Polypharmacy with potentially inappropriate medications as a risk factor of new onset sarcopenia among community-dwelling Japanese older adults: a 9-year Kashiwa cohort study.

BACKGROUND: Clinical evidence demonstrating a longitudinal association between prescribed medications and sarcopenia onset is lacking. We investigated the association of polypharmacy (the use of five or more medications) and potentially inappropriate medications (PIMs) with sarcopenia risk in community-dwelling older adults. METHODS: In this longitudinal population-based cohort study, 2,044 older residents with no long-term care needs were randomly selected from a community in Kashiwa, Japan. Baseline data collection was conducted in 2012, with follow-ups in 2013, 2014, 2016, 2018, and 2021. Prescribed medications and PIMs (drugs listed in the Screening Tool for Older Person's Appropriate Prescriptions for the Japanese or potentially muscle-wasting drugs) were identified through interviews. New-onset sarcopenia was identified according to the 2019 criteria of the Asian Working Group for Sarcopenia over a 9-year period and analyzed. We used Cox proportional hazards models to test the longitudinal association of prescribed medications with sarcopenia onset. RESULTS: Of the 1,549 participants without sarcopenia at baseline (mean age, 72.5 ± 5.5 years; 49.1% women; median and interquartile range, 6.0 [4.0-9.0] years), 230 experienced new-onset sarcopenia during the follow-up. After adjusting for confounders, polypharmacy combined with PIM use was strongly associated with new-onset sarcopenia (adjusted hazard ratio, 2.35; 95% confidence interval, 1.58-3.51; P < 0.001). No significant associations were observed for either PIM use or polypharmacy alone. CONCLUSIONS: Polypharmacy combined with PIM use, but not polypharmacy alone, was associated with an increased risk of new-onset sarcopenia over the 9-year follow-up period among community-dwelling older adults. Limiting polypharmacy and imposing the prescription of appropriate medications may facilitate sarcopenia prevention.

Low-Intensity Exercise Suppresses CCAAT/Enhancer-Binding Protein δ/Myostatin Pathway Through Androgen Receptor in Muscle Cells.

BACKGROUND: Androgen production following exercise has been suggested to contribute anabolic actions of muscle. However, the underlying mechanisms of the androgen receptor (AR) in androgen's action are still unclear. OBJECTIVE: In the present study, we examined androgen/AR-mediated action in exercise, especially for the suppression of myostatin, a potent negative regulator of muscle mass. METHODS: To examine the effects of exercise, we employed low-intensity exercise in mice and electric pulse stimulation (EPS) in C2C12 myotubes. Androgen production by C2C12 myotubes was measured by enzyme-linked immunosorbent assay. To block the action of AR, we pretreated C2C12 myotubes with flutamide. Quantitative real-time polymerase chain reaction was used to determine the expression levels of proteolytic genes including CCAAT/enhancer-binding protein delta (C/EBPδ), myostatin and muscle E3 ubiquitin ligases, as well as myogenic genes such as myogenin and PGC1α. The activation of 5'-adenosine-activated protein kinase and STAT3 was determined by Western blot analysis. RESULTS: Both mRNA and protein levels of AR significantly increased in skeletal muscle of low-intensity exercised mice and C2C12 myotubes exposed to EPS. Production of testosterone and dihydrotestosterone from EPS-treated C2C12 myotubes was markedly increased. Of interest, we found that myostatin was clearly inhibited by EPS, and its inhibition was significantly abrogated when AR was blocked by flutamide. To test how AR suppresses myostatin, we examined the effects of EPS on C/EBPδ because the promoter region of myostatin has several C/EBP recognition sites. C/EBPδ expression was decreased by EPS, and this decrease was negated by flutamide. IL-6 and phospho-STAT3 (pSTAT3) expression, the downstream pathway of myostatin, were decreased by EPS and this was also reversed by flutamide. Similar downregulation of C/EBPδ, myostatin, and IL-6 was seen in skeletal muscle of low-intensity exercised mice. CONCLUSIONS: Muscle AR expression and androgen production were increased by exercise and EPS treatment. As a mechanistical insight, it is suggested that AR inhibited myostatin expression transcriptionally by C/EBPδ suppression, which negatively influences IL-6/pSTAT3 expression and consequently contributes to the prevention of muscle proteolysis during exercise.

