FL118 Is a Potent Therapeutic Agent against Chronic Myeloid Leukemia Resistant to BCR-ABL Inhibitors through Targeting RNA Helicase DDX5.

Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious issue. We herein demonstrated that BCR-ABL induced the expression of the RNA helicase DDX5 in K562 cells derived from CML patients in a manner that was dependent on its kinase activity, which resulted in cell proliferation and survival. The knockout of DDX5 decreased the expression of BIRC5 (survivin) and activated caspase 3, leading to apoptosis in K562 cells. Similar results were obtained in cells treated with FL118, an inhibitor of DDX5 and a derivative compound of camptothecin (CPT). Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML.

[A framework for promoting and evaluating "Kayoi-no-ba" initiatives according to the Plan-Do-Check-Action cycle: The ACT-RECIPE framework].

Objective　In 2019, the Ministry of Health, Labour and Welfare emphasized the importance of promoting "Kayoi-no-ba" (or "places to go") initiatives according to the Plan-Do-Check-Action (PDCA) cycle. However, it proposed no specific promotion measures or standardized evaluation frameworks. This study is intended to propose a framework for local government officials to promote and evaluate "Kayoi-no-ba" initiatives according to the PDCA cycle.Methods　The working group (WG) conducted a narrative review of research and extracted evaluation models and indicators that could be used to create the framework. The co-researcher review committee discussed a draft framework prepared by the WG, and the WG revised it based on the discussion; this process was repeated four times. Using the completed framework, we calculated the score of the "Kayoi-no-ba" initiatives in 50 Tokyo municipalities and conducted regional correlation analyses on the relationship between the score of the "Kayoi-no-ba" initiatives in 50 Tokyo municipalities and the number of "Kayoi-no-ba" per 1,000 older persons.Results　The completed framework (named "ACT-RECIPE" by rearranging the underlined characters below) comprised the following six evaluation phases: (1) Comprehension: understanding the key lessons around disability and frailty prevention, and the necessity for "Kayoi-no-ba"; (2) Research and Planning: clarifying the current status of "Kayoi-no-ba," the strengths of the community, and the issues to be addressed through a community assessment, and developing a plan to resolve the issues; (3) Team Building and Collaboration: building a team by collaborating with organizations to solve problems; (4) Implementation: implementing the initiatives necessary to solve problems; (5) Evaluation: verifying changes in output and outcome indicators from the initiatives; and (6) Adjustment and Improvement: re-examining plans, teams, content, and goals based on the evaluation results. In these six phases, we designated 10 core items and accompanying subitems. The median score rate of the ACT-RECIPE framework in 50 municipalities was 75% for "Comprehension," 61% for "Research and Planning," 69% for "Team Building and Collaboration," 64% for "Implementation," 31% for "Evaluation," and 56% for "Adjustment and Improvement," and the mean ACT-RECIPE score rate was 57%. A significant positive correlation (rs=0.43, P=0.002) was observed between the ACT-RECIPE mean score rate and the number of "Kayoi-no-ba" per 1,000 older persons.Conclusion　We proposed the ACT-RECIPE as a framework for promoting and evaluating "Kayoi-no-ba" initiatives according to the PDCA cycle. We hope that this framework will lead to further progress in "Kayoi-no-ba" initiatives and facilitate evaluation of their effectiveness according to the PDCA cycle.

Let us move forward: Comment on "are generations a useful concept?"

Generational labels (e.g., Millennials and Baby Boomers) are widely used in daily life to represent the unique characteristics of groups of people. However, the existence of generational differences remains contentious. In their focal paper, Costanza et al. (2023) critically reviewed the literature on generational differences and proposed two future research directions: the social constructionist and lifespan development perspectives. In this commentary, we aimed to extend the proposed directions for future research on generational differences by integrating the two perspectives into one theoretical framework. Future research should investigate how proximal social relationships (e.g., intergenerational relations) and distal social norms (e.g., age norms) change over historical time and whether these historical changes shape individuals' development and aging. The theoretical framework that integrates the two proposed research directions may stimulate research on generational differences to progress beyond the concept of generations.

