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Abstract Background Multimorbidity increases with age, leading to various adverse outcomes, including higher mortality, care dependency, hospitalizations, and healthcare costs. Polydoctoring, managing a patient with multimorbidity by multiple healthcare providers, can be a risk of fragmented care and increased healthcare expenditures. This study aims to identify patient‐related factors contributing to polydoctoring in older adults with multimorbidity. Methods This study is a cross‐sectional study using baseline data from the Kawasaki Aging and Wellbeing Project. Participants were residents of Kawasaki City aged 85–89 years, without disability in basic activities of daily living, and being able to visit study site. The regularly visited facilities (RVF) index was employed to quantify polydoctoring. Polydoctoring was defined as having two or more RVFs. Poisson regression analysis was conducted to assess the association between polydoctoring and patient demographics, including types of chronic conditions and socioeconomic factors. Results A total of, 968 participants with multimorbidity were analyzed. Increased RVF was significantly associated with eye diseases (rate ratio [RR] 1.27, 95% confidence interval [CI] 1.12–1.44), osteoporosis (RR 1.22, 95% CI 1.08–1.38), prostate diseases (RR 1.22, 95% CI 1.07–1.40), and osteoarthritis (RR 1.16, 95% CI 1.05–1.27). No significant correlation was found with educational status or financial hardship. Conclusion The study indicated that certain chronic conditions are linked to increased polydoctoring among multimorbid older adults in Japan. However, most of those conditions are considered to be within a scope of family medicine/general practice. Training general practitioners to manage these conditions could reduce healthcare costs and the treatment burden, indicating a direction for future healthcare policy and medical education.

Abstract Background The relationship between inflammatory response, fish consumption, and mortality risk in older individuals is unclear. We investigated whether C-reactive protein (CRP) levels ≥ 0.1 mg/dL, fish intake, and inflammatory responses are associated with all-cause mortality risk in older adults. Methods This prospective cohort study included older adults aged 85–89 years from the Kawasaki Aging and Wellbeing Project, who did not require daily care. Cohort was recruited from March 2017 to December 2018 (follow-up ended on December 31, 2021). Dietary assessment was conducted using the Brief Self-Administered Diet History Questionnaire. Multivariate Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality in the CRP ≥ 0.1 mg/dL group; the CRP

Abstract Background A decline in cognitive function is associated with inflammatory processes. However, the association between high-sensitivity C-reactive protein (hs-CRP) levels and cognitive decline in the Japanese population remains inconclusive. Thus, this study aimed to determine whether hs-CRP is associated with low cognitive function in 70- and 80-year-old community-dwelling Japanese individuals. Methods The participants in this cross-sectional study were 872 Japanese residents aged 70 and 80 years who voluntarily participated in the Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC) study between 2010 and 2011. Blood sample collection, cognitive assessment, and other measurements were performed at the venue. Low cognitive function was defined as a score of 25 points or lower on the Japanese version of the Montreal Cognitive Assessment. The odds ratio (OR) and 95% confidence interval (95% CI) for each hs-CRP quartile were calculated using logistic regression analysis. Results A total of 288 (69.9%) parsons in the 70-year-old group and 372 (80.9%) in the 80-year-old group exhibited low cognitive function. The association between hs-CRP levels and low cognitive function was significant among 70- and 80-year-old Japanese community-dwelling adults. In particular, the fourth quartile of hs-CRP (0.727–7.420 mg/L) in the 70-year-old group and the second and fourth quartiles (0.214–0.404 and 0.911–9.890 mg/L) in the 80-year-old group were associated with low cognitive function. Furthermore, the third quartile (0.409–0.892 mg/L) in the 80-year-old group was closely associated with low cognitive function. Conclusions High hs-CRP levels were associated with lower cognitive function in 70- and 80-year-old Japanese community-dwelling individuals, suggesting that high hs-CRP levels may influence cognitive function.

Abstract Background A new diagnostic criterion for malnutrition, the Global Leadership Initiative on Malnutrition (GLIM) criteria, has been proposed. Despite a recognized link between malnutrition and oral health, further clarification is needed regarding this association when using the GLIM criteria. This study examined the association between malnutrition and oral health in community-dwelling older adults aged ≥ 85. Methods This study was conducted using data from the Tokyo Oldest Old Survey on Total Health study, and altogether 519 participants ≥ 85 years were enrolled. Malnutrition was assessed using the GLIM criteria. Oral health information, on the number of teeth, maximum occlusal force (MOF), saliva production, denture-related questions (dissatisfaction and frequency of use), dental visit history in the past year, whether participants enjoyed meals, and oral-related quality of life was assessed using the Geriatric Oral Health Assessment Index (GOHAI) were collected. MOF was assessed the average values of three measurements and lower tertile by sex as decline in MOF. For GOHAI, the score for each items (Q1-Q12) was also evaluated, and further, the decline in each item (score: 1–2 points on a 5-point scale) was assessed as a “problem with each items.” Oral health factors differing between those with and without malnutrition were analyzed. For differing items, malnutrition risk was evaluated using Cox regression. Results Eighty-nine (17.1%) participants experienced malnutrition. Significant differences were observed in the decline in MOF, enjoyment of meals, individual scores for Q2, Q4, and Q6, and the problem with Q3, Q6, Q7, and Q11. Cox regression analysis showed that decline in MOF (odds ratio [OR]: 1.728, 95% confidence interval [CI]: 1.010–2.959), enjoyment of meals (OR: 0.502, 95% CI: 0.289–0.873), problem with Q3 (OR: 5.474, 95% CI: 1.301–23.028), Q6 (OR: 5.325, 95% CI: 1.026–27.636), and Q7 (OR: 2.867, 95% CI: 1.397–5.882) were associated with ORs of malnutrition. Conclusion Decline in MOF, enjoyment of meals, swallowing problem (problem with Q3), limit contact due to oral condition (problem with Q6), and esthetics problem (problem with Q7) were associated with malnutrition as assessed using the GLIM criteria.

Background: Polydoctoring can increase the risk of care fragmentation among patients with multimorbidity, but its impact on health outcomes remains unclear. Aim: To determine the effects of polydoctoring, as measured by the regularly visited facilities (RVF) indicator, on patient outcomes among older individuals with multimorbidity. Design & setting: Data from the ongoing prospective cohort study, Kawasaki Aging and Wellbeing Project (KAWP), was utilised in this study. Among the 1026 KAWP participants aged 85–89 years, those with two or more chronic conditions were enrolled in this study. Method: Care fragmentation and polydoctoring was evaluated using the RVF, which is a new indicator that measures the number of medical facilities consistently involved in a patient’s care. Based on RVF, mortality was analysed using the Cox proportional hazards model, with adjustments for age, sex, frailty, and number of comorbidities. Results: A significant reduction in mortality rates was observed in participants with an RVF of ≥3 and 2–4 comorbidities (hazard ratio [HR] 0.43, 95% confidence interval [CI] = 0.18 to 0.99, P value = 0.048). However, no significant difference in mortality based on RVF was observed for those with ≥5 comorbidities. Notably, individuals with ≥5 comorbidities and an RVF of 0 had a significantly higher HR for death (HR 2.68, 95% CI = 1.05 to 6.84, P value = 0.039). Conclusion: In older patients with multimorbidity, polydoctoring may reduce mortality in patients with ≤4 coexisting conditions, but it does not significantly impact mortality in those with ≥5 conditions. These findings provide insights for healthcare decision making in managing older patients with multimorbidity.