Protective effects of estrogen against vascular calcification via estrogen receptor α-dependent growth arrest-specific gene 6 transactivation.

Vascular calcification is one of the major complications of cardiovascular disease and is an independent risk factor for myocardial infarction and cardiac death. Postmenopausal women have a higher prevalence of vascular calcification compared with premenopausal women, suggesting protective effects of estrogen (E2). However, the underlying mechanisms of its beneficial effects remain unclear. In the present study, we examined the inhibitory effects of E2 on vascular smooth muscle cell (VSMC) calcification, and found that growth arrest-specific gene 6 (Gas6), a crucial molecule in vascular calcification, is transactivated by estrogen receptor α (ERα) in response to E2. In human aortic smooth muscle cells, physiological levels of E2 inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner. This inhibitory effect was significantly abolished by MPP, an ERα-selective antagonist, and ERα siRNA, but not by PHTPP, an ERß-selective antagonist, and ERß siRNA, implicating an ERα-dependent action. Apoptosis, an essential process for Pi-induced VSMC calcification, was inhibited by E2 in a concentration-dependent manner and further, MPP abolished this inhibition. Mechanistically, E2 restored the inhibited expression of Gas6 and phospho-Akt in Pi-induced apoptosis through ERα. Furthermore, E2 significantly activated Gas6 transcription, and MPP abrogated this E2-dependent Gas6 transactivation. E2-BSA failed to activate Gas6 transcription and to inhibit Ca deposition in VSMC, suggesting beneficial actions of genomic signaling by E2/nuclear ERα. Taken together, these results indicate that E2 exerts inhibitory effects on VSMC apoptosis and calcification through ERα-mediated Gas6 transactivation. These findings indicate a potential therapeutic strategy for the prevention of vascular calcification, especially in postmenopausal women.

Medical care priorities of community-dwelling older adults according to three dimensions of quality of life: Quality of daily living, satisfaction and happiness from birth to death, and human vitality.

AIM: Although the maintenance and improvement of quality of life (QoL) through holistic care are important in geriatric medical care, care priorities might differ depending on three essential aspects of QoL: the quality of daily living, satisfaction and happiness from birth to death, and human vitality, which are "Seikatsu," "Jinsei," "Seimei" in Japanese, respectively. We aimed to clarify these priorities in terms of medical care and examined how the definitions of QoL affected these priorities' rankings. METHODS: This cross-sectional study involved community-dwelling older adults aged ≥65 years living in Kashiwa City, Chiba Prefecture, Japan. The number of participants was 1550 (mean age, 76.1 ± 5.8 years; 699 women [45.1%]). A self-administered questionnaire distributed in advance was used to rank 12 items sought in medical care. Participants were randomly assigned to one of three groups and sent the corresponding questionnaire, which differed only in the definition of QoL. RESULTS: The top priorities for medical care were "effective treatment of illness," "improvement of physical function," and "maintaining a high level of activity." When QoL was defined as "the quality of daily living, satisfaction and happiness from birth to death, and human vitality," participants were significantly more likely to rank QoL improvement as one of the top three items (adjusted odds ratio, 1.46; 95% confidence interval, 1.03-2.05). CONCLUSIONS: As a medical care priority, older adults desire improvement of multidimensional elements of life, including human vitality. Health care providers should consider this when making medical care decisions. Geriatr Gerontol Int 2024; 24: 493-498.

Multifaceted well-being experienced by community dwelling older adults engaged in volunteering activities of frailty prevention in Japan.