Universal health coverage in the context of population ageing: catastrophic health expenditure and unmet need for healthcare.

BACKGROUND: Universal health coverage means that all people can access essential health services without incurring financial hardship. Even in countries with good service coverage and financial protection, the progress towards universal health coverage may decelerate or be limited with respect to the growing older population. This study investigates the incidence/prevalence, determinants, and consequences of catastrophic health expenditure (CHE) and unmet need for healthcare and assesses the potential heterogeneity between younger (≤ 64 years) and older people (65 years≤). METHODS: Utilising an annual nationally representative survey of Japanese aged 20 years and over, we estimated the incidence of CHE and unmet need for healthcare using disaggregated estimates by household members' age (i.e. ≤64 years vs. 65 years≤) between 2004 and 2020. Using a fixed-effects model, we assessed the determinants of CHE and unmet need along with the consequences of CHE. We also assessed the heterogeneity by age. RESULTS: Households with older members were more likely to have their healthcare needs met but experienced CHE more so than households without older members. The financial consequences of CHE were heterogeneous by age, suggesting that households with older members responded to CHE by reducing food and social expenditures more so than households without older members reducing expenditure on education. Households without older members experienced an income decline in the year following the occurrence of CHE, while this was not found among households with older members. A U-shaped relationship was observed between age and the probability of experiencing unmet healthcare need. CONCLUSIONS: Households with older members are more likely to experience CHE with different financial consequences compared to those with younger members. Unmet need for healthcare is more common among younger and older members than among their middle-aged counterparts. Different types and levels of health and financial support need to be incorporated into national health systems and social protection policies to meet the unique needs of individuals and households.

Cohort differences in trajectories of life satisfaction among Japanese older adults.

Individual development and aging are shaped by historical changes in sociocultural contexts. Studies indicate that later-born cohorts experience improvements in well-being in the young-old. However, whether this historical trend holds in the old-old remains unknown. Using longitudinal data of Japanese older adults, we examined birth cohort differences in trajectories of well-being as measured by life satisfaction. Data were derived from a nationally representative study conducted from 1987 to 2012. We compared earlier- and later-born cohorts over 10 years in two age groups: the young-old (n = 1,195 per cohort; age 63-74; years of birth: 1913-1924 and 1925-1936) and the old-old (n = 436 per cohort; age 75-86; years of birth: 1901-1912 and 1913-1924). To control for covariates, we used case-matched cohorts based on age and sex. Growth curve models were employed to estimate age-related changes in life satisfaction by age group. At age 75 years, life satisfaction was higher in the later-born cohort than in the earlier-born cohort across age groups. Cohort differences in the rate of change in life satisfaction were absent among the young-old. Among the old-old, the later-born cohort showed steeper declines than the earlier-born cohort. Socioeconomic, social, and health resources did not fully explain the cohort differences in both age groups. Our results suggest that historical improvements in well-being in the young-old do not persist into the old-old. Societal advancements may enable later-born cohorts to survive with limited resources. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effects of adverse life events on mental health in single older adults in Japan.

BACKGROUND: This study tested a hypothesised model of the effects of adverse life events on the mental health of middle-aged and older adults living alone, as mediated by thought suppression and help-seeking behaviours, considering gender differences. METHODS: A questionnaire survey was conducted on a sample of 1202 (622 men; 580 women) individuals from 247445 residents aged 50-79 in District A of Tokyo. The questionnaire items covered parameters on adverse life events, help-seeking behaviour, thought suppression, and mental health status. RESULTS: Multiple group structural equation-modelling analysis revealed that the seriousness of adverse life events, help-seeking behaviours, and mental health scores were higher in women than in men. No significant gender differences were observed in thought suppression. The findings support all three proposed hypotheses: severe adverse life events will: (a) give rise to help-seeking behaviours, which will have a positive effect on mental health; (b) intensify thought suppression, which will harm mental health; and (c) inhibit help-seeking behaviour, especially in single middle-aged and older adult men. CONCLUSION: There is a need to develop interventional programs based on the theory of replacement thinking to encourage help-seeking behaviours in middle-aged and older adults.

The Impact of Generativity on Maintaining Higher-Level Functional Capacity of Older Adults: A Longitudinal Study in Japan.