Background: Physical performance is a major contributor to frailty and sarcopenia. Healthier behaviour (diet and physical activity (PA)) are important, but the applicability of the evidence should be carefully discussed in the general older population and the population aged 85 years and older (85+ population). Evidence in the 85+ population is rare and there are no studies focusing on the healthier behaviours. Methods: Data (n = 519) from the Tokyo Oldest Old survey on Total Health study were used. From each validated questionnaire in this age group, the dietary patterns (DPs) was identified, and the PA was estimated. Physical performance tests included grip strength, timed up-and-go test, and chair standing, which are important for assessing frailty or sarcopenia. Linear regression models were used to examine the relationship between the combination of DP and PA to physical performance. Results: DPs identified `Various plant foods' (DP1), `Fish and mushrooms' (DP2), and `Cooked rice and miso soup' (DP3) were identified. The median PAI was 9.0 METs × h/week. Based on the characteristics of the combination of DP and PA with unhealthy behaviour as the reference group, all combinations were significantly associated with all physical performance tests if both achieved. However, it was observed that some combinations were not significantly associated with DP or PA alone. Conclusions: Healthy behaviours (both diet and PA) are important for physical performance in the 85+ population. The association of PA in the 85+ population may vary depending on the dietary status of the individual.

Abstract Background Care fragmentation, characterized by the uncoordinated involvement of multiple healthcare providers, leads to inefficient and ineffective healthcare, posing a significant challenge in managing patients with multimorbidity. In this context, “polydoctoring,” where patients see multiple specialists, emerges as a crucial aspect of care fragmentation. This study seeks to develop an indicator to assess polydoctoring, which can subsequently enhance the management of multimorbidity. Methods Baseline survey data from the Kawasaki Aging and Wellbeing Project (KAWP) involving independent community‐dwelling older adults aged 85–89 were utilized in this cross‐sectional study. Polydoctoring measure was defined as the number of regularly visited facilities (RVFs). The association of RVF with the Fragmentation of Care Index (FCI) and the outcome measures of polypharmacy and ambulatory care costs were examined as indicators of care fragmentation. Results The analysis comprised 968 participants, with an average of 4.70 comorbid chronic conditions; 65.3% of the participants had two or more RVFs, indicating polydoctoring. A significant correlation between RVF and FCI was observed. Modified Poisson regression analyses revealed associations between higher RVF and increased prevalence ratio of polypharmacy. Likewise, a higher RVF was associated with higher outpatient medical costs. Conclusions RVF was significantly correlated with FCI, polypharmacy, and higher outpatient medical costs. Unlike complex indices, RVF is simple and intuitively comprehensible. Further research is needed to evaluate the impact of care fragmentation on patient outcomes, considering factors such as RVF thresholds, patient multimorbidity, and social support. Understanding the influence of polydoctoring can enhance care quality and efficiency for patients with multimorbidity.

Abstract Background Increased protein intake has been recommended to prevent sarcopenia/frailty, reports on the quantity and quality of protein intake needed and the associated prognosis, particularly in the aging population of Asia, are limited. In this study, we aimed to investigate the relationship between protein intake and mortality in Japanese individuals, aged 85 years and older. Methods The data were obtained from The Kawasaki Aging and Wellbeing Project, which is a prospective cohort study of older adults aged between 85 and 89 years with no physical disability at baseline. Of the 1,026 adults in the cohort, 833 were included in the analysis, after excluding those who had not completed a brief, self-administered diet history questionnaire or those who scored less than 24 on the Mini-Mental State Examination. The participants were grouped into quartiles based on protein intake: Q1 (protein

Abstract Objectives: As the world’s population is ageing, improving the physical performance (PP) of the older population is becoming important. Although diets are fundamental to maintaining and improving PP, few studies have addressed the role of these factors in adults aged ≥ 85 years, and none have been conducted in Asia. This study aimed to determine the dietary patterns (DP) and examine their relationship with PP in this population. Design: This cross-sectional study (Kawasaki Aging and Wellbeing Project) estimated food consumption using a brief-type self-administered diet history questionnaire. The results were adjusted for energy after aggregating into thirty-three groups, excluding possible over- or underestimation. Principal component analysis was used to identify DP, and outcomes included hand grip strength (HGS), timed up-and-go test, and usual walking speed. Setting: This study was set throughout several hospitals in Kawasaki city. Participants: In total, 1026 community-dwelling older adults (85–89 years) were enrolled. Results: Data of 1000 participants (median age: 86·9 years, men: 49·9 %) were included in the analysis. Three major DP (DP1: various foods, DP2: red meats and coffee, DP3: bread and processed meats) were identified. The results of multiple regression analysis showed that the trend of DP2 was negatively associated with HGS (B, 95 % CI –0·35, –0·64, –0·06). Conclusions: This study suggests a negative association between HGS and DP characterised by red meats and coffee in older adults aged ≥ 85 years in Japan.

Abstract Background Factors associated with weight loss in community-dwelling older people have been reported in several studies, but few studies have examined factors associated with weight loss by age groups. The purpose of this study was to clarify factors associated with weight loss by age in community-dwelling older people through a longitudinal study. Methods Participants in the SONIC study (Longitudinal Epidemiological Study of the Elderly) were community-dwelling people aged 70 or older. The participants were divided into two groups: 5% weight loss and maintenance groups, and compared. In addition, we examined factors affecting weight loss by age. The analysis method used was the χ2 test, and the t-test was used for comparison of the two groups. Factors associated with 5% weight loss at 3 years were examined using logistic regression analysis with sex, age, married couple, cognitive function, grip strength, and the serum albumin level as explanatory variables. Results Of the 1157 subjects, the proportions showing 5% weight loss after 3 years among all subjects, those aged 70 years, 80 years, and 90 years, were 20.5, 13.8, 26.8, and 30.5%, respectively. In logistic regression analysis, factors associated with 5% weight loss at 3 years by age were influenced by BMI of 25 or higher (OR = 1.90, 95%CI = 1.08–3.34, p = 0.026), a married couple (OR = 0.49, 95% = 0.28–0.86, p = 0.013), serum albumin level below 3.8 g/dL (OR = 10.75, 95% = 1.90–60.73, p = 0.007) at age 70, and the grip strength at age 90 (OR = 1.24, 95%CI = 1.02–1.51, p = 0.034), respectively. Conclusions The results suggest that factors associated with weight loss by age in community-dwelling older people through a longitudinal study differ by age. In the future, this study will be useful to propose effective interventions to prevent factors associated with weight loss by age in community-dwelling older people.