AIM: This study aims to elucidate what volunteering activities mean for older adults in Japan by analyzing their emotions and evaluations from hedonic (e.g., happiness), eudaimonic (e.g., self-growth), and social (e.g., social coherence) well-being. METHODS: The qualitative research was conducted to describe the subjective experience of older adults' volunteering activities (frailty checkups) in the community-setting. Eight older adults were interviewed about their experiences during these activities. The interview data were analyzed from two assumption frameworks: first, three aspects of well-being, and second, timeframes of well-being, during the activity, medium-term, and long-term. Previous studies have not focused on the polysemy or the timeframe of well-being. RESULTS: Our results showed that hedonic, eudaimonic, and social well-being are not independent, but overlap. Furthermore, even if older adults experience certain emotions at a point of time, they may change in the long term. This implies that it is important to analyze older adults' feelings and experiences from not only one aspect but from different perspectives and measure their feelings not just at a particular moment but in the long term. This is the first empirical study to examine qualitatively the holistic experiences of well-being among older adults who volunteer. CONCLUSIONS: We conclude that this study is unique in that it attempted to associate empirically the experiences of older adults during volunteering with their general psychological status of well-being. These findings could help make volunteering activities more meaningful for older adults and create or promote an active community. Geriatr Gerontol Int 2024; 24: 273-278.

Effects of a high-phosphate diet on vascular calcification and abdominal aortic aneurysm in mice.

AIM: Vascular aging is an important risk factor for cardiovascular diseases, including abdominal aortic aneurysm (AAA) and pathological aortic dilatation, playing a critical role in the morbidity and mortality of older adults. Vascular calcification, a phenotype of vascular aging, is frequently associated with AAA. However, this association remains unclear owing to the lack of animal models. This study investigated the effects of a high-phosphate diet (HPD), a prominent trigger of vascular calcification in AAA. METHODS: Eight-week-old male mice were fed either a normal diet (ND; Ca 1.18%/P 1.07% = 1.10) or an HPD (Ca 1.23%/P 1.65% = 0.75) for 4 weeks. Subsequently, AAA was induced using CaCl2 application and angiotensin II (AngII) infusion for 4 weeks. RESULTS: The HPD resulted in more pronounced AAA formation than did the ND. Importantly, vascular calcification was observed only in the aorta of the HPD mice. Enhanced Runt-related transcription factor 2 expression and apoptosis (downregulation of growth arrest-specific gene 6/pAkt survival pathway), two major mechanisms of vascular calcification, were also observed. Furthermore, increased IL-6 and F4/80 expression was observed in the aorta of HPD mice. In RAW264.7 cells, inorganic phosphate enhanced IL-6 and IL-1ß expression under AngII priming. Ferric citrate, a phosphate binder, significantly inhibited HPD-induced AAA formation. CONCLUSIONS: These findings suggest that HPD induces vascular calcification and AAA formation, possibly through inflammation. This murine model suggests that vascular calcification induced by phosphate burden may be a therapeutic target for vascular diseases, including AAA. Geriatr Gerontol Int 2024; ••: ••-••.

Impact of the anti-inflammatory diet on serum high-sensitivity C-Reactive protein and new-onset frailty in community-dwelling older adults: A 7-year follow-up of the Kashiwa cohort study.

AIM: Chronic inflammation is a pathophysiological cause of age-related diseases, including frailty. Although diet is a determinant of inflammation, few prospective studies have investigated its role in frailty onset. This study used the dietary inflammatory index to investigate whether a proinflammatory diet affects the incidence of frailty in a 7-year follow-up of older Japanese adults. METHODS: We enrolled community-dwelling older adults without frailty from the 2014 Kashiwa cohort study. Energy-adjusted dietary inflammatory index (E-DII) scores were calculated using a brief self-administered diet history questionnaire. Serum high-sensitivity C-reactive protein (hsCRP) levels were measured by immunoassays. Frailty was defined as meeting three of Fried's five phenotypic criteria. Cox regression was used to analyze associations between E-DII scores and new-onset frailty after adjusting for relevant confounders. RESULTS: Overall, 95 (11.7%) of 811 participants (73.7 ± 4.8 years, women 47.3%) developed new-onset frailty during the 7-year follow-up. The baseline E-DII scores significantly correlated with log-hsCRP levels, even after adjustment (ß = 0.075, P = 0.035). The highest tertile of E-DII scores (proinflammatory diet) showed a 2.03 times (95% confidence interval, 1.22-3.36) higher risk of new-onset frailty than that associated with the lowest tertile (P = 0.006). When E-DII was calculated on the basis of anti-inflammatory food parameters only, the highest tertile showed a 2.32 times (95% confidence interval, 1.36-3.95) higher risk than that associated with the lowest tertile (P = 0.002). CONCLUSIONS: E-DII scores significantly correlated with serum hsCRP levels. High E-DII scores caused by low intake of anti-inflammatory foods are associated with frailty incidence. For community-dwelling older adults, dietary interventions that lower E-DII scores (e.g., encouraging dietary fiber intake) may help prevent frailty. Geriatr Gerontol Int 2024; 24: 189-195.

