A genome-wide association study identifies a locus associated with knee extension strength in older Japanese individuals.

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10-8). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia.

Corrigendum: Playing basketball and volleyball during adolescence is associated with higher bone mineral density in old age: the Bunkyo Health Study.

[This corrects the article DOI: 10.3389/fphys.2023.1227639.].

Assessing interstitial fluid dynamics in type 2 diabetes mellitus and prediabetes cases through diffusion tensor imaging analysis along the perivascular space.

Background and purpose: Glymphatic system in type 2 diabetes mellitus (T2DM) but not in the prodrome, prediabetes (Pre-DM) was investigated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Association between glymphatic system and insulin resistance of prominent characteristic in T2DM and Pre-DM between is yet elucidated. Therefore, this study delves into the interstitial fluid dynamics using the DTI-ALPS in both Pre-DM and T2DM and association with insulin resistance. Materials and methods: In our cross-sectional study, we assessed 70 elderly individuals from the Bunkyo Health Study, which included 22 with Pre-DM, 18 with T2DM, and 33 healthy controls with normal glucose metabolism (NGM). We utilized the general linear model (GLM) to evaluate the ALPS index based on DTI-ALPS across these groups, considering variables like sex, age, intracranial volume, years of education, anamnesis of hypertension and hyperlipidemia, and the total Fazekas scale. Furthermore, we have explored the relationship between the ALPS index and insulin resistance, as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) using GLM and the same set of covariates. Results: In the T2DM group, the ALPS index demonstrated a reduction compared with the NGM group [family-wise error (FWE)-corrected p < 0.001; Cohen's d = -1.32]. Similarly, the Pre-DM group had a lower ALPS index than the NGM group (FWE-corrected p < 0.001; Cohen's d = -1.04). However, there was no significant disparity between the T2DM and Pre-DM groups (FWE-corrected p = 1.00; Cohen's d = -0.63). A negative correlation was observed between the ALPS index and HOMA-IR in the combined T2DM and Pre-DM groups (partial correlation coefficient r = -0.35, p < 0.005). Conclusion: The ALPS index significantly decreased in both the pre-DM and T2DM groups and showed a correlated with insulin resistance. This indicated that changes in interstitial fluid dynamics are associated with insulin resistance.

Low Handgrip Strength (Possible Sarcopenia) With Insulin Resistance Is Associated With Type 2 Diabetes Mellitus.

Context: Older adults with sarcopenic obesity are at high risk for type 2 diabetes mellitus (T2DM). However, few East Asians have sarcopenic obesity. Since many East Asians have insulin resistance (IR) without obesity, it is possible that older East Asians with sarcopenia and IR might be at high risk for T2DM. However, this relationship has not been studied. Methods: This cross-sectional study included 1629 older adults aged 65 to 84 years registered in the Bunkyo Health Study. All underwent a 75-g oral glucose tolerance test and handgrip strength measurement. Participants were classified into 4 groups by possible sarcopenia (handgrip strength <28 kg in men and <18 kg in women) and IR status (triglyceride glucose [TyG] index ≥8.79 for men and ≥8.62 for women [third quartile]). Modified Poisson regression was used to estimate relative risk (RR) and 95% CIs for T2DM with adjustment for confounding factors. Results: The mean age was 73.1 ± 5.4 years. T2DM was diagnosed in 212 (13.0%) participants. After adjusting for age, sex, body mass index, use of lipid-lowering medications, hypertension, and cardiovascular disease, possible sarcopenia and IR were associated with T2DM, with their coexistence showing a notably stronger association (control: RR, 1.00 [Reference]; possible sarcopenia: RR, 1.55 [95% CI, 1.04-2.30]; IR: RR, 2.69 [95% CI, 1.99-3.65]; and IR possible sarcopenia: RR, 4.76 [95% CI, 3.34-6.79]). Conclusion: Possible sarcopenia based on low handgrip strength and IR based on the TyG index are independently associated with T2DM in older Japanese individuals. Their coexistence shows a particularly strong association with T2DM.

Fat Accumulation and Elevated Free Fatty Acid Are Associated With Age-Related Glucose Intolerance: Bunkyo Health Study.