Objective: We aimed to determine whether the association of sleep status with frailty differs between age groups of older adults. Method: This cross-sectional study was part of the observational Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC) study. Subjects were community-dwelling older adults in their 70s and 80s. Frailty was evaluated using the Japanese version of the Cardiovascular Health Study criteria (J-CHS). Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep status. Poor sleep quality was defined as a PSQI global score ≥6. Sleep duration was categorized as short (8). We performed multivariable logistic regression to investigate the association between sleep status and frailty separately for each age group adjusted for multiple covariates. Results: In those in their 70s, long sleep duration and sleep medication use were independently associated with frailty. In those in their 80s, poor sleep quality was independently associated with frailty. Conclusions: The association between sleep status and frailty was different between age groups. The findings underscore the importance of incorporating the evaluation of sleep quantity and non-pharmacological therapies in those in their 70s and the evaluation of sleep quality in those in their 80s to help prevent the onset of frailty.

Background: High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60–70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85–89 years of age) and centenarians. Methods: The study included 812 (women: 84.4%) for centenarians and 1498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole-genome sequencing or DNA microarray-imputation methods. Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression. Results: The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p=2.21 × 10-22) and ADIPOQ (p=5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low-level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI. Conclusions: cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old. Funding: This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program "Tonomachi Research Complex" Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology

Abstract Background The oldest old, defined as those aged 90 or over, is now the fastest-growing population sector. This study aimed to determine reference values for several physical performance measures (PPMs) among 90-year-olds using internationally standardized measurements and to clarify the characteristics of these indices by comparing their results for 90-year-olds with those for older people 70 and 80. Methods We used the Septuagenarians, Octogenarians, and Nonagenarians Investigation with Centenarians (SONIC) study data from 2010 to 2018. The study subjects were 70, 80, and 90-year-olds in the target area eligible to participate in the venue. Excluding those certified for long-term care, the final number of eligible persons is 70s cohort 1000 (2010), 80s cohort 973 (2011), and 90s cohort 690. 90s cohort only consisted of three survey waves: 2012, 2015, and 2018. We used hand grip strength and score on the Short Physical Performance Battery (SPPB) for our physical performance measurements. In addition, we statistically analyzed sex and age differences. Result The simple mean ± standard deviation (SD) for the 90-year-old respondents were in men, 24.1 ± 5.4 kg in hand grip strength, 0.80 ± 0.22 m/s in usual gait speed, 17.2 ± 6.73 s in 5times chair stand, 5.89 ± 4.42 s in tandem balance, and 8.3 ± 2.2 in SPPB respectively and in women, 14.4 ± 4.0 kg in hand grip strength, 0.72 ± 0.20 m/s in usual gait speed, 17.8 ± 7.89 s in 5times chair stand, 4.72 ± 4.35 s in tandem balance, and 7.5 ± 2.4 in SPPB, respectively. For all PPMs, the age 90 cohort was statistically significantly different from the age 70 and 80 cohorts (all trends P

Sarcopenia is one of the primary risk factors for various adverse health events in later life. However, its pathophysiology in the very old population remains unclear. Hence, this study aimed to examine whether plasma free amino acids (PFAAs) correlate with major sarcopenic phenotypes (i.e., muscle mass, muscle strength, and physical performance) in community-dwelling adults aged 85–89 years living in Japan. Cross-sectional data from the Kawasaki Aging Well-being Project were used. We included 133 adults aged 85–89 years. In this study, fasting blood was collected to measure 20 plasma PFAAs. Measures for the three major sarcopenic phenotypes included appendicular lean mass assessed by multifrequency bioimpedance, isometric handgrip strength, and gait speed from a 5 m walk at a usual pace. Furthermore, we used phenotype–specific elastic net regression models adjusted for age centered at 85 years, sex, body mass index, education level, smoking status, and drinking habit to identify significant PFAAs for each sarcopenic phenotype. Higher histidine and lower alanine levels were associated with poor gait speed, but no PFAAs correlated with muscle strength or mass. In conclusion, PFAAs such as plasma histidine and alanine are novel blood biomarkers associated with physical performance in community-dwelling adults aged 85 years or older.

Abstract Background Polypharmacy is a serious concern among older adults and is frequently related to adverse outcomes, including health problems, reduced quality of life, and increased medical expenses. Although personality traits are associated with health behaviors and diseases, the effect of polypharmacy on personality traits is unclear. Therefore, we examined the association of personality traits with polypharmacy among community-dwelling older adults. Methods This cross-sectional study analysed data on 836 community-dwelling older adults aged 69–71 years who participated in the Japanese longitudinal cohort study of Septuagenarians, Octogenarians, and Nonagenarians Investigation with Centenarians. Polypharmacy was defined as the intake of ≥ 5 medications concurrently. Personality traits were assessed using the Japanese version of the NEO-Five-Factor Inventory (NEO-FFI). A five-factor model of personality traits, including “neuroticism,” “extraversion,” “openness,” “agreeableness,” and “conscientiousness,” was measured by the NEO-FFI. Results The average number of medications was about 3 in both men and women. Among the participants, polypharmacy was observed in 23.9% of men and 28.0% of women. Multivariable logistic regression analysis showed that neuroticism (adjusted odds ratio [aOR] per 1 point increase = 1.078, 95% confidence interval [CI] = 1.015–1.144) in men and extraversion (aOR = 0.932, 95% CI = 0.884–0.983) in women were associated with polypharmacy. Conclusions Higher neuroticism in men and lower extraversion in women were associated with polypharmacy. This study suggests that personality traits may be involved in the process leading to the development of polypharmacy. Information on individual personality traits may help medical professionals in decision-making regarding medication management for lifestyle-related diseases.