Validity of a simple self-reported questionnaire "Eleven-Check" for screening of frailty in Japanese community-dwelling older adults: Kashiwa cohort study.

PURPOSE: Frailty was indicated to be closely related to older adults' lifestyles, especially in nutrition-related factors (such as balanced diet and oral functions), physical factors, and social factors in our previous study. Here, we developed an "Eleven-Check" (EC) questionnaire containing the aforementioned three factors. This study tested whether the EC questionnaire can estimate frailty in community-dwelling older adults. MATERIALS AND METHODS: The study sample comprised 1,523 independent older adults. The primary outcome of frailty was assessed using the Cardiovascular Health Study index. The secondary outcome of sarcopenia was assessed by the criteria of the Asian Working Group for Sarcopenia 2019. The EC questionnaire comprised 11 dichotomous factors related to nutrition-related (diet and oral functions), physical, and social factors. RESULTS: Frailty prevalence was 8.5 % (76.1 ± 5.8y, 45.1 % women). The accuracy of the EC questionnaire for frailty was optimal when the total scores of 4/5 were used as the threshold. Compared to the low-risk group (<5), the high-risk group (≥5) had a significant association between frailty with an adjusted odds ratio (aOR) of 4.68 (95 %CI, 3.10-7.05). Moreover, the high-risk group also had a significant association with sarcopenia, with an aOR of 1.82 (1.27-2.61). CONCLUSIONS: For community-dwelling older adults, the EC questionnaire was able to simply screen frailty and sarcopenia status. Further, it might raise older adults' self-awareness from a multifaceted perspective in their daily life to prevent steady decline and frailty sustainably in a community setting.

Relationship between a gum-chewing routine and oral, physical, and cognitive functions of community-dwelling older adults: A Kashiwa cohort study.

AIM: As associations between oral function and general health have been reported in community-dwelling older adults, easily implementable preventive measures are urgently required. We focused on the health benefits of gum chewing, as no studies have been carried out on the impact of gum-chewing routines on the health of older adults. This cross-sectional study aimed to determine whether the gum-chewing routine is associated with oral, physical and cognitive functions in community-dwelling older adults. METHODS: This study included 1617 community-dwelling older participants in a health survey carried out in 2021. The gum-chewing routine and weekly chewing time were assessed using a self-administered questionnaire. The outcome measures, including actual measurements of oral function, physical function, cognitive function, dietary intake and lifestyle, were evaluated using self-administered questionnaires or health surveys. RESULTS: We analyzed 1474 (mean age 76.1 ± 5.8 years, 45% women) participants for whom all data were not missing, and 14% of them had a gum-chewing routine for more than 30 min weekly. Oral functions were significantly higher in older adults with a gum-chewing routine, and there were substantially fewer participants with oral frailty (adjusted odds ratio 0.581, 95% confidence interval 0.340-0.993). Additionally, cognitive and physical functions, including grip strength, were significantly higher in the gum-chewing routine group. CONCLUSIONS: Community-dwelling older adults with a gum-chewing routine have higher oral, physical and cognitive functions. These findings indicate that a gum-chewing routine might contribute to maintaining oral function and preventing frailty. Geriatr Gerontol Int 2024; 24: 68-74.

Association of coexistence of frailty and depressive symptoms with mortality in community-dwelling older adults: Kashiwa Cohort Study.

