUREMENTS: Transitions of frailty were categorized by changes in status from baseline to follow-up: "deterioration (prefrail to frail)," "persistence (persistent prefrail)," and "reversal (prefrail to robust)." Estimated dietary (nutrients and food) intakes assessed by 3-day dietary records in each frailty transition were analyzed with a multivariate-adjusted general linear model after adjusting for sex, age, education, family income, smoking, and chronic disease. RESULTS: At the 2-year follow-up, 28%, 7%, and 65% of participants had robust, frail, and pre-frail status, respectively. Among 13 food groups, only milk and dairy product intake was positively associated with frailty reversal even after adjusting for all frailty criteria at baseline. Despite insignificant differences in the estimated mean intakes, the baseline intake of saturated fatty acids, potassium, and vitamin B1 tended to be the highest in the reversal group. The estimated mean (standard error) for milk and dairy product intake (g/day) was 79.1 (28.6), 129.3 (19.9), and 161.7 (21.7) for the deterioration, persistence, and reversal groups, respectively (P=0.0036, P-trend=0.0019). CONCLUSIONS: Daily consumption of dairy products may contribute to frailty reversal and frailty prevention among older community dwellers who consume small amounts of dairy products. Other food groups showed no association with frailty status transitions.

Impact of Frailty on Dietary Habits among Community-Dwelling Older Persons during the COVID-19 Pandemic in Japan.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has resulted in reduced physical activity and social interaction. These restrictions may have affected the food intake habits of frail older people more than non-frail older people. OBJECTIVES: To investigate the association between frailty and change in dietary habit during the pandemic. DESIGN: Cross-sectional mail survey. SETTING: Community-based. PARTICIPANTS: The study questionnaire was mailed to 4,436 older residents of Higashiura, Aich Japan, who were aged ≥75 years and who did not need care as of April 1, 2020. Of these, 2,738 participants provided complete answers to the questionnaires (75-96 years old, 49.3% males). MEASUREMENTS: The participants' frailty status and changes in food consumption during social isolation were assessed. Frailty status was assessed using the five-item frailty screening index (i.e., weight loss, low physical function, low physical activity, cognition, and exhaustion). Any participant who reported an increase or a decrease in ≥1 of the 12 food categories was defined as having change in dietary habit. Using multivariate logistic regression analysis, the odds ratios (ORs) and 95% confidence intervals (CIs) of frailty for changes in diet were estimated by adjusting for age, sex, BMI, and living alone. In each of the 12 food categories, the proportion of participants with increased and decreased food intake was compared between the groups. RESULTS: Among the participants, 470 (17.2%) were frail, and 1,097 (40.1%) experienced a change in dietary habit under social restriction. The adjusted OR (95% CI) of the frail group for a change in dietary habit was 2.01 (1.63-2.47, p<0.001). Participants with decreased consumption of meat, fish, seaweed and mushroom, and fruits and those with increased consumption of eggs, bread, and noodles tended to be frail. CONCLUSION: The nutritional intervention for frail older people should be strengthened during the pandemic.

Low Amino Acid Score of Breakfast is Associated with the Incidence of Cognitive Impairment in Older Japanese Adults: A Community-Based Longitudinal Study.

BACKGROUND: The protein digestibility-corrected amino acid score (PDCAAS) represents the degree of utilizable dietary protein, namely the protein quality. The PDCAAS of a diet is required to be evaluated on a meal-by-meal basis, as food digestion and absorption occur with each meal intake. Although a positive association between protein intake and cognitive function has been reported, no study has investigated the association between PDCAAS of a diet and cognitive function. OBJECTIVES: To investigate the relationship between PDCAAS of a diet and cognitive impairment in older adults. DESIGN: Longitudinal epidemiological study. SETTING: Community-based setting. PARTICIPANTS: We analyzed 541 community-dwellers who participated in both baseline and follow-up survey. They were 60-83 years of age without cognitive impairment at baseline. MEASUREMENTS: Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score ≤27. Individual PDCAASs were calculated for each of three regular meals from the 3-day dietary records at baseline. Participants were classified into two groups according to the sex-specific tertiles (T1-T3) of the PDCAAS for each meal (i.e., T1 as the low score group and T2-T3 as the medium and high score group). The dependent variable was cognitive impairment observed after 4 years, and the explanatory variables were the PDCAAS groups for each meal (the medium and high group as the reference) and covariates (sex, age, body mass index, education, depressive symptoms, medical history, protein intake at each meal, and the MMSE score at baseline). Multivariable logistic regression analysis was performed to evaluate the low PDCAAS group for cognitive impairment after 4 years. RESULTS: A significant association was observed only between a low PDCAAS of breakfast and the incidence of cognitive impairment (the adjusted odds ratios [95% confidence intervals] of low PDCAAS for cognitive impairment for breakfast, lunch, and dinner were 1.58 [1.00-2.50], 0.85 [0.54-1.34], and 1.08 [0.71-1.65], respectively). CONCLUSION: A lower PDCAAS of breakfast, i.e., a diet with poor quality of protein, was associated with the incidence of cognitive impairment in older adults of the community.