Generativity is defined as an individual's concern for and actions dedicated toward the well-being of others, especially youth and subsequent generations. It is a key stage of psychological development from midlife to older age and can be a guiding concept for promoting engagement of older adults in productive and contributive activities, which benefit their well-being. This study examined the longitudinal association between generativity and higher-level functional capacity (HLFC) decline in older Japanese adults. The two-year longitudinal data of 879 older adults aged 65-84 years were analyzed. Participants' HLFC and generativity were assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence and the Revised Japanese version of the Generativity Scale, respectively. The binary logistic regression analysis results showed that a higher generativity score was negatively associated with HLFC decline, indicating that generativity effectively prevents HLFC decline over 2 years. On adding the interaction term between generativity and sex to examine whether the protective effect of generativity differed by sex, we found that generativity was especially effective in protecting the HLFC decline in men with higher generativity. The study results highlight the importance of promoting engagement of older adults in generative activities to maintain their HLFC.

Economic effects of healthy ageing: functional limitation, forgone wages, and medical and long-term care costs.

This study aims to estimate the potential economic benefits of healthy ageing by obtaining estimates of the economic losses generated by functional limitations among middle-aged and older people. Utilising two data sources retrieved from nationally representative samples of the Japanese people, we analysed the association between functional limitation and economic indicators, including labour market outcomes, savings, investment, consumption, and unpaid activities among individuals aged ≥ 60. Using the estimated parameters from our micro-econometric analyses and the official statistics by the Japanese government and a previous study, we calculated the financial costs that can be averted if healthy ageing is achieved as foregone wages and formal medical/long-term care costs incurred by functional limitations. Our micro-econometric analyses found that functional limitation was associated with a 3% point increase in retirement probability, with a stronger association among those aged 60-69. Moreover, functional limitation was linked with higher total health spending and less active involvement in domestic work. Foregone wages generated by functional limitation were estimated to be approximately USD 266.4 million, driven mainly by individuals in their 60s. Long-term care costs, rather than medical care costs, for older people aged ≥ 85 accounted for most of the additional costs, indicating that the estimated medical and long-term costs generated by functional limitations were approximately USD 72.7 billion. Health interventions can yield economic benefits by preventing exits from the labour market due to health issues and reducing medical and long-term care costs.

Living Alone and Depressive Symptoms Among Older Japanese: Do Urbanization and Time Period Matter?

OBJECTIVES: Previous research has suggested cross-national differences in the association between living alone and well-being among older adults. This study examined whether the association varied across social contexts within the country, Japan, in terms of varying degree of urbanization and differential time periods. METHODS: Data were obtained from a nine-wave nationwide longitudinal survey with a probability sample of Japanese adults aged 60 years and over. Respondents belonged to one of the three periods (around 1990, 2000, and 2015) according to the year they commenced participation. As many as 4,655 individuals from 575 municipalities provided 9,016 observation sets of two consecutive waves (t - 1 and t). Within a framework of the Hierarchical Generalized Linear Model, depressive symptoms at t were predicted based on changes in living arrangements from t - 1 to t and their cross-level interactions with gender, level of urbanization, and time period, controlling for various covariates at t - 1. RESULTS: In general, older adults living alone continuously as well as those who started living alone between the waves showed more depressive symptoms than those coresiding with someone continuously. However, this tendency was more prominent among rural residents than their urban counterparts, especially for men. Moreover, the effect of continuously living alone on depressive symptoms became smaller in Period 2015 than that in Period 1990, because of the increase in depressiveness in coresident older adults. DISCUSSION: Our findings indicate that living alone has a differential effect on older adults' well-being depending on the social context where residents' preferences for living arrangements and availability of formal services could vary.

The Retirement-Health Puzzle: A Sigh of Relief at Retirement?