Abstract Background The relationship between moderate alcohol drinking or other alcohol drinking patterns such as frequency, beverage type, and situation of drinking and cognitive function is not sufficiently clear in older people. The purpose of this study was to investigate the association between alcohol drinking patterns and cognitive function in community-dwelling Japanese people aged 75 and over. Methods This study was a cross-sectional design based on a prospective cohort study called the SONIC study. Subjects were older people aged 75-77 or 85-87 who voluntarily participated in 2016-2017. Drinking information was collected for daily drinking frequency, daily drinking intake, beverage type, and non-daily drinking opportunity. Cognitive function was measured using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Other potential confounding factors evaluated were age, sex, medical factors, and psychosocial factors. An analysis of covariance was performed to evaluate the MoCA-J score relative to drinking frequency or alcohol intake. Multiple regression analysis was performed to investigate the association between beverage type or non-daily drinking opportunity and the MoCA-J score. Results The final number of participants analyzed was 1,226. The MoCA-J score for participants who reported drinking alcohol 1–6 days/week was significantly higher than that for those who reported drinking none or every day. No significant difference in the MoCA-J score was observed relative to daily alcohol intake. In terms of beverage type, wine was associated positively with the MoCA-J score. Non-daily drinking opportunity was also associated positively with the MoCA-J score. Conclusions Moderate-frequency drinking, wine consumption, and non-daily drinking opportunities were associated with higher cognitive function in community-dwelling Japanese aged 75 and over. Further longitudinal studies are needed to clarify the causal relationships.

This study aimed to evaluate cognitively stimulating environments throughout life and to examine direct and indirect associations between these environments and late-life cognition. Early-life education, three domains of work complexity (data, people, and things) based on the longest-held occupation, and engagement in late-life leisure activities (LAs) were assessed. A structural equation model was developed using cross-sectional data of 1721 Japanese older adults in 70 ± 1 and 80 ± 1 years. The model confirmed significant direct effects of work complexity with data and late-life LAs on late-life cognitive performance. The associations of education and work complexity with late-life cognition were mediated through the subsequent environment(s). However, the total effects of work complexity with people and things on late-life cognition were insignificant. The findings suggest that cognitively stimulating activities in adulthood and beyond may lead to individual differences in late-life global cognition. In addition, antecedent complex environments might make subsequent life environments more cognitively stimulating. The results are discussed from the perspectives of cognitive plasticity and environmental complexity.

Abstract Background and objectives Nutritional deficiencies, renal impairment and chronic inflammation are commonly mentioned determinants of anaemia. The aim of this study was to investigate the effects of these determinants, singly and in combination, on anaemia in the very old. Method The TULIPS Consortium consists of four population-based studies in oldest-old individuals: Leiden 85-plus Study, LiLACS NZ, Newcastle 85+ study, and TOOTH. Five selected determinants (iron, vitamin B12, and folate deficiency; low estimated glomerular filtration rate (eGFR); and high C-reactive protein (CRP)) were summed. This sum score was used to investigate the association with the presence and onset of anaemia (WHO definition). The individual study results were pooled using random-effects models. Results In the 2216 participants (59% female, 30% anaemia) at baseline, iron deficiency, low eGFR and high CRP were individually associated with the presence of anaemia. Low eGFR and high CRP were individually associated with the onset of anaemia. In the cross-sectional analyses, an increase per additional determinant (adjusted OR 2.10 (95% CI 1.85–2.38)) and a combination of ≥2 determinants (OR 3.44 (95% CI 2.70–4.38)) were associated with the presence of anaemia. In the prospective analyses, an increase per additional determinant (adjusted HR 1.46 (95% CI 1.24–1.71)) and the presence of ≥2 determinants (HR 1.95 (95% CI 1.40–2.71)) were associated with the onset of anaemia. Conclusion Very old adults with a combination of determinants of anaemia have a higher risk of having, and of developing, anaemia. Further research is recommended to explore causality and clinical relevance.

Abstract Superoxide dismutase 3 (SOD3), an antioxidant enzyme, is known as extracellular SOD (EC-SOD) because it is the predominant form in extracellular fluids. The diversity of plasma EC-SOD concentration is associated with the SOD3 p.R231G missense variant genotype. To clarify the association among SOD3 genotype, plasma EC-SOD concentration, and comorbidity in Oldest Old, we analyzed genome-wide associations with plasma EC-SOD concentration and associations between EC-SOD concentration and medical history classified by the SOD3 genotype in the Very Old (85–99 years old, n = 505) and Centenarians (over 100 years old, n = 595). The results revealed that SOD3 p.R231G was the most significant variant associated with plasma EC-SOD concentration. Although no significant difference was observed in medical histories between the SOD3 p.R231G variant non-carriers and carriers, higher EC-SOD concentration in plasma of SOD3 p.R231G variant non-carriers was associated with a high odds ratio for chronic kidney disease (OR = 2.70, 95% CI = 1.98–3.72) and low odds ratio for diabetes mellitus (DM) (OR = 0.61, 95% CI = 0.39–0.95). Comparison with 11 plasma biomarkers for age-related disease showed that plasma EC-SOD concentration correlated with adiponectin and estimated glomerular filtration rate with creatinine correction; therefore, we deduced that EC-SOD co-operates with adiponectin and possesses beneficial functions for DM in the Oldest Old.

Abstract Background Very few studies have examined the relationship of oral health with physical functioning and frailty in the oldest old (> 85 years). We examined the association of poor oral health with markers of disability, physical function and frailty in studies of oldest old in England and Japan. Methods The Newcastle 85+ Study in England (n = 853) and the Tokyo Oldest Old Survey on Total Health (TOOTH; n = 542) comprise random samples of people aged > 85 years. Oral health markers included tooth loss, dryness of mouth, difficulty swallowing and difficulty eating due to dental problems. Physical functioning was based on grip strength and gait speed; disability was assessed as mobility limitations. Frailty was ascertained using the Fried frailty phenotype. Cross-sectional analyses were undertaken using logistic regression. Results In the Newcastle 85+ Study, dry mouth symptoms, difficulty swallowing, difficulty eating, and tooth loss were associated with increased risks of mobility limitations after adjustment for sex, socioeconomic position, behavioural factors and co-morbidities [odds ratios (95%CIs) were 1.76 (1.26–2.46); 2.52 (1.56–4.08); 2.89 (1.52–5.50); 2.59 (1.44–4.65) respectively]. Similar results were observed for slow gait speed. Difficulty eating was associated with weak grip strength and frailty on full adjustment. In the TOOTH Study, difficulty eating was associated with increased risks of frailty, mobility limitations and slow gait speed; and complete tooth loss was associated with increased risk of frailty. Conclusion Different markers of poor oral health are independently associated with worse physical functioning and frailty in the oldest old age groups. Research to understand the underlying pathways is needed.