Context: Older adults have a high prevalence of new-onset diabetes, often attributed to age-related decreases in insulin sensitivity and secretion. It remains unclear whether both insulin sensitivity and secretion continue to deteriorate after age 65. Objective: To investigate the effects of aging on glucose metabolism after age 65 and to identify its determinants. Methods: This cross-sectional study involved 1438 Japanese older adults without diabetes. All participants underwent a 75-g oral glucose tolerance test (OGTT). Body composition and fat distribution were measured with dual-energy X-ray absorptiometry and magnetic resonance imaging. Participants were divided into 4 groups by age (65-69, 70-74, 75-79, and 80-84 years) to compare differences in metabolic parameters. Results: Mean age and body mass index were 73.0 ± 5.4 years and 22.7 ± 3.0 kg/m2. The prevalence of newly diagnosed diabetes increased with age. Fasting glucose, fasting insulin, the area under the curve (AUC)-insulin/AUC-glucose and insulinogenic index were comparable between groups. AUC-glucose and AUC-insulin during OGTT were significantly higher and Matsuda index and disposition index (Matsuda index · AUC-insulin/AUC-glucose) were significantly lower in the age 80-84 group than in the age 65-69 group. Age-related fat accumulation, particularly increased visceral fat area (VFA), and elevated free fatty acid (FFA) levels were observed. Multiple regression revealed strong correlations of both Matsuda index and disposition index with VFA and FFA. Conclusion: Glucose tolerance declined with age in Japanese older adults, possibly due to age-related insulin resistance and ß-cell deterioration associated with fat accumulation and elevated FFA levels.

Medial meniscus extrusion is invariably observed and consistent with tibial osteophyte width in elderly populations: The Bunkyo Health Study.

We reported that the full-length width of medial tibial osteophytes comprising cartilage and bone parts correlates with medial meniscus extrusion (MME) in early-stage knee osteoarthritis (OA). However, no data exist on the prevalence of MME and its relationship with osteophytes in the elderly population. 1191 elderly individuals (females 57%; 72.9 years old on average) in the Bunkyo Health Study underwent standing plain radiograph and proton density-weighted MRI on knee joints. MRI-detected OA changes were evaluated according to the Whole-Organ Magnetic Resonance Imaging Score. A new method of assessing the cartilage and bone parts of osteophytes was developed using pseudo-coloring images of proton density-weighted fat-suppressed MRI. Most subjects showed Kellgren-Lawrence grade 1 or 2 radiographic medial knee OA (88.1%), MME (98.7%, 3.90 ± 2.01 mm), and medial tibial osteophytes (99.3%, 3.27 ± 1.50 mm). Regarding OA changes, MME was closely associated with the full-length width of medial tibial osteophytes (ß = 1.114; 95% CI 1.069-1.159; p < 0.001) in line with osteophyte width (intraclass correlation coefficient, 0.804; 95% CI 0.783-0.823). Our data revealed that MME and medial tibial osteophytes are observed in the elderly and demonstrate that the degree of MME is consistent with the full-length width of medial tibial osteophytes, suggesting that osteophytes might be implicated in MME.

Playing basketball and volleyball during adolescence is associated with higher bone mineral density in old age: the Bunkyo Health Study.

Introduction: Exercise is beneficial for increasing areal bone mineral density (aBMD) in adolescence and maintaining it in old age. Moreover, high-impact sports are more effective than low-impact sports in increasing aBMD. This study aimed to determine the types of adolescent sports played in school-based sports clubs associated with aBMD in old age. Methods: In total, 1,596 older adults (681 men and 915 women, age: 65-84 years) living in an urban area of Japan were evaluated for the femoral neck and lumbar spine aBMD using dual-energy X-ray absorptiometry. The association between adolescent sports played in sports clubs and aBMD in old age was analyzed using multiple regression analysis, with femoral neck and lumbar spine aBMD as dependent variables, and sports type and participant characteristics such as age, body weight, and serum 25-hydroxyvitamin D [25(OH)D] level, as independent variables. Results: For the femoral neck, basketball was associated with aBMD in older men (ß = 0.079, p < 0.05) and women (ß = 0.08, p < 0.01), whereas current body weight and 25(OH)D level were associated with aBMD in both sexes. For the lumbar spine, volleyball (ß = 0.08, p < 0.01) and swimming (ß = 0.06, p < 0.05) was significantly associated with lumbar spine aBMD, whereas current body weight, 25(OH)D, and diabetes mellitus were associated with aBMD in older women. Conclusion: Both men and women who played basketball in adolescence had higher femoral neck aBMD in old age. Moreover, women who played volleyball in adolescence had higher lumbar spine aBMD in old age.