OBJECTIVES: This study aimed to determine the longitudinal associations of the coexistence of frailty and depressive symptoms with mortality among older adults. METHODS: The study participants were community-dwelling older adults aged ≥65 years who participated in the baseline survey of the Kashiwa Cohort Study in Japan in 2012. We used Fried's frailty phenotype criteria to classify participants as non-frail (score = 0), pre-frail (1 or 2), or frail (≥3). Depressive symptoms were assessed using the GDS-15 (≥6 points). Cox proportional hazards models were used to evaluate the association of co-occurring frailty and depressive symptoms with all-cause mortality, after adjusting for sociodemographic and clinical characteristics. RESULTS: The study included 1920 participants, including 810 non-frail, 921 pre-frail, and 189 frail older adults, of which 9.0 %, 15.7 %, and 36.0 %, respectively, had depressive symptoms. Ninety-one (4.7 %) participants died during the average follow-up period of 4.8 years. Compared with non-frail participants without depressive symptoms, frail participants had greater adjusted hazard ratios for mortality: 2.47 (95 % CI, 1.16 to 5.25) for frail participants without depressive symptoms and 4.34 (95 % CI, 1.95 to 9.65) for frail participants with depressive symptoms. However, no statistically significant associations were observed in non-frail or pre-frail participants irrespective of depressive symptoms. CONCLUSION: Frail older adults with depressive symptoms have a substantially greater risk of mortality. Screening for depressive symptoms and frailty in older adults should be incorporated into health checkups and clinical practice to identify high-risk populations.

AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells.

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

Thrombomodulin, a novel molecule regulating inorganic phosphate-induced vascular smooth muscle cell calcification.

Hyperphosphatemia has emerged as a cardiovascular risk factor that stimulates calcification in vessels. We explored molecules that were induced by inorganic phosphate (Pi) at an early stage in vascular smooth muscle cells (VSMC). In the present study, we examined the role of thrombomodulin (TM) in Pi-induced VSMC calcification based on the results of DNA microarray analysis. Both mRNA and protein expression of TM were markedly augmented in Pi-induced calcification. Conversely, knockdown of TM by siRNA significantly inhibited calcification, in addition to Pi-induced apoptosis which plays critical roles in VSMC calcification. We further found that TM suppressed both of mRNA and protein expression of growth arrest-specific gene 6 (Gas6), a key molecule regulating apoptosis. Recombinant extracellular epidermal growth factor (EGF)-repeat domain of TM exaggerated calcification and this effect was abrogated by a neutralizing antibody for EGF receptor, suggesting that the cleaved and secreted form of TM may activate EGF receptor. We also found that downregulation of Gas6 by TM/EGF receptor axis was mediated by ERK in VSMC calcification. In the aorta of adenine-fed rat, a typical medial calcification model with hyperphosphatemia, we found that TM expression was increased. Furthermore, in human calcified aorta, increased TM expression was also observed. These results indicate that TM is a novel molecule that promotes apoptosis and vascular calcification by regulation of Gas6, presumably via EGF receptor/ERK axis.

The Co-Design/Co-Development and Evaluation of an Online Frailty Check Application for Older Adults: Participatory Action Research with Older Adults.

Frailty is an age-related condition characterized by a decline in physical capacity with an increased vulnerability to stressors. During the COVID-19 pandemic, there was considerable progression in frailty in older adults. Therefore, an online frailty check (FC) is required for continuous screening, especially acceptable to older adults. We aimed to co-design/co-develop an online FC application with FC supporters who were facilitators in a pre-existing onsite FC program in the community. It consisted of a self-assessment of sarcopenia and an 11-item questionnaire assessing dietary, physical, and social behaviors. Opinions obtained from FC supporters (median 74.0 years) were categorized and implemented. The usability was assessed using the system usability scale (SUS). For both FC supporters and participants (n = 43), the mean score was 70.2 ± 10.3 points, which implied a "marginally high" acceptability and a "good" adjective range. Multiple regression analysis showed that the SUS score was significantly correlated with onsite-online reliability, even after adjusting for age, sex, education level, and ICT proficiency (b = 0.400, 95% CI: 0.243-1.951, p = 0.013). We also validated the online FC score, which showed a significant association between onsite and online FC scores (R = 0.670, p = 0.001). In conclusion, the online FC application is an acceptable and reliable tool to check frailty for community-dwelling older adults.

Oral frailty as a risk factor for mild cognitive impairment in community-dwelling older adults: Kashiwa study.