Physio-Cognitive Decline Syndrome as the Phenotype and Treatment Target of Unhealthy Aging.

In this era of unprecedented longevity, healthy aging is an important public health priority. Avoiding or shortening the period of disability or dementia before death is critical to achieving the defining objectives of healthy aging, namely to develop and maintain functional capabilities that enable wellbeing in older age. The first step is to identify people who are at risk and then to implement effective primary interventions. Geriatricians have identified a distinct clinical phenotype of concurrent physical frailty and cognitive impairment, which predicts high risk of incident dementia and disability and is potentially reversible. Differing operational definitions for this phenotype include "cognitive frailty", "motoric cognitive risk syndrome" and the recently proposed "physio-cognitive decline syndrome (PCDS)". PCDS is defined as concurrent mobility impairment no disability (MIND: slow gait or/and weak handgrip) and cognitive impairment no dementia (CIND: ≥1.5 SD below the mean for age-, sex-, and education-matched norms in any cognitive domain but without dementia). By these criteria, PCDS has a prevalence of 10-15% among community-dwelling older persons without dementia or disability, who are at increased risk for incident disability (HR 3.9, 95% CI 3.0-5.1), incident dementia (HR 3.4, 95% CI 2.4-5.0) and all-cause mortality (HR 6.7, 95% CI 1.8-26.1). Moreover, PCDS is associated with characteristic neuroanatomic changes in the cerebellum and hippocampus, and their neurocircuitry, which are distinct from neuroimaging features in normal aging and common dementia syndromes. Basic research and longitudinal clinical studies also implicate a hypothetical muscle-brain axis in the pathoetiology of PCDS. Most important, community-dwelling elders with PCDS who participated in a multidomain intervention had significant improvements in global cognitive function, and especially in the subdomains of naming and concentration. Our proposed operational definition of PCDS successfully identifies an appreciable population of at-risk older people, establishes a distinct phenotype with an apparently unique pathoetiology, and is potentially reversible. We now need further studies to elucidate the pathophysiology of PCDS, to validate neuroimaging features and muscle-secreted microRNA biomarkers, and to evaluate the effectiveness of sustained multidomain interventions.

The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial.

BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer's Disease.

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the "ATN" (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer's disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aß1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines.

The human ageing process is universal, ubiquitous and inevitable. Every physiological function is being continuously diminished. There is a range between two distinct phenotypes of ageing, shaped by patterns of living - experiences and behaviours, and in particular by the presence or absence of physical activity (PA) and structured exercise (i.e., a sedentary lifestyle). Ageing and a sedentary lifestyle are associated with declines in muscle function and cardiorespiratory fitness, resulting in an impaired capacity to perform daily activities and maintain independent functioning. However, in the presence of adequate exercise/PA these changes in muscular and aerobic capacity with age are substantially attenuated. Additionally, both structured exercise and overall PA play important roles as preventive strategies for many chronic diseases, including cardiovascular disease, stroke, diabetes, osteoporosis, and obesity; improvement of mobility, mental health, and quality of life; and reduction in mortality, among other benefits. Notably, exercise intervention programmes improve the hallmarks of frailty (low body mass, strength, mobility, PA level, energy) and cognition, thus optimising functional capacity during ageing. In these pathological conditions exercise is used as a therapeutic agent and follows the precepts of identifying the cause of a disease and then using an agent in an evidence-based dose to eliminate or moderate the disease. Prescription of PA/structured exercise should therefore be based on the intended outcome (e.g., primary prevention, improvement in fitness or functional status or disease treatment), and individualised, adjusted and controlled like any other medical treatment. In addition, in line with other therapeutic agents, exercise shows a dose-response effect and can be individualised using different modalities, volumes and/or intensities as appropriate to the health state or medical condition. Importantly, exercise therapy is often directed at several physiological systems simultaneously, rather than targeted to a single outcome as is generally the case with pharmacological approaches to disease management. There are diseases for which exercise is an alternative to pharmacological treatment (such as depression), thus contributing to the goal of deprescribing of potentially inappropriate medications (PIMS). There are other conditions where no effective drug therapy is currently available (such as sarcopenia or dementia), where it may serve a primary role in prevention and treatment. Therefore, this consensus statement provides an evidence-based rationale for using exercise and PA for health promotion and disease prevention and treatment in older adults. Exercise prescription is discussed in terms of the specific modalities and doses that have been studied in randomised controlled trials for their effectiveness in attenuating physiological changes of ageing, disease prevention, and/or improvement of older adults with chronic disease and disability. Recommendations are proposed to bridge gaps in the current literature and to optimise the use of exercise/PA both as a preventative medicine and as a therapeutic agent.

Impact of the Coronavirus Disease 2019 Outbreak on Activity and Exercise Levels among Older Patients.