Reduced gray matter volume in the default-mode network associated with insulin resistance.

Insulin resistance may lead to structural and functional abnormalities of the human brain. However, the mechanism by which insulin resistance impairs the brain remains elusive. In this study, we used two large neuroimaging databases to investigate the brain regions where insulin resistance was associated with the gray matter volume and to examine the resting-state functional connectivity between these brain regions and each hypothalamic nucleus. Insulin resistance was associated with reduced gray matter volume in the regions of the default-mode and limbic networks in the cerebral cortex in older adults. Resting-state functional connectivity was prominent between these networks and the paraventricular nucleus of the hypothalamus, a hypothalamic interface connecting functionally with the cerebral cortex. Furthermore, we found a significant correlation in these networks between insulin resistance-related gray matter volume reduction and network paraventricular nucleus of the hypothalamus resting-state functional connectivity. These results suggest that insulin resistance-related gray matter volume reduction in the default-mode and limbic networks emerged through metabolic homeostasis mechanisms in the hypothalamus.

Physical inactivity induces insulin resistance in plantaris muscle through protein tyrosine phosphatase 1B activation in mice.

Inactivity causes insulin resistance in skeletal muscle and exacerbates various lifestyle-related diseases. We previously found that 24-h hindlimb cast immobilization (HCI) of the predominantly slow-twitch soleus muscle increased intramyocellular diacylglycerol (IMDG) and insulin resistance by activation of lipin1, and HCI after a high-fat diet (HFD) further aggravated insulin resistance. Here, we investigated the effects of HCI on the fast-twitch-predominant plantaris muscle. HCI reduced the insulin sensitivity of plantaris muscle by approximately 30%, and HCI following HFD dramatically reduced insulin sensitivity by approximately 70% without significant changes in the amount of IMDG. Insulin-stimulated phosphorylation levels of insulin receptor (IR), IR substrate-1, and Akt were reduced in parallel with the decrease in insulin sensitivity. Furthermore, tyrosine phosphatase 1B (PTP1B), a protein known to inhibit insulin action by dephosphorylating IR, was activated, and PTP1B inhibition canceled HCI-induced insulin resistance. In conclusion, HCI causes insulin resistance in the fast-twitch-predominant plantaris muscle as well as in the slow-twitch-predominant soleus muscle, and HFD potentiates these effects in both muscle types. However, the mechanism differed between soleus and plantaris muscles, since insulin resistance was mediated by the PTP1B inhibition at IR in plantaris muscle.

A Short-Term High-Fat Diet Worsens Insulin Sensitivity with Changes in Metabolic Parameters in Non-Obese Japanese Men.

A short-term high-calorie high-fat diet (HCHFD) impairs insulin sensitivity in non-obese South Asian but not Caucasian men; however, the effect of short-term HCHFD on insulin sensitivity in East Asians is unknown. We recruited 21 healthy non-obese Japanese men to evaluate metabolic parameters and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus a 45% energy excess with dairy fat supplementation. We evaluated tissue-specific insulin sensitivity and metabolic clearance rate of insulin (MCRI) using a two-step hyperinsulinemic euglycemic clamp, glucose tolerance using the glucose tolerance test, and measured ectopic fat in muscle and the liver using ¹H-magnetic resonance spectroscopy. The primary outcome of this study was insulin sensitivity measured by the clamp study. The secondary/exploratory outcomes were other metabolic changes. After HCHFD, levels of circulating lipopolysaccharide binding protein (LBP), a marker of endotoxemia, increased by 14%. In addition, intramyocellular lipid levels in the tibialis anterior and soleus and intrahepatic lipid levels increased by 47%, 31%, and 200%, respectively. Insulin sensitivity decreased by 4% in muscle and 8% in liver. However, even with reduced insulin sensitivity, glucose metabolism was maintained by increased serum insulin concentrations due to lower MCRI and higher endogenous insulin secretion during the clamp. Glucose levels during the meal tolerance test were comparable before and after HCHFD. In conclusion, short-term HCHFD impaired insulin sensitivity in the muscle and livers of non-obese Japanese men with increased LBP and ectopic fat accumulation. Elevated insulin levels from modulated insulin secretion and clearance might contribute to the maintenance of normal glucose metabolism during the clamp and meal tolerance test.