Abstract Background On April 7, 2020, Japan declared a state of emergency due to the first wave of coronavirus disease 2019 (COVID-19) with the associated social distancing likely to have had a great impact on older adults’ lifestyle and health. This study aimed to explore the behavioral changes and personal hygiene practices in relation with background psychosocial and health characteristics of older adults during the COVID-19 emergency. Methods A cross-sectional telephonic survey was conducted with the participants of the Kawasaki Aging and Wellbeing Project (KAWP), an on-going longitudinal cohort study of older adults aged 85 or older. The interviews were conducted using a structured questionnaire consisting of 11 closed questions regarding behavioral changes and personal hygiene practices during the state of emergency. Sociodemographic and health data were obtained from the KAWP baseline survey conducted 2.2 years before the telephonic survey. Results Overall, 487 participants from the KAWP responded to the telephonic survey (response rate: 89.2%). 94.5% of the respondents reported no changes in basic lifestyle habits, such as eating, sleeping, smoking, and drinking, whereas 28.1% reported a decrease in physical activity, and 54.6% reported going out less frequently. One-third of the respondents reported a decrease in the number of people to converse with, as well as the amount of time to converse. For personal hygiene practices, 93.8% reported wearing a mask when they went out, and 50.3% reported an increased frequency of handwashing. Multiple logistic regression analysis revealed that engagement in physical activity at baseline (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.23–3.08), smartphone ownership (OR = 2.15, 95% CI = 1.33–3.47), and visual impairment (OR = 1.79; 95% CI = 1.10–2.91) were independently associated with decreased physical activity during the COVID-19 emergency. Female respondents and smartphone ownership were significantly associated with more frequent handwashing. Conclusions The study revealed that older adults in an urban setting responded to the COVID-19 emergency with behavioral changes. The findings of this study have implications for the design of preventive strategies to maintain the health and wellbeing of at-risk older adults.

In the context of global population ageing and concentration in cities, the population aged 80 and over (80+) is growing rapidly. Japan has the fastest ageing population and longest healthy average life expectancy, while health decline becomes pronounced and care needs increase in the 85+ age group post the ‘average life expectancy’. The healthy ageing of older urban community dwellers is a pressing issue in world initiatives for sustainable urbanisation. However, for the 85+ age group, less is known about how promoting/inhibiting factors and their pathways influence healthy ageing, and related longitudinal studies remain insufficient. Using data from a longitudinal cohort study conducted from 2008–2009 to 2014–2015 among independent dwellers aged 85+ in central Tokyo (men = 203, women = 232), this study analysed the impact pathways of environmental, social, and behavioural factors on health and survival to explore promoters and potential risks on healthy ageing by gender, with multi-group structural equation modelling (SEM) and Bayesian SEM. For both genders, there was a positive chained pathway starting from friends as facilitators through positive interactions between 'social participation’ and 'active behaviour' to 'ageing-related health'. Additionally, their personal networks were small, suggesting that men with family-centred networks and women with non-family-centred networks require different approaches and supports. Implications of the results are discussed, and an organised social watch and support system, which becomes more important in the ‘new normal’ for urban dwellers aged 85+, is recommended.

Abstract Background Preventing the need for long-term care (LTC) by identifying physical function risk factors are important to decrease the LTC burden. The objective of this study was to investigate whether grip strength and/or walking speed, which are components of the frailty definition, are associated with LTC in community-dwelling older and oldest people. Methods The participants were 1098 community-dwelling older and oldest people who had not received LTC at the baseline. The endpoint was receiving LTC after the baseline survey. The independent variables were grip strength and walking speed, and participants were divided into two groups based on these variables. The confounding factors were age, sex, the Japanese version of the Montreal Cognitive Assessment (MoCA-J), hypertension, diabetes mellitus, stroke, joint diseases, living alone, body mass index, and serum albumin. We calculated the hazard ratio of receiving LTC using the Cox proportional hazard model. Results Among the 1098 participants, 107 (9.7%) newly received LTC during the follow-up. Regarding the physical function, only slow walking speed was significantly correlated with LTC after adjusting for all confounding factors except the MoCA-J score (HR = 1.74, 95% CI = 1.10–2.75, P = .018). However, slow walking speed was still a risk factor for LTC after adjusting for the MoCA-J score and other confounding factors (HR = 1.64, 95% CI = 1.03–2.60, P = .037). Conclusions The findings from this study may contribute to a better understanding of slow walking speed as a factor related to LTC, which might be a criterion for disability prevention and could serve as an outcome measure for physical function in older people.

Supercentenarians are approaching the current longevity limit by avoiding or surviving major illness, thus identifying biomarkers for exceptional survival might provide insights into the protection against disease of aging. Here, the authors show low NT-proBNP and high albumin in plasma are the biological correlates of survival to the highest ages.

Some studies reported that home blood pressure (HBP) monitoring was conducted by community-dwelling older people themselves, but there have been few studies on HBP including very old populations aged over 90 years old. Thus, the aim of the present study was to clarify the current situation of white-coat and masked phenomena defined by on-site and home BP measurements in community-dwelling old and oldest-old populations. The study subjects were 380 participants from the SONIC study, a cohort study of a community-dwelling old population, who measured their HBP in a series of 3–5 days by themselves and brought their HBP records to the venue on the survey day. Study participants’ characteristics were as follows: female, 185 (48.7%); male, 195 (51.3%); 70s, 95 (25.0%); 80s, 245 (64.5%); and 90s, 40 (10.5%). A total of 344 (90.5%) participants had hypertension. A total of 291 (76.6%) hypertensive participants taking antihypertensive medication were analyzed in the present study. Regarding the types of hypertension defined by home and on-site BP, they showed white-coat phenomenon, 183 (48.2%); masked phenomenon, 115 (30.3%); sustained hypertension, 130 (34.2%); and normotension, 82 (21.6%). On comparison of age groups, there was a tendency for the white-coat phenomenon to be common in young-old people in their 70s and the masked phenomenon to be common in very old people in their 90s. Therefore, since the detection of white-coat and masked phenomena is closely associated with appropriate BP management, it is very important for community-dwelling older populations to self-monitor HBP.

Abstract Background Cognitive impairment is a major health concern among older and oldest people. Moreover, stroke is a relevant contributor for cognitive decline and development of dementia. The study of cognitive decline focused on stroke as the important risk factor by recruiting older and oldest is still lagging behind. Therefore, the aim of this study was to investigate the importance of stroke as a risk factor of cognitive decline during 3 years in community dwelling older and oldest people. Methods This study was longitudinal study with a 3-year follow-up in Japan. The participants were 1333 community dwelling older and oldest people (70 years old = 675, 80 years old = 589, and 90 years old = 69). Data collected included basic data (age, sex, and history of stroke), vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, and current smoking), and social factors (educational level, frequency of going outdoors, long-term care (LTC) service used, and residential area). The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was decline of ≥2 points was defined as cognitive decline. Multiple logistic regression analysis was used to investigate the association between stroke and other risk factors with cognitive decline during a 3-year follow-up. Results The fit of the hypothesized model by multiple logistic regression showed that a history of stroke, advanced age, and greater MoCA-J score at the baseline were important risk factors, while the presence of dyslipidemia and a higher educational level were protective factors that were significantly correlated with cognitive decline during the 3-year follow-up. Conclusions The cognitive decline after the 3-year follow-up was influenced by the history of stroke and advanced age, while greater MoCA-J score at the baseline was positively associated with subsequent 3 years cognitive decline. The protective factors were the presence of dyslipidemia and a higher educational level. Therefore, these factors are considered important and should be taken into consideration when searching for creative solutions to prevent cognitive decline after stroke in community dwelling older and oldest people.