BACKGROUND: Oral frailty is defined as a slight decline in comprehensive oral function and can predict the onset of adverse health outcomes including morbidity in community-dwelling older adults. Previously, the number of remaining teeth and masticatory status had been suggested to be associated with cognitive decline. The effects of comprehensive oral condition on cognitive decline have not been adequately examined. In this study, we aimed to examine whether oral frailty is associated with new-onset mild cognitive impairment (MCI) among community-dwelling older adults. METHODS: Two thousand and forty-four participants of a longitudinal cohort study in Kashiwa City, Chiba Prefecture, without cognitive decline who participated in at least one follow-up survey, were included. New-onset MCI was assessed using the Mini-Mental State Examination (score < 27 defined as MCI). Oral frailty was evaluated based on six components including the number of remaining teeth, masticatory status, tongue pressure, oral motor skills, and subjective difficulties in eating and swallowing. "Oral non-frailty" was defined as good performance on all six measures, "oral pre-frailty" was defined as poor performance on one or two measures, and "oral frailty" was defined as poor performance on three or more measures. Statistical analysis was performed, mainly using a Cox proportional hazards model. RESULTS: Of the 1410 participants who did not fit the exclusion criteria (mean 72.4 ± 5.2 years; 49 % female), 19 % had new-onset MCI during the follow-up period. When comparing the status of oral frailty (non-frailty, oral pre-frailty, and oral frailty), the oral frailty group had a significantly higher hazard ratio for new-onset MCI than the other groups, even after adjusting for confounding factors. Among the six components, a decrease in the number of remaining teeth, low tongue pressure, and difficulty eating tough foods significantly correlated with new-onset MCI. Additionally, we found individuals with co-existing oral frailty and physical frailty to be associated with an increased risk of MCI. However, no significant increase in hazard ratio was observed in participants with either physical or oral frailty. CONCLUSIONS: The study findings suggest that oral frailty could predict the risk of new-onset MCI in community-dwelling older adults. Further, we found that oral frailty with physical frailty exacerbated this risk, implying the existence of direct or additive effects on cognitive dysfunction. Comprehensive oral health focusing on maintaining eating function can be a strategy to prevent MCI and delay dementia in community-dwelling older adults.

Population-based reference values for tongue pressure in Japanese older adults: A pooled analysis of over 5,000 participants.

PURPOSE: To establish age- and sex-specific population reference values for tongue pressure (TP) in community-dwelling Japanese older adults. METHODS: For this analysis, we pooled four population-based studies on community-dwelling adults aged ≥65 years that measured TP using a JMS tongue pressure measuring device. We calculated the means and deciles of TP per 5-year age group for each sex. We also estimated age trends in TP for men and women. RESULTS: In total, 5,083 individuals (2,150 men and 2,933 women, with a mean [standard deviation] age of 75.2 [6.5] years) were included in the present analysis. In male participants, the mean (standard deviation) TPs for ages 65-69, 70-74, 75-79, 80-84, and ≥85 years were 34.0 (8.4), 32.2 (8.1), 30.8 (8.3), 28.4 (8.9), and 24.4 (8.2) kPa, respectively. In female participants, the corresponding values were 31.5 (7.1), 30.5 (7.5), 29.6 (7.3), 28.4 (8.0), and 26.4 (7.6) kPa, respectively. For both sexes, there were significant declining trends in TP with advanced age. In addition, the interaction between age and sex had a significant effect on TP (regression coefficient [95% confidence interval] = -0.18 [-0.25 to -0.11] when age was modeled as a continuous variable and sex was modeled as a categorical variable [coded as 0=women, 1=men]). CONCLUSIONS: This study determined age- and sex-specific reference values for TP, presented as means and deciles, in community-dwelling Japanese older adults aged ≥65 years. This study also demonstrated sex differences in age-related declines in TP.

Sirtuin 1 retards hyperphosphatemia-induced calcification of vascular smooth muscle cells.