Anterior meniscus extrusion is associated with anterior tibial osteophyte width in knee osteoarthritis - The Bunkyo Health Study.

Background: In knee osteoarthritis (OA), medial meniscus extrudes both medially and anteriorly. We reported that full-length width of medial tibial osteophyte, which comprises cartilage and bone parts, is directly associated with medial meniscus extrusion in early-stage knee OA and hypothesized that anterior tibial osteophyte (ATO) is also associated with anterior meniscus extrusion (AME). Thus, we aimed to examine their prevalence and relationship. Methods: Elderly subjects (638 females and 507 males; average 72.9 years old) in the Bunkyo Health Study cohort were enrolled. MRI-detected OA changes were evaluated according to the Whole Organ Magnetic Resonance Imaging Score. ATO was evaluated using the method which can assess both cartilage and bone parts of osteophyte by pseudo-coloring images of proton density-weighted fat-suppressed MRI. Results: Most subjects showed the Kellgren-Lawrence grade 1/2 of the medial knee OA (88.1%), AME (94.3%, 3.7 â€‹± â€‹2.2 â€‹mm), and ATO (99.6%, 4.2 â€‹± â€‹1.5 â€‹mm). Among the OA changes, AME was most closely associated with full-length width of ATO (multivariable ߠ​= â€‹0.877, p â€‹< â€‹0.001). The area under the receiver operating characteristic curve for determining the presence of AME as evaluated by ATO width was 0.75 (95% confidence interval 0.60-0.84, p â€‹< â€‹0.001). The odds ratio for the presence of AME as evaluated by ATO width at 2.9 â€‹mm was 7.16 (4.23-12.15, p â€‹< â€‹0.001, age, gender, BMI, and K-L adjusted). Conclusions: AME and ATO were inevitably observed in the elderly subjects and AME was closely associated with full-length width of ATO. Our study provides the first evidence on the close relationship between AME and ATO in knee OA.

A chronic high-fat diet does not exacerbate muscle atrophy in fast-twitch skeletal muscle of aged mice.

NEW FINDINGS: What is the central question of this study? Ageing leads to a loss of mass in skeletal muscle, but the effect of obesity on ageing-related muscle wasting is unclear. In this study, we aimed to demonstrate the specific effect of obesity on fast-twitch skeletal muscle in ageing. What is the main finding and its importance? Our findings show that the obesity induced by long-term ingestion of a high-fat diet does not aggravate muscle wasting in fast-twitch skeletal muscle of aged mice, indicating that the present study provides morphological characteristics for skeletal muscle of sarcopenic obesity. ABSTRACT: Obesity and ageing reduce muscle mass and lead to deficits in muscle maintenance, but it is not known whether obesity accelerates muscle wasting additively in the setting of ageing. We investigated morphological characteristics in fast-twitch extensor digitorum longus (EDL) muscle of mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 months. The fast-twitch EDL muscle was harvested, and the muscle fibre-type composition, individual muscle cross-sectional area and myotube diameter were measured. We found an increase in the percentage of type IIa and IIx myosin heavy chain fibres in the whole EDL muscle, but a decrease in type IIB myosin heavy chain in both HFD protocols. The cross-sectional area and myofibre diameter were lower in both groups of aged mice (after 20 months of LFD or HFD) compared with young mice (after 4 months of the diets), but there were no differences between mice fed LFD or HFD for 20 months. These data suggest that long-term feeding of HFD does not aggravate muscle wasting in fast-twitch EDL muscle of male mice.

Effects of exercise habits in adolescence and older age on sarcopenia risk in older adults: the Bunkyo Health Study.