OBJECTIVES: While the health effects of retirement have been well studied, existing findings remain inconclusive, and the mechanisms underlying the linkage between retirement and health are unclear. Thus, this study aimed to evaluate the effects of retirement on health and its potential mediators. METHODS: Using a national household survey conducted annually from 2004 to 2019 in Japan (the Japan Household Panel Survey), we evaluated the effects of retirement among Japanese men aged 50 or older on their health, in addition to other outcomes that could be attributed to health changes associated with retirement (i.e., health behaviors, psychological well-being, time use for unpaid activities, and leisure activities). As outcomes are not measured every year, we analyzed 5,794-10,682 person-year observations for 975-1,469 unique individuals. To address the potential endogeneity of retirement, we adopted an instrumental variable fixed-effects approach based on policy changes in eligibility ages for employee pensions. RESULTS: We found that retirement improved psychological well-being, exercise habits, and time spent on unpaid work. The psychological benefits of retirement were no longer observed for longer durations after retirement, whereas healthy habits and unpaid activities continued. Moreover, health-related improvements after retirement occurred mostly in the higher-income group. DISCUSSION: Enhancement in personal quality of life owing to increased leisure time and stress reduction from work in addition to lifestyle changes may be key to understanding the health benefits of retirement. Considering the mechanisms behind retirement-health relationships and potential heterogeneous effects is essential for healthy postretirement lives when increasing the retirement age.

Psychological Factors That Suppress Help-Seeking among Middle-Aged and Older Adults Living Alone.

Help-seeking among destitute adults has not been adequately investigated. Therefore, this study clarifies the mechanisms that suppress help-seeking in middle-aged and older adults living alone. Data were collected from 1274 individuals (aged 50-79 years) who were living alone, using a survey that measured future time perspective, barriers to help-seeking, help-seeking intentions, and current and childhood economic statuses. Men living alone experienced lower help-seeking intention than women, were more likely to try to solve problems by themselves, and experienced greater distrust in others. No sex differences were observed in "future anxiety" and "resignation to the future." Poor economic status was associated with high "resignation to the future," "future anxiety," and "distrust of others" for both sexes. "Resignation to the future" was particularly higher among men with a poorer current economic status, which suppressed help-seeking. Abandoning hope for the future, which is characteristic of middle-aged and older men living alone, may inhibit help-seeking behavior.

Effects of intergenerational contact on social capital in community-dwelling adults aged 25-84 years: a non-randomized community-based intervention.

BACKGROUND: Accumulating social capital in urban areas is essential to improve community health. Previous studies suggested that intergenerational contact may be effective for enhancing social capital. However, no study has examined the effect of intergenerational contact on social capital through a population-based evaluation. This study aimed to investigate the effects of a community-based intervention to increase the frequency of intergenerational contact on social capital among adults aged 25-84 years. METHODS: This study used a non-randomized controlled trial design to conduct a community-based intervention (from March 2016 to March 2019). The study area was Tama ward, Kawasaki city, Kanagawa, Japan. The area comprises five districts; one district was assigned as the intervention group and the other four districts as the control group. We provided the intervention to residents in the intervention group. The intervention comprised three phases: Phase 1 was the preparation term (organizing the project committee); Phase 2 was the implementation term (trained volunteer staff members, conducted the intergenerational greeting campaign, and held intergenerational contact events); and Phase 3 was the transition term (surrendering the lead role of the project to the city hall field workers). In the control group, field workers provided public health services as usual. We conducted mail surveys in September 2016 and November 2018 to assess the effects of the intervention on social capital during Phase 2. Eligible participants were randomly selected from community-dwelling adults aged 25-84 years according to age (10,620 control group individuals and 4479 intervention group individuals). We evaluated social trust, norm of reciprocity, and social support as outcome variables. RESULTS: In total, 2518 participants completed both surveys and were analyzed (control group: 1727; intervention group: 791). We found that social trust (coefficient = 0.065; 95% confidence interval [CI]: 0.006, 0.125) and norm of reciprocity (coefficient = 0.084; 95% CI: 0.020, 0.149) positively changed in the intervention group compared with the control group. CONCLUSIONS: This community-based intervention may contribute to sustaining and improving social capital among community-dwelling adults. TRIAL REGISTRATION: UMIN000046769 (UMIN-CTR); first registered on January 28, 2022 (retrospectively registered).

[Diversity of participants and autonomy of community residents by types of "Kayoi-no-ba": findings from a survey of urban voluntary groups in which older adults participate].