Abstract Background Instrumental Activities of Daily Living (IADL) is an indicator of whether a community-dwelling elderly can live independently. IADL decline was reported to be associated with aging and depression. The present study aimed to investigate whether the association between IADL decline and depressive symptoms differs with aging, using two age groups of community-dwelling Japanese elderly in their 70s and 80s. Methods We conducted longitudinal analysis among participants in their 70s and 80s at the baseline from Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC) study. IADL was assessed by The Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence. As a main predictor, depressive symptoms were measured by the five-item version of the Geriatrics Depression Scale (GDS-5). As possible confounders, we considered cognitive function, body mass index, solitary living, education, economic status, medical history of stroke and heart disease, hypertension, dyslipidemia, diabetes, and sex. We obtained odds ratios (ORs) of IADL decline for having depressive symptoms in each age group (70s/80s) and tested interactions between depressive symptoms and age groups in relation to IADL decline in 3 years by logistic regression. Additionally, to confirm age group differences, we conducted multiple group analysis. Results There were 559 participants in their 70s and 519 in their 80s. Compared to participants without depressive symptoms, those with depressive symptoms had higher OR of IADL decline in 70s (OR [95% CI] = 2.33 [1.13, 4.78]), but not in 80s (OR [95% CI] = 0.85 [0.46, 1.53]). There were significant interactions between depressive symptoms and age groups in relation to IADL decline (p-value = 0.03). Multiple group analyses showed differences between the age groups by Akaike information criterion (AIC), and ORs (95%CI) decline for depressive symptoms was 2.33 (1.14, 4.77) in 70s and 0.85 (0.47, 1.54) in 80s. Conclusion The association of depressive symptoms and IADL decline during the 3 years was significantly different between the 70s and 80s age groups, and significant association was found only in people in their 70s. Detecting depressive symptoms may be a key for preventing IADL decline in people in their 70s and not for those in their 80s.

Objectives To measure the use of healthcare services and assistive devices by centenarians in five countries.Design Cross-sectional study using a survey questionnaire.Setting Community-dwelling and institutionalised centenarians living in Japan, France, Switzerland, Sweden and Denmark.Participants 1253 participants aged 100 or in their 100th year of life, of whom 1004 (80.1%) were female and 596 (47.6%) lived in institutions.Main outcome measures Recent use of medical visits, nursing care at home, home-delivered meals, acute care hospital stays overnight, professional assessments such as sight tests, mobility aids and other assistive devices. A set of national healthcare system indicators was collected to help interpret differences between countries.Results There was considerable variability in the healthcare services and assistive devices used by centenarians depending on their country and whether they were community-dwelling or institutionalised. In contrast to the relatively homogeneous rates of hospitalisation in the past year (around 20%), community-dwelling centenarians reported widely ranging rates of medical visits in the past 3 months (at least one visit, from 32.2% in Japan to 86.6% in France). The proportion of community-dwellers using a mobility device to get around indoors (either a walking aid or a wheelchair) ranged from 48.3% in Japan to 79.2% in Sweden. Participants living in institutions and reporting the use of a mobility device ranged from 78.6% in Japan to 98.2% in Denmark.Conclusions Our findings suggest major differences in care received by centenarians across countries. Some may result from the characteristics of national healthcare systems, especially types of healthcare insurance coverage and the amounts of specific resources available. However, unexplored factors also seem to be at stake and may be partly related to personal health and cultural differences.

Recent natural selection left signals in human genomes. Here, Okada et al. generate high-depth whole-genome sequence (WGS) data (25.9×) from 2,234 Japanese people of the BioBank Japan Project (BBJ), and identify signals of recent natural selection which overlap variants associated with human traits.

Abstract Background Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of ‘modifier genes’, may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. Results We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P

Abstract Background An increasing number of studies in Western countries have shown that healthy dietary patterns may have a protective effect against cognitive decline and dementia. However, information on this relationship among non-Western populations with different cultural settings is extremely limited. We aim to examine the relationship between dietary patterns and cognitive function among older Japanese people. Methods This cross-sectional study included 635 community-dwelling people aged 69–71 years who participated in the prospective cohort study titled Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC). Diet was assessed over a one-month period with a validated, brief-type, self-administered diet history questionnaire. Dietary patterns from thirty-three predefined food groups [energy-adjusted food (g/d)] were extracted by factor analysis. Cognitive function was assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Multivariate regression analysis was performed to examine the relationship between dietary patterns and cognitive function. Results Three dietary patterns were identified: the ‘Plant foods and fish’, ‘Rice and miso soup’, and ‘Animal food’ patterns. The ‘Plant foods and fish’ pattern, characterized by high intakes of green and other vegetables, soy products, seaweeds, mushrooms, potatoes, fruit, fish, and green tea, was significantly associated with a higher MoCA-J score [MoCA-J score per one-quartile increase in dietary pattern: β = 0.56 (95% CI: 0.33, 0.79), P for trend

Adipose tissue, which was once considered as a simple energy storage depot, is now recognized as an active endocrine organ that regulates the whole-body energy homeostasis by secreting hundreds of bioactive substances termed adipokines. Dysregulation of adipokines is a key feature of insulin resistance and a metabolic syndrome associated with obesity. Adipokine dysregulation and insulin resistance are also associated with energy-deprivation conditions, such as frailty in old age. Previous studies have demonstrated that preserved insulin sensitivity and low prevalence of diabetes are the metabolic peculiarities of centenarians, suggesting the possible role of adipokine homeostasis in healthy longevity. Among the numerous adipokines, adiponectin is regarded as unique and salutary, showing negative correlations with several age- and obesity-related metabolic disturbances and a positive correlation with longevity and insulin sensitivity among centenarians. However, large-scale epidemiological studies have implied the opposite aspect of this adipokine as a prognostic factor for all-cause and cardiovascular mortality in patients with heart failure or kidney disease. In this review, the clinical significance of adiponectin was comparatively addressed in centenarians and the very old, in terms of frailty, cardiovascular risk, and mortality.