BACKGROUND: Sarcopenia, defined as an age-associated loss of skeletal muscle mass and function, is a major risk factor for requiring long-term care. Because physical activity in adolescence and older age enhances peak muscle function in youth and prevents muscle function decline in older age, older adults with exercise habits during both periods may be at a lower risk for sarcopenia. We investigated the relationship between exercise habits in adolescence and older age and sarcopenia and its components in community-dwelling older Japanese adults. METHODS: This study included 1607 community-dwelling individuals (aged 65-84, medians 73 years, 679 men and 928 women) with complete health examinations, including measurements of skeletal muscle index, handgrip strength and gait speed, who were enrolled in the Bunkyo Health Study. We divided the participants into four groups according to exercise habits in adolescence and older age: no exercise in either period (none-none; NN), exercise only in adolescence (active-none; AN), exercise only in older age (none-active; NA) and exercise in both periods (active-active; AA). Multivariate-adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each group for the prevalence of sarcopenia, defined as low muscle mass and low muscle performance, as compared with the NN group. Low muscle performance was defined as low muscle strength and/or low gait speed. RESULTS: The total prevalence of sarcopenia was 6.6% (45/679) in men and 1.7% (16/928) in women, the total prevalence of low muscle mass was 14.3% (97/679) in men and 5.2% (48/928) in women, and the total prevalence of low muscle performance was 25.6% (174/679) in men and 19.6% (182/928) in women. In men, the ORs (95% CIs) for sarcopenia, low muscle mass and low muscle performance were significantly lower in the AA group (sarcopenia: 0.29 [0.09-0.95], P = 0.041; low muscle mass: 0.21 [0.09-0.52], P = 0.001; and low muscle performance: 0.52 [0.28-0.97], P = 0.038). In women, the OR (95% CI) for low muscle performance was significantly lower in the AA group than in the other groups (0.48 [0.27-0.84], P = 0.010), whereas none of the ORs for sarcopenia and low muscle mass were significant. CONCLUSIONS: Older men with exercise habits in both adolescence and older age were at a lower risk of sarcopenia, low muscle mass and low muscle performance, whereas older women with exercise habits at both time periods were at a lower risk of low muscle performance.

Glymphatic system impairment in nonathlete older male adults who played contact sports in their youth associated with cognitive decline: A diffusion tensor image analysis along the perivascular space study.

Background and purpose: Exposure to contact sports in youth causes brain health problems later in life. For instance, the repetitive head impacts in contact sports might contribute to glymphatic clearance impairment and cognitive decline. This study aimed to assess the effect of contact sports participation in youth on glymphatic function in old age and the relationship between glymphatic function and cognitive status using the analysis along the perivascular space (ALPS) index. Materials and methods: A total of 52 Japanese older male subjects were included in the study, including 12 who played heavy-contact sports (mean age, 71.2 years), 15 who played semicontact sports (mean age, 73.1 years), and 25 who played noncontact sports (mean age, 71.3 years) in their youth. All brain diffusion-weighted images (DWIs) of the subjects were acquired using a 3T MRI scanner. The ALPS indices were calculated using a validated semiautomated pipeline. The ALPS indices from the left and right hemispheres were compared between groups using a general linear model, including age and years of education. Furthermore, partial Spearman's rank correlation tests were performed to assess the correlation between the ALPS indices and cognitive scores (Mini-Mental State Examination and the Japanese version of the Montreal Cognitive Assessment [MoCA-J]) after adjusting for age years of education and HbA1c. Results: The left ALPS index was significantly lower in the heavy-contact and semicontact groups than that in the noncontact group. Although no significant differences were observed in the left ALPS index between the heavy-contact and semicontact groups and in the right ALPS index among groups, a trend toward lower was found in the right ALPS index in individuals with semicontact and heavy-contact compared to the noncontact group. Both sides' ALPS indices were significantly positively correlated with the MoCA-J scores. Conclusion: The findings indicated the potential adverse effect of contact sports experience in youth on the glymphatic system function in old age associated with cognitive decline.

