Increased BMI and late-life mobility dysfunction; overlap of genetic effects in brain regions.

BACKGROUND: How obesity earlier in life impacts upon mobility dysfunctions in late life is not well understood. Pernicious effects of excess weight on the musculoskeletal system and mobility dysfunctions are well-recognized. However, increasingly more data support the link of obesity to overall motor defects that are regulated in the brain. OBJECTIVES: To assess the causal relationship between body mass index (BMI) at midlife and performance of the Timed Up-and-Go test (TUG) in late life among a population-based longitudinal cohort of Chinese adults living in Singapore. METHODS: We evaluated genetic predispositions for BMI in 8342 participants who were followed up from measurement of BMI at average 53 years, to TUG test (as a functional mobility measure) 20 years later. RESULTS: A robust 75.83% of genetically determined BMI effects on late-life TUG scores were mediated through midlife BMI (Pindirect-effect = 9.24 × 10-21). Utilizing Mendelian randomization, we demonstrated a causal effect between BMI and functional mobility in late life (ßIVW = 0.180, PIVW = 0.001). Secondary gene enrichment evaluations highlighted down-regulation of genes at BMI risk loci that were correlated with poorer functional mobility in the substantia nigra and amygdala regions as compared to all other tissues. These genes also exhibit differential expression patterns during human brain development. CONCLUSIONS: We report a causal effect of obesity on mobility dysfunction. Our findings highlight potential neuronal dysfunctions in regulating predispositions on the causal pathway from obesity to mobility dysfunction.

Gender and physical frailty modify the association between abdominal obesity and functional disability in older adults.

BACKGROUND: Abdominal obesity is associated with functional disability in older adults. AIM: We evaluated whether this association was modified by gender and/or physical frailty. METHODS: We used cross-sectional data from 12,583 participants in the third follow-up of the population-based Singapore Chinese Health Study, when participants had mean age of 74 years (range 63-97). Abdominal obesity was defined using waist circumference, physical frailty was established using the modified Cardiovascular Health Study phenotype, and functional disability was determined by the Lawton Instrumental Activities of Daily Living Scale. We used logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between abdominal obesity and disability. RESULTS: Abdominal obesity was associated with increased likelihood of functional disability, and this association was stronger in women than in men [OR (95% CI): 1.27 (1.11-1.46) vs. 1.08 (0.93-1.25); P for interaction < 0.001]. Furthermore, there was a significantly stronger association between abdominal obesity and functional disability in participants who were physically frail compared to those who were not [OR (95% CI): 1.57 (1.19-2.08) vs. 1.11 (0.99-1.23); P for interaction = 0.003], and this phenomenon was observed in both genders. When compared to participants who were neither abdominally obese nor physically frail, participants who were both abdominally obese and physically frail had a synergistically increased risk of functional disability [OR (95% CI): 3.61 (3.03-4.30)]. CONCLUSIONS: Women with abdominal obesity had higher risk of functional disability compared to men, and older adults who were both abdominally obese and physically frail had a synergistically increased risk of disability.

Visceral fat area is the measure of obesity best associated with mobility disability in community dwelling oldest-old Chinese adults.

BACKGROUND: Although obesity can be clinically defined by body mass index (BMI), waist circumference, percent body fat, or visceral fat area, it is unclear which specific measure is best associated with mobility disability in oldest-old adults. METHODS: Among 589 Chinese participants aged 85 years and older in a population-based cohort in Singapore, we measured waist circumference, computed BMI, estimated appendicular skeletal muscle mass, percent body fat, and visceral fat area using bioelectrical impedance analysis, and evaluated mobility disability using the Loco-Check questionnaire. We computed areas under the receiver operating characteristic curves (AUCROC) to compare how well these measures discriminated between those with and without mobility disability. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between obesity defined by these measures and mobility disability. RESULTS: Compared to BMI, which had an AUCROC (95% CI) of 0.68 (0.64-0.72) for the discrimination of mobility disability, only visceral fat area had a significantly higher discriminative performance [AUCROC (95% CI) of 0.71 (0.67-0.75) (Padjusted = 0.002)]. The optimal cut-offs of visceral fat area for the discrimination of mobility disability were ≥ 104 cm2 in men and ≥ 137 cm2 in women. In fully adjusted models, only obesity defined by visceral fat area was significantly associated with mobility disability [OR (95% CI) of 2.04 (1.10-3.77)]; obesity defined by the other measures were not associated with mobility disability after adjusting for visceral fat. CONCLUSION: In oldest-old adults, visceral fat area was the best discriminator for obesity associated with mobility disability.

Reproductive factors and risk of physical frailty among Chinese women living in Singapore.