Engagement in leisure activities has been claimed to be highly beneficial in the elderly. Practicing such activities is supposed to help older adults to preserve cognitive function, physical function, and mental health, and thus to contribute to successful aging. We used structural equation modeling (SEM) to analyze the impact of leisure activities on these constructs in a large sample of Japanese older adults (N = 809; age range 72-74). The model exhibited an excellent fit (CFI = 1); engaging in leisure activities was positively associated with all the three successful aging indicators. These findings corroborate previous research carried out in Western countries and extend its validity to the population of Eastern older adults. Albeit correlational in nature, these results suggest that active engagement in leisure activities can help older adults to maintain cognitive, physical, and mental health. Future research will clarify whether there is a causal relationship between engagement in leisure activities and successful aging.

To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8.6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = −0.795 (−1.436 to −0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.

Growing evidence suggests that oral health may be an important factor associated with cognitive function in aged populations. However, many previous studies on this topic used insensitive oral indicators or did not include certain essential covariates. Thus, we examined the association between occlusal force and cognitive function in a large sample of older adults, controlling for dietary intake, vascular risk factors, inflammatory biomarkers, depression, and genetic factors.In this cross-sectional study of older community-dwelling Japanese adults, we examined data collected from 994 persons aged 70 years and 968 persons aged 80 years. Cognitive function was measured using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Oral status and function were evaluated according to the number of remaining teeth, periodontal pocket depth, and maximal occlusal force. Associations between MoCA-J scores and occlusal force were investigated via bivariate and multivariate analyses.Education level, financial status, depression score, and intake of green and yellow vegetables, as well as number of teeth and occlusal force, were significantly correlated with MoCA-J scores in both age groups. Among individuals aged 80 years, CRP and periodontal status were weakly but significantly associated with MoCA-J score. After controlling for all significant variables via bivariate analyses, the correlation between maximal occlusal force and cognitive function persisted. A path analysis confirmed the hypothesis that cognitive function is associated with occlusal force directly as well as indirectly via food intake.After controlling for possible factors, maximal occlusal force was positively associated with cognitive function directly as well as indirectly through dietary intake.

Human influenza A(H2N2) viruses emerged in 1957 and were replaced by A(H3N2) viruses in 1968. The antigenicity of human H2N2 viruses has been tested by using ferret antisera or mouse and human monoclonal antibodies. Here, we examined the antigenicity of human H2N2 viruses by using human plasma samples obtained from 50 aged individuals who were born between 1928 and 1933 and from 33 younger adult individuals who were born after 1962. The aged individuals possessed higher neutralization titers against H2N2 viruses isolated in 1957 and 1963 than those against H2N2 viruses isolated in 1968, whereas the younger adults who were born between 1962 and 1968 possessed higher neutralization titers against H2N2 viruses isolated in 1963 than those against other H2N2 viruses. Antigenic cartography revealed the antigenic changes that occurred in human H2N2 viruses during circulation in humans for 11 years, as detected by ferret antisera. These results show that even though aged individuals were likely exposed to more recent H2N2 viruses that are antigenically distinct from the earlier H2N2 viruses, they did not possess high neutralizing antibody titers to the more recent viruses, suggesting immunological imprinting of these individuals with the first H2N2 viruses they encountered and that this immunological imprinting lasts for over 50 years.

Whereas most of studies investigating relationship between oral health and atherosclerosis have focused on periodontitis, very few of them were examined about occlusal status of natural teeth which possibly influence dietary habit. The primary aim of this cross-sectional study was to investigate the association between the occlusal support of posterior teeth and the prevalence of atherosclerosis in community-dwelling septuagenarians. Also, the second aim was to test the hypothesis that the intake of key nutrients for atherosclerosis prevention would have a mediating effect on the relationship between the occlusal status and atherosclerosis. The study population included 468 community-dwelling dentate persons aged 69-71 years recruited from the local residential registration in Japan. Participants were divided into three groups, according to the number of occlusal support zones (OSZ) in the posterior area: Complete (four OSZ), Moderate (three or two OSZ), and Collapsed (one or no OSZ). Dietary intakes were assessed using a brief-type self-administered diet history questionnaire. Atherosclerosis was defined as carotid intima-media thickness ≧1.10 mm by using carotid ultrasonography test. The logistic or linear regression model was used in multivariate analysis to assess relationship between occlusal status and atherosclerosis, and the mediating effect of key nutrients within the relationship. Multivariable analysis showed a significant association between occlusal status and atherosclerosis (odds ratio for Collapsed group to Complete group: 1.87; 95% CI: 1.45-2.41), independent of periodontal status (odds ratio: 2.01, 95%CI: 1.46-2.78). Fish and shellfish, vitamin B6 and n-3PUFAs were significantly related to both of occlusal status and atherosclerosis, and also was indicated a mediating effect on the association between occlusal status and atherosclerosis. This study implied that, within the limitation of the cross-sectional study design, the reduced posterior occlusion was related to the increased prevalence of atherosclerosis via the decline of key dietary intakes among Japanese community-dwelling dentate individuals.

Myostatin (MSTN) and α-actinin-3 (ACTN3) genes are potentially associated with preservation of muscle mass and oxidative capacity, respectively. To explore the possible role of these genes in exceptional longevity (EL), the allele/genotype frequency distribution of two polymorphisms in MSTN (rs1805086, K153R) and ACTN3 (rs1815739, R577X) was studied in Japanese centenarians of both sexes (n = 742) and healthy controls (n = 814). The rs1805086 R-allele (theoretically associated with muscle mass preservation at the expense of oxidative capacity) was virtually absent in the two groups, where genotype distributions were virtually identical. Likewise, no differences in allele (p = 0.838 (women); p = 0.193 (men); p = 0.587 (both sexes)) or genotype distribution were found between groups for ACTN3 rs1815739 (p = 0.975 (women), p = 0.136 (men), p = 0.752 (both sexes)). Of note, however, the frequency of the rs1805086 R-allele observed here is the lowest been reported to date whereas that of the 'highly oxidative/efficient' rs1815739 XX genotype in Japanese male centenarians (33.3%) or supercentenarians of both sexes (≥110 years) are the highest (32.6%), for a non-American population. No definite conclusions can be inferred in relation to EL owing to its lack of association with both rs1815739 and rs1805086. However, it cannot be excluded that these gene variants could eventually be related to a "healthy" metabolic phenotype in the Japanese population. Further research might determine if such metabolic profile is among the factors that can potentially predispose these individuals to live longer than Caucasians and what genetic variants might be actually involved.