Neuroimaging findings related to glymphatic system alterations in older adults with metabolic syndrome.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Reduced glymphatic flow has been observed in rat models of type 2 diabetes and hypertension, indicating the role of vascular risk factors in the glymphatic system. However, little is known about how vascular risk factors affect the human glymphatic system. The present study aims to assess the relationships between metabolic syndrome (MetS), a cluster of vascular risk factors, and the glymphatic system function using diffusion magnetic resonance imaging (MRI)-based measures of water diffusivity in the glymphatic compartments, including the brain interstitial space and perivascular spaces around the deep medullary vein. We hypothesized that vascular risk factors are associated with glymphatic dysfunction, leading to cognitive impairment in older adults. METHODS: This cross-sectional study assessed 61 older adults (age range, 65-82 years) who had participated in the Bunkyo Health Study, including 15 healthy controls (mean age, 70.87 ± 4.90 years) and 46 individuals with MetS (mean age, 71.76 ± 4.61 years). Fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. RESULTS: After adjusting for age, sex, years of education, total Fazekas scale, Pittsburgh sleep quality index (PSQI) score, and intracranial volume (ICV), a significantly (P = 0.030; Cohen's d = 1.01) higher FW was observed in individuals with MetS than in the healthy controls. Furthermore, individuals with MetS had a significantly (P = 0.031; Cohen's d = 0.86) lower ALPS index than the healthy controls, with age, sex, years of education, total Fazekas scale, PSQI score, ICV, fractional anisotropy, and mean diffusivity included as confounding factors. Higher FW was significantly associated with lower ALPS index (r = -0.37; P = 0.004). Multiple linear regression (MLR) with backward elimination analyses showed that higher diastolic blood pressure (BP; standardized ß = 0.33, P = 0.005) was independently associated with higher FW, whereas higher fasting plasma glucose levels (standardized ß = -0.63, P = 0.002) or higher Brinkman index of cigarette consumption cumulative amount (standardized ß = -0.27, P = 0.022) were associated with lower ALPS index. The lower ALPS index (standardized ß, 0.28; P = 0.040) was associated with poorer global cognitive performance, which was determined using the Japanese version of the Montreal Cognitive Assessment (MOCA-J) scores. Finally, partial correlation analyses showed a significant correlation between higher FW and lower MOCA-J scores (r = -0.35; P = 0.025) and between higher FW and higher diastolic BP (r = 0.32, P = 0.044). CONCLUSION: The present study shows the changes in diffusion MRI-based measures reflected by the higher FW and lower ALPS index in older adults with MetS, possibly due to the adverse effect of vascular risk factors on the glymphatic system. Our findings also indicate the associations between the diffusion MRI-based measures and elevated diastolic BP, hyperglycemia, smoking habit, and poorer cognitive performance. However, owing to the limitations of this study, the results should be cautiously interpreted.

Association of ALDH2 Genotypes and Alcohol Intake with Dietary Patterns: The Bunkyo Health Study.

Dietary habits are associated with various diseases and assessed by dietary patterns (DPs). Since the ALDH2 genotype is correlated with alcohol and several food preferences, this genotype is probably associated with DPs. In this cross-sectional study of 1612 elderly adults, we investigated the effects of the ALDH2 genotype on DPs and the mediating role of alcohol intake. We identified the ALDH2 genotype and conducted a dietary history survey, then used principal component analysis to determine DPs for each gender. We performed multiple regression analysis to determine the independent contribution of the ALDH2 genotype and alcohol intake to DP scores. We identified three DPs: the "Japanese side dish type" (DP1), the "Japanese dish with alcohol type" (DP2), and the "Western dish with alcohol type" (DP3). In men, the single nucleotide polymorphism ALDH2 rs671 was significantly associated with all DP scores. When alcohol intake was added as a covariate, ALDH2 rs671 was still significantly correlated with the DP2 score but not with the DP1 or DP3 score, and alcohol intake was significantly correlated with all DP scores. In women, ALDH2 rs671 was significantly associated with the DP2 and DP3 scores; however, after adding alcohol intake as a covariate, these associations disappeared, and alcohol intake significantly correlated with all DP scores. In conclusion, the ALDH2 genotype was associated with several DPs in elderly adults, but most associations were mediated by alcohol intake.

Impaired fatigue resistance, sarcoplasmic reticulum function, and mitochondrial activity in soleus muscle of db/db mice.