OBJECTIVES: This study aimed to clarify the impact of the coronavirus disease 2019 outbreak on the levels of activity among older patients with frailty or underlying diseases. A total of 175 patients (79.0±7.0 years) undergoing outpatient or home-based rehabilitation, stratified into groups, based on frailty status. The percentage of patients who went out at least once a week decreased after the outbreak from 91% to 87%, from 65% to 46%, and from 47% to 36% in the non-frail, frail, and nursing care requirement groups, respectively. The proportion of older patients participating in exercise during the outbreak was 75%, 51%, and 41% in the non-frail, frail, and nursing care requirement groups, respectively. The proportion of older patients participating in voluntary exercise after instruction was lowest in the frail group (35%). Older patients with frailty are susceptible to the negative effects of refraining from physical activity and require careful management.

Relationship between Serum Fatty Acids and Components of Physical Frailty in Community-Dwelling Japanese Older Adults.

Polyunsaturated fatty acids help maintain insulin sensitivity, mitochondrial function, and anti-inflammation. It is well known that deterioration in these areas can cause frailty. However, little is known about the differences in serum polyunsaturated fatty acid levels among frailty components. We investigated the cross-sectional relationship between frailty and serum fatty acids in 1,033 community-dwelling older adults aged 60-88 years. Polyunsaturated fatty acid concentrations were measured from fasting blood samples. The modified phenotype criteria defined frailty. Polyunsaturated fatty acid levels were compared among each component using general linear modeling after controlling for sex, age, body mass index, smoking status, household income, and medical history. Lower polyunsaturated fatty acid levels were associated with the modified frailty criteria, including shrinking and weakness (p < 0.05). Our findings suggest that serum polyunsaturated fatty acid levels differ depending on the frailty status of older adults.

The Influence of the COVID-19 Pandemic on Physical Activity and New Incidence of Frailty among Initially Non-Frail Older Adults in Japan: A Follow-Up Online Survey.

OBJECTIVES: The objective of this study was to investigate the influence of the COVID-19 pandemic on physical activity (PA) and the incidence of frailty among initially non-frail older adults in Japan. DESIGN: A follow-up online survey. SETTING AND SUBJECTS: Among the 1,600 baseline online survey participants, 388 adults were already frail, and 275 older adults did not respond to the follow-up survey. Thus, the final number of participants in this study was 937 (follow-up rate: 77.3%). METHODS: We assessed the total PA time at four time points according to the COVID-19 waves in Japan: January 2020 (before the pandemic), April 2020 (during the first wave), August 2020 (during the second wave), and January 2021 (during the third wave). We then investigated the incidence of frailty during a one-year follow-up period (during the pandemic). RESULTS: The total PA time during the first, second, and third waves of the pandemic decreased from the pre-pandemic PA time by 33.3%, 28.3%, and 40.0%, respectively. In particular, the total PA time of older adults who were living alone and socially inactive decreased significantly: 42.9% (first wave), 50.0% (second wave), and 61.9% (third wave) less than before the pandemic, respectively. Additionally, they were at a significantly higher risk of incident frailty than those who were not living alone and were socially active (adjusted odds ratio: 2.04 [95% confidence interval: 1.01-4.10]). CONCLUSION: Our findings suggest that older adults who live alone and are socially inactive are more likely to experience incident frailty/disability due to decreased PA during the pandemic. Understanding this mechanism may be crucial for maintaining the health status of older adults.

Association between Sarcopenia and Fall Risk According to the Muscle Mass Adjustment Method in Japanese Older Outpatients.

We investigated whether the association between sarcopenia and fall risk (FR) differs according to the muscle mass adjustment method in 357 outpatients who were not disabled in the activities of daily living or indicated for orthopedic surgery. Sarcopenia was diagnosed by the Asian Working Group for Sarcopenia (AWGS) 2019 criteria, using adjusting methods of muscle mass by height squared (ht2), body mass index (BMI), or any of these (i.e., ht2-adjusted Sarc", "BMI-adjusted Sarc", or "ht2 and/or BMI-adjusted Sarc, respectively). FR was defined by FR index ≥10. There were 111, 105, and 157 participants with ht2-adjusted, BMI-adjusted, and ht2 and/or BMI-adjusted Sarc, respectively. After multivariable adjustment, ht2 and/or BMI-adjusted Sarc was the most closely associated with FR [odds ratio and 95% confidence interval: 2.94, 1.75-4.93]. Our data suggest that the sarcopenia definition using low ASM/ht2 and/or ASM/BMI muscle mass might better predict adverse outcomes in older patients.

Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy.

BACKGROUND: The impact of molecular alterations on programmed death-ligand 1 (PD-L1) combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs. PATIENTS AND METHODS: Genomic alterations of 2518 GEAs were compared in three groups (PD-L1 CPS ≥ 10, high; CPS = 1-9, intermediate; CPS < 1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases. RESULTS: High, intermediate, and low CPSs were seen in 18%, 54% and 28% of GEAs, respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS-mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 13 months, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.19-0.7, P = 0.016] and a similar trend was observed in the MSS subgroup (P = 0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24-4.61, P = 0.016). CONCLUSIONS: This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and for the development of rational combination immunotherapies in GEAs.