OBJECTIVE: Arterial calcification is associated with cardiovascular disease as a complication of advanced atherosclerosis. Aged vascular cells manifest some morphological features of a senescent phenotype. Recent studies have demonstrated that mammalian sirtuin 1 (SIRT1), a histone deacetylase, is an exciting target for cardiovascular disease management. Here, we investigated the role of SIRT1 in a calcification model of vascular smooth muscle cells (SMCs). METHODS AND RESULTS: In adenine-induced renal failure rats with hyperphosphatemia, massive calcification was induced in the aortic media. Senescence-associated ß-galactosidase (SAß-gal) activity, a marker of cellular senescence, in medial SMCs was significantly increased, and its induction was positively associated with the degree of calcification. In cultured SMCs, inorganic phosphate (Pi) stimulation dose-dependently increased SAß-gal-positive cells, and Pi-induced senescence was associated with downregulation of SIRT1 expression, leading to p21 activation. The activation via SIRT1 downregulation was blunted by inhibition of Pi cotransporter. Activation of SIRT1 by resveratrol significantly reduced the senescence-associated calcification. Conversely, SIRT1 knockdown by small interfering RNA accelerated the Pi-induced SMC senescence and subsequent calcification. In addition, SIRT1 knockdown induced phenotypic change from a differentiated state to osteoblast-like cells. The senescence-related SMC calcification was completely prevented by p21 knockdown. In addition to Pi-induced premature senescence, SMCs with replicative senescence were also more sensitive to Pi-induced calcification compared with young SMCs, and this finding was attributable to augmented p21 expression. CONCLUSIONS: SIRT1 plays an essential role in preventing hyperphosphatemia-induced arterial calcification via inhibition of osteoblastic transdifferentiation. In addition, Pi-induced SMC calcification may be associated with both premature and replicative cellular senescence.

Impact of social engagement on the development of sarcopenia among community-dwelling older adults: A Kashiwa cohort study.

AIM: How older adults develop sarcopenia in the community setting is unclear. Focusing on social engagement, we aimed to validate our hypothesized model of sarcopenia development with various contributing factors, such as physical activity, oral function, psychological status and nutritional status. We also clarified direct and indirect effects of social engagement, physical activity, nutritional status, oral function and psychological status on new-onset sarcopenia. METHODS: We analyzed 1483 participants' (72.6 ± 5.4 years) longitudinal data from the Kashiwa study. Sarcopenia was assessed in all the surveys in the Kashiwa study. Measures regarding social engagement, physical activity, oral function, psychological status and nutritional status were assessed at baseline. Structural equation modeling was used to analyze the efficiency of the hypothesized model, and calculate direct and indirect effects of factors affecting new-onset sarcopenia. RESULTS: Over the follow-up period (median 6 years [interquartile range 4-6 years]), 12% of individuals developed new-onset sarcopenia. Our structural hypothesis model starting from social engagement to new-onset sarcopenia was suitable (root mean square error of approximation = 0.031, goodness-of-fit index = 0.967, adjusted goodness-of-fit index = 0.954, comparative fix index = 0.911, parsimonious comparative fit index = 0.755; all paths were significant), showing direct effects of social engagement on psychological status, physical activity and oral function, and indirect effects on nutritional status through oral function and psychological status. CONCLUSIONS: The present results showed that social engagement could potentially decrease new-onset sarcopenia risks by influencing multidimensional factors, such as physical activity, oral function, and psychological and nutritional status. To prevent sarcopenia, it might be essential to promote social engagement through populational approaches. Geriatr Gerontol Int 2022; 22: 384-391.

Associations of multi-faceted factors and their combinations with frailty in Japanese community-dwelling older adults: Kashiwa cohort study.

PURPOSE: To investigate the cross-sectional associations of nutrition-related, physical, and social factors and their combinations with frailty in community-dwelling older adults. METHODS: The participants in this study were 1,161 adults (≥ 65 years). The outcome was frailty severity as assessed by the Cardiovascular Health Study index (score 0: no-frailty, score 1-2: pre-frailty, score ≥ 3: frailty). The independent variables included nutrition-related factors comprising a balanced diet and oral functions, physical factors including exercise habits and awareness of physical function, and social factors including social organizational participation, social support, and social networks. According to the quantity of factors the participants met, four groups were divided. An ordinal logistic regression analysis was conducted to evaluate the associations between frailty severity and the three factors individually and comprehensively. RESULTS: The mean age was 74.6 (±5.4) and the women is 47.8%. 47.7% and 8.7% of participants had pre-frailty or frailty respectively. Meeting no nutrition-related, physical, or social factors individually showed significantly associated with greater adjusted odds ratio (aORs) of frailty severity [aORs (95% confidence interval)]: nutrition-related factors: 1.58 [1.25-2.01]; physical factors: 2.53 [1.98-3.22]; social factors: 1.52 [1.19-1.93]. Referred to participants who met three factors, participants who met two, one, or none showed significantly associated with increased aORs of frailty severity: two: 1.88 [1.34-2.65]; one: 2.97 [2.09-4.23]; none: 7.52 [4.87-11.62]. CONCLUSION: Meeting no nutrition-related, physical, or social factors individually showed higher risk of being (pre-)frailty. Meeting three factors showed lowest risk of being (pre-)frailty and this risk increased with the quantity decreasing of met factors.