Type 2 diabetes mellitus (T2DM) is characterized by reduced exercise tolerance due to increased fatigability in skeletal muscle. In this study, we investigated muscle fatigue resistance of soleus (SOL) muscle in obese type 2 diabetic model mice (db/db). No differences in muscle volume, absolute force, or specific force in SOL muscle were observed between db/db mice and control mice (db/+), while fatigue resistance evaluated by repeated tetanic contractions was significantly lower in db/db mice (30th tetani, db/+: 63.7 ± 4.7%, db/db: 51.3 ± 4.8%). The protein abundance related to Ca2+ release from the sarcoplasmic reticulum (SR) in SOL muscle was not different between db/db mice and db/+ mice, while SR Ca2+ -ATPase (Ca2+ reuptake to SR) protein was decreased in db/db mice compared to db/+ mice (db/+: 1.00 ± 0.17, db/db: 0.60 ± 0.04, relative units). In addition, mitochondrial oxidative enzyme activity (succinate dehydrogenase) was decreased in the SOL muscle of db/db mice (p < 0.05). These data suggest that fatigue resistance in slow-twitch dominant muscle is impaired in mice with T2DM. Decreased mitochondrial oxidative enzyme activity and impairment of Ca2+ uptake to SR, or both might be involved in the mechanisms.

Prediabetes is an independent risk factor for sarcopenia in older men, but not in older women: the Bunkyo Health Study.

BACKGROUND: Sarcopenia is a major cause of disability in the elderly. Although type 2 diabetes is a risk factor for increased sarcopenia, the relationship between prediabetes and sarcopenia has not been elucidated. We aimed to examine the relationship between sarcopenia and prediabetes. METHODS: The design of this study is a cross-sectional study. We evaluated glucose metabolism using the 75-g oral glucose tolerance test and glycated haemoglobin, appendicular skeletal muscle mass, and hand grip strength in 1629 older adults living in an urban area of Tokyo, Japan. We investigated the frequency of sarcopenia in participants with normal glucose tolerance (NGT), prediabetes and diabetes. A multivariable logistic regression model was used to analyse the association between glucose tolerance and the prevalence of sarcopenia. RESULTS: The mean age of participants was 73.1 ± 5.4 years. In men, 44.3% had NGT, 26.6% had prediabetes, and 29.1% had diabetes. In women, the distribution was 56.1%, 28.8% and 15.2%. The prevalence of sarcopenia was 12.7% in men and 11.9% in women. Logistic regression revealed that prediabetes and diabetes are independent risk factors for sarcopenia in men (prediabetes, odds ratio [OR] = 2.081 [95% confidence interval {CI}: 1.031-4.199]; diabetes, OR = 2.614 [95% CI: 1.362-5.018]) and diabetes, but not prediabetes, is an independent risk factor for sarcopenia in women (prediabetes, OR = 1.036 [95% CI: 0.611-1.757]; diabetes, OR = 2.099 [95% CI: 1.146-3.844]). In both sexes, higher age (men, OR = 1.086 [95% CI: 1.028-1.146]; women, OR = 1.195 [95% CI: 1.142-1.251]), higher body fat percentage (men, OR = 1.346 [95% CI: 1.240-1.461]; women, OR = 1.218 [95% CI: 1.138-1.303]) and lower body mass index (men, OR = 0.371 [95% CI: 0.299-0.461]; women, OR = 0.498 [95% CI: 0.419-0.593]) were independent risk factors for sarcopenia. CONCLUSIONS: Although we confirmed that diabetes mellitus is associated with sarcopenia in both sexes, prediabetes is associated with sarcopenia in men, but not in women.