Objectives　A recent long-term care insurance policy encourages the promotion of various types of "Kayoi-no-ba," or places to go, not limited to those focusing on functional training, as resident activities are expected to keep older adults from needing care. In this study, Kayoi-no-ba were voluntary groups in which older adults participated, and their attributes were examined in terms of "diversity of participants" and "autonomy of community residents," based on the type of group.Methods　The staff from the preventing long-term care division in each of the 38 municipalities in Tokyo selected 175 voluntary groups that met three criteria: (1) more than three community residents participate in activities at least once a month, (2) participants are primarily older adults or multi-generational residents including older adults, and (3) community residents participate in group management. Representatives from 165 groups responded to the questionnaire. For the group categorization, a latent class analysis was performed using the goals and activities of the group. Participants' age, gender, and health status were used to assess diversity. The number of residents who managed and/or supported group activities and the precise role the residents played in the activities were used to assess autonomy.Results　The groups were categorized into four types: "Physical Exercises," where the primary activity was physical exercise; "Multi-purpose," which included various purposes and activities; "Social Interaction Oriented," where interaction with others was the goal, but physical exercise was not; and "Non-Interaction," where social interaction was not the goal. Participants in the Multi-purpose group ranged in age and were more likely to have health problems, such as mobility limitations, dementia, and frailty, than those in the Physical Exercises and Social Interaction Oriented groups. Moreover, the Multi-purpose group had more resident managers and supporters involved in various roles.Conclusion　The Multi-purpose group had the most diverse participants and autonomy of residents. However, the type of Kayoi-no-ba should not be considered fixed. The support system should encourage flexible changes such as adding a new activity depending on the situation and the varying needs of the residents.

Influence of "Face-to-Face Contact" and "Non-Face-to-Face Contact" on the Subsequent Decline in Self-Rated Health and Mental Health Status of Young, Middle-Aged, and Older Japanese Adults: A Two-Year Prospective Study.

This study aims to identify the independent influence of face-to-face contact (FFC) and non-face-to-face contact (NFFC) on the subsequent decline in self-rated health and mental health status by age. A total of 12,000 participants were randomly selected among residents in the study area, and 1751 of them responded to both the 2016 and 2018 mail surveys. The participants were subsequently classified into three age groups (25-49: Young adults; 50-64: Mid-aged adults; and 65-84: Older adults). Social contact was assessed by computing the frequencies of FFC and NFFC. Multiple logistic regression analysis showed the risk of social contact on the decline in self-rated health and World Health Organization-Five Well-Being Index. Both FFC and NFFC were significantly associated with maintaining mental health; however, the impacts of FFC on mental health were more significant than that of NFFC among older adults and young adults. Compared with the no contact group, FFC was significantly associated with maintaining self-rated health in mid-aged adults. The influence of FFC and NFFC on health differed by age group.

Retirement and Social Activities in Japan: Does Age Moderate the Association?

Although retirement age is increasing in aging societies, its impact on individuals and communities is unclear. This study examined how age moderates the linkage between transition into retirement and participation in productive and non-productive social activities after retirement, using a nationwide longitudinal survey with a probability sample of Japanese aged 60 and over (n = 3,493). Multinomial logistic regression analyses were performed to predict changes in volunteering and hobbies/learning during 3-5 years of follow-up and their participation level at the follow-up. The significant interactions between change in work status (remained working as reference, full/partial retirement, remained not-working) and age at baseline showed that fully retired persons were more likely to increase these activities than remained workers only when they retired by their early seventies. Thus it is important to encourage engagement in social activities before retirement and remove psychological and environmental barriers that hinder starting new activities at old age.

Age trajectories of disability development after 65: A comparison between Japan and Taiwan.