An N-glycomic analysis of plasma proteins was performed in Japanese semisupercentenarians (SSCs) (mean 106.7 years), aged controls (mean 71.6 years), and young controls (mean 30.2 years) by liquid chromatography/mass spectrometry (LC/MS) using a graphitized carbon column. Characteristic N-glycans in SSCs were discriminated using a multivariate analysis; orthogonal projections to latent structures (O-PLS). The results obtained showed that multi-branched and highly sialylated N-glycans as well as agalacto- and/or bisecting N-glycans were increased in SSCs, while biantennary N-glycans were decreased. Since multi-branched and highly sialylated N-glycans have been implicated in anti-inflammatory activities, these changes may play a role in the enhanced chronic inflammation observed in SSCs. The levels of inflammatory proteins, such as CRP, adiponectin, IL-6, and TNF-α, were elevated in SSCs. These results suggested that responses to inflammation may play an important role in extreme longevity and healthy aging in humans. This is the first study to show that the N-glycans of plasma proteins were associated with extreme longevity and healthy aging in humans.

Induced pluripotent stem cell (iPSC) technology can be used to model human disorders, create cell-based models of human diseases, including neurodegenerative diseases, and in establishing therapeutic strategies. To detect subtle cellular abnormalities associated with common late-onset disease in iPSCs, valid control iPSCs derived from healthy donors free of serious late-onset diseases are necessary. Here, we report the generation of iPSCs from fibroblasts obtained immediately postmortem from centenarian donors (106- and 109-years-old) who were extremely healthy until an advanced age. The iPSCs were generated using a conventional method involving OCT4, SOX2, KLF4, and c-MYC, and then differentiated into neuronal cells using a neurosphere method. The expression of molecules that play critical roles in late-onset neurodegenerative diseases by neurons differentiated from the centenarian-iPSCs was compared to that of neurons differentiated from iPSCs derived from familial Alzheimer's disease and familial Parkinson's disease (PARK4: triplication of the α synuclein gene) patients. The results indicated that our series of iPSCs would be useful in neurodegeneration research. The iPSCs we describe, which were derived from donors with exceptional longevity who were presumed to have no serious disease risk factors, would be useful in longevity research and as valid super-controls for use in studies of various late-onset diseases.

Background: To date, there is no physical activity (PA) questionnaire with convergent and construct validity for the oldest-old. The aim of the current study was to investigate the validity of questionnaire-assessed PA in comparison with objective measures determined by uniaxial and triaxial accelerometers and physical performance measures in the oldest-old. Methods: Participants were 155 elderly (mean age 90 years) who were examined at the university and agreed to wear an accelerometer for 7 days in the 3-year-follow-up survey of the Tokyo Oldest-Old Survey of Total Health. Fifty-nine participants wore a uniaxial and triaxial accelerometer simultaneously. Self-rated walking, exercise, and household PA were measured using a modified Zutphen PA Questionnaire (PAQ). Several physical performance tests were done, and the associations among PAQ, accelerometer-assessed PA, and physical performances were compared by Spearman's correlation coefficients. Results: Significant, low to moderate correlations between PA measures were seen on questionnaire and accelerometer assessments (ρ = 0.19 to 0.34). Questionnaireassessed PA measure were correlated with a range of lower extremity performance (ρ = 0.21 to 0.29). Conclusions: This PAQ demonstrated convergent and construct validity. Our findings suggest that the PAQ can reasonably be used in this oldest-old population to rank their PA level. [ABSTRACT FROM AUTHOR]

This study investigated the relationships between muscle echo intensity (EI), physical activity (PA), and functional mobility in 108 Japanese (88–92 years). We measured EI and muscle thickness (MT) at the midpoint of the anterior superior iliac spine and patella using B-mode ultrasound. Light and moderate-to-vigorous PA (LPA and MVPA) were assessed with a triaxial accelerometer. The timed up and go (TUG) test was used to measure for functional mobility. EI, but not MT, was significantly associated with both TUG scores (β = 0.17, p = .047) and MVPA (β = –0.31, p = .01) when adjusted by potential confounders. However, association between EI and TUG disappeared after adjusted for MVPA. Meanwhile, MVPA was significantly associated with TUG scores independent of EI (β = –0.35, p < .001). Although EI of anterior thigh muscles might be a weaker predictor of functional morbidity than MVPA, it is a noninvasive and practical approach for assessing muscle quality in the very old. [ABSTRACT FROM AUTHOR]

The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered.Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function.Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan.

We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99-105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer's and Parkinson's disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain "beneficial" patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations.

Aim: The incidence of anemia increases with aging, and it is considered to affect mortality through complex pathophysiological outcomes. Although it has been suggested that self-rated health may also contribute to the prognosis of anemia in older people, the relationship between anemia and self-rated health is not well understood. This study thus examined the actual status of anemia in older community-dwelling Japanese people and clarified the relationship between anemia and self-rated health. Methods: We conducted medical interviews, physical measurements and blood testing in 2083 people aged 69-91 years who participated in the long-term observational Septuagenarians, Octogenarians, Nonagenarians, Investigation with Centenarians (SONIC) study. Subjects were divided into two groups according to whether they had anemia. Logistic regression analyses were used to assess the relationship between anemia and self-rated health after adjusting for possible confounding factors. Results: The prevalence of anemia was 22.3% in all participants, 7.2% in men and 11.6% in women aged 69-71 years, 27.4% in men and 26.3% in women aged 79-81 years, and 55.8% in men and 44.9% in women aged 89-91 years. Multivariate analysis revealed a correlation between the presence of anemia and poor self-rated health in all (odds ratio 0.67, 95% confidence interval 0.48-0.93) and aged 69-71 years (odds ratio 0.47, 95% confidence interval 0.25-0.86). Conclusions: Anemia was associated with self-rated health in older Japanese people, suggesting that careful management of anemia may contribute to health and longevity. Geriatr Gerontol Int 2020; 20: 720-726. [ABSTRACT FROM AUTHOR]

Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed singlecell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTLs]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-γ and TNF-a upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases. [ABSTRACT FROM AUTHOR]

Growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/insulin signaling is one of the most plausible biological pathways regulating aging and longevity. Previous studies have demonstrated that several single nucleotide polymorphisms (SNPs) in the GH/IGF-1/insulin signaling-associated genes influence both longevity and adult height, suggesting the possibility of a shared genetic architecture between longevity and height. We therefore examined the relationship between 30 height-associated SNPs and extreme longevity in a Japanese population consisting of 428 centenarians and 4,026 younger controls. We confirmed that height-increasing genetic scores (HGSs) constructed based on 30 SNPs were significantly associated with height in the controls (p = 6.95 × 10-23). HGS was significantly and inversely associated with extreme longevity in women (p = .011), but not in men, although no SNPs were significantly associated with extreme longevity after Bonferroni correction. The odds ratio for extreme longevity in the lowest HGS group (≤27) and the second lowest HGS group (28-30) relative to the highest HGS group (≥37) was 1.71 (p = .056) and 1.69 (p = .034), respectively, for women. In conclusion, the present study demonstrated an inverse association between height-increasing alleles with extreme longevity in Japanese women, providing novel insight into the genetic architecture of longevity and aging. [ABSTRACT FROM AUTHOR]