White matter fiber-specific degeneration in older adults with metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MetS) is defined as a complex of interrelated risk factors for type 2 diabetes and cardiovascular disease, including glucose intolerance, abdominal obesity, hypertension, and dyslipidemia. Studies using diffusion tensor imaging (DTI) have reported white matter (WM) microstructural abnormalities in MetS. However, interpretation of DTI metrics is limited primarily due to the challenges of modeling complex WM structures. The present study used fixel-based analysis (FBA) to assess the effect of MetS on the fiber tract-specific WM microstructure in older adults and its relationship with MetS-related measurements and cognitive and locomotor functions to better understand the pathophysiology of MetS. METHODS: Fixel-based metrics, including microstructural fiber density (FD), macrostructural fiber-bundle cross-section (FC), and a combination of FD and FC (FDC), were evaluated in 16 healthy controls (no components of MetS; four men; mean age, 71.31 ± 5.06 years), 57 individuals with premetabolic syndrome (preMetS; one or two components of MetS; 29 men; mean age, 72.44 ± 5.82 years), and 46 individuals with MetS (three to five components of MetS; 27 men; mean age, 72.15 ± 4.97 years) using whole-brain exploratory FBA. Tract of interest (TOI) analysis was then performed using TractSeg across 14 selected WM tracts previously associated with MetS. The associations between fixel-based metrics and MetS-related measurements, neuropsychological, and locomotor function tests were also analyzed in individuals with preMetS and MetS combined. In addition, tensor-based metrics (i.e., fractional anisotropy [FA] and mean diffusivity [MD]) were compared among the groups using tract-based spatial statistics (TBSS) analysis. RESULTS: In whole-brain FBA, individuals with MetS showed significantly lower FD, FC, and FDC compared with healthy controls in WM areas, such as the splenium of the corpus callosum (CC), corticospinal tract (CST), middle cerebellar peduncle (MCP), and superior cerebellar peduncle (SCP). Meanwhile, in fixel-based TOI, significantly reduced FD was observed in individuals with preMetS and MetS in the anterior thalamic radiation, CST, SCP, and splenium of the CC compared with healthy controls, with relatively greater effect sizes observed in individuals with MetS. Compared with healthy controls, significantly reduced FC and FDC were only demonstrated in individuals with MetS, including regions with loss of FD, inferior cerebellar peduncle, inferior fronto-occipital fasciculus, MCP, and superior longitudinal fasciculus part I. Furthermore, negative correlations were observed between FD and Brinkman index of cigarette consumption cumulative amount and between FC or FDC and the Trail Making Test (parts B-A), which is a measure of executive function, waist circumference, or low-density lipoprotein cholesterol. Finally, TBSS analysis revealed that FA and MD were not significantly different among all groups. CONCLUSIONS: The FBA results demonstrate that substantial axonal loss and atrophy in individuals with MetS and early axonal loss without fiber-bundle morphological changes in those with preMetS within the WM tracts are crucial to cognitive and motor function. FBA also clarified the association between executive dysfunction, abdominal obesity, hyper-low-density lipoprotein cholesterolemia, smoking habit, and compromised WM neural tissue microstructure in MetS.

Sarcopenic obesity is associated with cognitive impairment in community-dwelling older adults: The Bunkyo Health Study.

BACKGROUND & AIMS: Coexistence of obesity and decreased muscle strength, defined as sarcopenic obesity, is often observed in the older adults. The present study investigated whether sarcopenic obesity, defined as reduced handgrip strength and increased body mass index (BMI), is associated with cognitive impairment. METHODS: Study participants include 1615 older adults aged 65-84 years who lived in an urban area of Tokyo, Japan and participated in the Bunkyo Health Study. Mild cognitive impairment (MCI) and dementia were defined based on ≤22 points of Montreal Cognitive Assessment and ≤23 points of the Mine-Mental State Examination, respectively. Handgrip strength was measured using a dynamometer in a standing position. We divided participants into four groups according to their sarcopenia (probable) (handgrip strength <28 kg in men and <18 kg in women) and obesity status (BMI ≥25 kg/m2) as control, obesity, sarcopenia and sarcopenic obesity, and investigated the association between cognitive function, sarcopenia, and obesity status. RESULTS: Mean age was 73.1 ± 5.4 years, and 57.6% of study participants were female. The prevalence of control, obesity, sarcopenia, and sarcopenic obesity was 59.4%, 21.2%, 14.6%, and 4.7%, respectively. The prevalence of MCI and dementia, respectively, was highest in participants with sarcopenic obesity, followed by those with sarcopenia, obesity, and control. After multivariate adjustment, sarcopenic obesity was independently associated with increased odds of MCI and dementia compared with the control (MCI: 2.11 [95% confidence interval, 1.12-3.62]; dementia: 6.17 [2.50-15.27]). CONCLUSIONS: Sarcopenic obesity was independently associated with MCI and dementia among Japanese older adults. Future studies are necessary to clarify the causal relationship.