INTRODUCTION: Disability development using age as the axis was void in the literature. Identification of the age trajectory of disability development across populations enables preparation for aging-related policies when conducting cross-national comparisons. This study compared three indicators of the development of physical disability in populations of Taiwan and Japan. METHODS: Data comprised two nationally representative panel surveys (1) the Taiwan Longitudinal Study on Aging (N = 3,037) in 1996-2011 and (2) the National Survey of the Japanese Elderly in 1996-2012 (N = 1,974). Older adults (65+) were examined longitudinally. Activities of daily living (ADL), instrumental activities of daily living (IADL), and mobility disability development during aging were analyzed using multilevel models. RESULTS: After age standardization, Japan reported higher prevalence rate of ADL disability (14.95% vs. 9.65%) but lower IADL (19.30% vs. 30.36%) and mobility disability (36.07% vs. 49.82%) as compared with Taiwan. ADL limitation occur (ADL limitation>=1) at the age of 77.9 and 77.2 for populations in Japan and Taiwan, respectively. Populations reached three ADL limitations at the age of 86.7 and 85.0 in Japan and in Taiwan, respectively. IADL limitation occur (IADL limitation>=1) at the age of 79.1 and 74.5 for populations in Japan and Taiwan, respectively. Mobility limitation occur (Mobility limitation>=1) at the age of 70.7 and 65.3 for populations in Japan and Taiwan, respectively. CONCLUSIONS: Older adults generally do not report ADL limitation until 77 and do not face serious disability until 85 or 86 in Taiwan or Japan, respectively. Mobility limitation occurs at a various age in different countries.

Short-, Medium-, and Long-term Weight Changes and All-Cause Mortality in Old Age: Findings From the National Survey of the Japanese Elderly.

BACKGROUND: Recent studies, predominantly in Western populations, suggest that both weight loss and weight gain are associated with an increased mortality risk in old age. However, evidence of this association in older Asian populations remains sparse. This study aimed to examine the association between weight change and all-cause mortality in a nationally representative sample of community-dwelling older Japanese people. METHODS: Data were obtained from the National Survey of the Japanese Elderly, which included 4869 adults aged ≥60 years. Participants were followed for up to 30 years. We considered 3 indicators of weight change according to the follow-up interval: short-term (3 years), medium-term (6-7 years), and long-term (12-13 years). Weight change was classified as loss ≥ 5%, loss 2.5%-4.9%, stable (±2.4%), gain 2.5%-4.9%, and gain ≥ 5%. Cox proportional hazards models were used to calculate the relative mortality risk of each weight change category. RESULTS: Weight loss ≥ 5% for all intervals was associated with higher mortality than stable weight and the effects were largely similar across all 3 intervals (hazard ratio [95% confidence interval]: 1.36 [1.22-1.51] for short-term, 1.36 [1.22-1.51] for medium-term, and 1.31 [1.11-1.54] for long-term). A similar pattern of results was observed among the young-old and old-old, and among men and women. The effect of weight loss on higher mortality was greater among those with a lower body mass index at baseline. CONCLUSIONS: These findings could inform clinical and public health approaches to body-weight management aimed at improving the health and survival of older adults, particularly in Asian populations.

Decomposition of gender differences in cognitive functioning: National Survey of the Japanese elderly.

BACKGROUND: It is well known that females generally live longer than males, but women tend to suffer from more illnesses and limitations than men do, also for dementia. However, limited empirical evidence is available why this 'male-female health-survival paradox' is observed. This study aimed to investigate factors which account for gender differences in health, particularly cognitive functioning and decline among older adults. METHODS: Data were retrieved from the National Survey of the Japanese Elderly, which is a longitudinal survey of a nationwide representative sample of Japanese adults aged 60 or over. Gender differences in cognitive functioning and decline in three-year follow-ups were decomposed using Blinder-Oaxaca decomposition analysis, regarding demographic, socioeconomic, and health-related factors into the 'explained' component, by differences in individual attributes listed above, and the 'unexplained' component. RESULTS: Empirical analyses showed that women's lower cognitive functioning was partly explained by the endowment effect. Moreover, a shorter duration of formal education and a larger proportion with their longest occupation being domestic worker accounted for steeper cognitive decline and more prevalent mild cognitive impairment in women than in men. CONCLUSION: This empirical study suggested that gender differences in cognitive functioning and decline account for different individual attributes of social determinants among men and women. Particularly, men seem to be more engaged in activities which accumulate intellectual experiences through education and occupation, as suggested by the cognitive reserve hypothesis.