Lower urinary tract symptoms and functional ability in older adults: a community-based cross-sectional study.

OBJECTIVES: Functional ability, or the ability to live actively in older age, is essential for healthy ageing. This study assessed the association between the five types of lower urinary tract symptoms (LUTS) and functional ability among community-dwelling older adults (≥65 years old). DESIGN: A cross-sectional study. SETTING: Community-dwelling older adults (≥65 years old) randomly selected from the basic resident register of Kashiwa city as part of the Kashiwa study. PARTICIPANTS: The study included 916 community-dwelling older adults (481 male participants) in Japan. OUTCOME MEASURES: A self-administered questionnaire was used to collect data regarding LUTS, which included frequency, nocturia, urgency, urinary incontinence and overactive bladder (OAB). Functional ability was measured using the Japan Science and Technology Agency Index of Competence. Sex-stratified logistic regression analyses were conducted, adjusting age, obesity, alcohol consumption, polypharmacy and comorbidities. RESULTS: Male participants experienced symptoms of frequency, nocturia, urgency, urinary incontinence and OAB at rates of 68.0%, 89.0%, 16.0%, 3.7% and 4.3%, respectively. Female participants experienced these symptoms at rates of 68.3%, 80.0%, 11.0%, 7.4% and 8.5%, respectively. Among male participants, lower functional ability was only associated with nocturia (≥3 times/night) (adjusted OR (AOR): 1.71, 95% CI 1.05 to 2.79). Contrarily, lower functional ability among female participants was significantly associated with frequency (AOR: 1.61, 95% CI 1.04 to 2.49), urgency (AOR: 2.06, 95% CI 1.08 to 3.95) and OAB (AOR: 2.43, 95% CI 1.15 to 5.11). CONCLUSION: The different associations between LUTS and functional ability by sex might be related to differences in the effect of comorbidities and physical fatigue. Our results help clarify the multifaceted effects of LUTS in old age, the need for early detection and treatment of LUTS, and the importance of maintaining functional ability.

Associations of Nutrition-Related, Physical, and Social Factors and Their Combinations with Sarcopenia in Community-Dwelling Older Adults: Kashiwa Cohort Study.

BACKGROUND: Sarcopenia is a major cause of frailty, which relates to nutrition-related, physical, and social factors. In this study, we aimed to discuss the cross-sectional association of sarcopenia with the above three factors both individually and comprehensively. METHODS: Overall, 1257 older adults (≥65 years old) participated in this study. Sarcopenia was determined via the Asian Working Group for Sarcopenia 2019 criteria. The independent variables for nutrition-related, physical, and social factors and especially their criteria for health condition were defined separately. Binomial logistic regression analysis was carried out to testify the associations of sarcopenia with three factors individually and in combination. RESULTS: The mean age was 74.6 (±5.5), and women were 47.7%. Sarcopenia prevalence was 7.5%. Participants who did not meet the criteria of nutritional health, physical fitness, or social robustness independently had significant associations with a higher adjusted odds ratio (aOR) of sarcopenia or its indices of lower grip strength, muscle mass, or gait speed. In comparison to participants meeting three criteria, those who met two, one, or none showed (marginally) significant association with increased aOR for sarcopenia (aOR (95% confidence interval)): two: 1.97 (0.84-4.64); one: 2.35 (1.00-5.23); none: 5.52 (2.30-13.23). CONCLUSIONS: Comprehensive countermeasures with the above three factors are indispensable for sarcopenia prevention.