SETTING: Although age at menopause has been linked to higher risk of physical frailty in later life, little is known about other reproductive factors. OBJECTIVES: Our study aimed to investigate the associations between 1) age at menarche, 2) age at natural menopause, 3) duration of reproductive period, 4) number of children, 5) use of oral contraceptives (OCP), and 6) use of hormone replacement therapy (HRT) with the risk of physical frailty in late life. DESIGN: We used data from 5934 women of the Singapore Chinese Health Study who experienced natural menopause, and participated in the third follow-up interviews when physical frailty was assessed. Logistic regression was used to evaluate association of reproductive factors evaluated during baseline and prior follow-up interviews with physical frailty at follow-up 3. PARTICIPANTS: Community-dwelling Chinese women living in Singapore. Participants had a mean age of 52.6 years at baseline (1993-1998), and a mean age of 72.8 years during the third follow-up (2014-2017). MEASUREMENTS: Sociodemographic characteristics, level of education, smoking history, physical activity, and history of physician-diagnosed comorbidities were collected. Participants' weight and height were self-reported. We used a modified Cardiovascular Health Study phenotype to assess physical frailty. RESULTS: Age at menarche was inversely associated with the likelihood of physical frailty (Ptrend = 0.001); each one-year decrease in age at menarche was associated with a 9% increase (95% CI: 4%-14%) in odds of physical frailty. Age at menopause was also inversely associated with the likelihood of physical frailty (Ptrend = 0.009); every one-year decrease in age at menopause was associated with 2% (0%-4%) increased odds. In the assessment of frailty, younger ages at menarche and menopause were associated with greater likelihood of being in the slowest quintile for timed up-and-go and weakest quintile for handgrip strength. Conversely, duration of reproductive period, parity, and use of oral contraceptives or hormone replacement therapy were not significantly associated with the likelihood of physical frailty. CONCLUSIONS: In our population-based cohort of Chinese women, younger ages at menarche and menopause were associated with higher likelihood of physical frailty in later life.

Higher handgrip strength is linked to higher salience ventral attention functional network segregation in older adults.

Converging evidence suggests that handgrip strength is linked to cognition in older adults, and this may be subserved by shared age-related changes in brain function and structure. However, the interplay among handgrip strength, brain functional connectivity, and cognitive function remains poorly elucidated. Hence, our study sought to examine these relationships in 148 community-dwelling older adults. Specifically, we examined functional segregation, a measure of functional brain organization sensitive to ageing and cognitive decline, and its associations with handgrip strength and cognitive function. We showed that higher handgrip strength was related to better processing speed, attention, and global cognition. Further, higher handgrip strength was associated with higher segregation of the salience/ventral attention network, driven particularly by higher salience/ventral attention intra-network functional connectivity of the right anterior insula to the left posterior insula/frontal operculum and right midcingulate/medial parietal cortex. Importantly, these handgrip strength-related inter-individual differences in salience/ventral attention network functional connectivity were linked to cognitive function, as revealed by functional decoding and brain-cognition association analyses. Our findings thus highlight the importance of the salience/ventral attention network in handgrip strength and cognition, and suggest that inter-individual differences in salience/ventral attention network segregation and intra-network connectivity could underpin the handgrip strength-cognition relationship in older adults.

CXCL9 Predicts the Risk of Osteoporotic Hip Fracture in a Prospective Cohort of Chinese Men-A Matched Case-Control Study.

Recent experimental work has identified CXCL9 as a promoter for the differentiation of osteoclast progenitors into osteoclasts, with resultant bone resorption. However, no human study has validated an association between this chemokine and osteoporosis or fracture risk. We conducted a matched case-control study nested in the prospective, population-based Singapore Chinese Health Study. Fifty-five men and 119 women with incident hip fractures, occurring median 6.2 years after blood collection, were matched individually to controls by age at recruitment, sex, and duration of blood storage. Serum chemokines, CXCL9 and CXCL10, were measured using immunoassays. Multivariable conditional logistic regression models that included age at blood collection, body mass index, smoking, and diabetes as covariates were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association with hip fracture risk. Predictive utility of chemokine for hip fracture risk was examined by comparing area under receiver operating characteristic curves (AUC) between prognostic models with and without the chemokine. Increasing CXCL9 levels were associated with increasing hip fracture risk in men but not in women (pinteraction  = 0.002); comparing extreme quartiles, the OR (95% CI) in the highest quartile was 10.35 (1.90-56.39) in men (ptrend  = 0.002) but 1.46 (0.59-3.60) in women (ptrend  = 0.32). Adding CXCL9 to a prognostic model that already incorporated age and other risk factors improved the AUC (95% CI) from 0.65 (0.55-0.76) to 0.74 (0.65-0.83) for the predictive utility of hip fractures in men but not in women. Conversely, the association between CXCL10 and hip fracture risk was not statistically significant in either sex. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Midlife Leukocyte Telomere Length as an Indicator for Handgrip Strength in Late Life.

BACKGROUND: Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality. METHODS: In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581). RESULTS: We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010). CONCLUSIONS: Longer midlife LTL was associated with increased handgrip strength later in life.