Novel Loci (EIF4A2, ADIPOQ, TPRG1) for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change (ΔTHR) among Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Heart Study (FHS) Offspring Cohort (OS).

Aims/hypothesis: Triglyceride (TG) /High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark. Methods: Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Results: Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (p=1.58e-9) for ΔTHR; this gene locus has been reported before influencing baseline THR levels. Our GWLS found evidence for a significant linkage with a logarithm of the odds (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families (pedigree-specific LODs>0.1), we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2/ADIPOQ-rs114108468, p=5e-6, MAF=1.8%; TPRG1-rs16864075, p=3e-6, MAF=8%; accounted for ~28% and ~29% of the linkage, respectively, and 57% jointly). While the former variant was associated with EIF4A2 (p=7e-5) / ADIPOQ (p=3.49e-2) RNA transcriptional levels, the latter variant was not associated with TPRG1 (p=0.23) RNA transcriptional levels. Replication in FHS OS observed modest effect of these loci on ΔTHR. Of 188 metabolites from 13 compound classes assayed in LLFS, we observed multiple metabolites (e.g., DG.38.5, PE.36.4, TG.58.3) that were significantly associated with the variants (p<3e-4). Conclusions: our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes selected for exceptional survival and healthy aging.

Levels of Sex Hormones and Abdominal Muscle Composition in Men from The Multi-Ethnic Study of Atherosclerosis.

Information on the associations of testosterone levels with abdominal muscle volume and density in men is limited, while the role of estradiol and SHBG on these muscle characteristics are unclear. Therefore, this study aimed to investigate the association between fasting serum sex hormones and CT-derived abdominal muscle area and radiodensity in adult men. Conducted as a cross sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis, our analyses focused on a community-based sample of 907 men aged 45-84 years, with 878 men having complete data. CT scans of the abdomen were interrogated for muscle characteristics, and multivariable linear regressions were used to test the associations. After adjustment for relevant factors, higher levels of both total testosterone and estradiol were associated with higher abdominal muscle area (1.74, 0.1-3.4, and 1.84, 0.4-3.3, respectively). In the final analyses, levels of total testosterone showed a positive association, while an inverse relationship was observed for SHBG with abdominal muscle radiodensity (0.3, 0.0-0.6, and - 0.33, - 0.6 to - 0.1, respectively). Our results indicate a complex association between sex hormones and abdominal muscle characteristics in men. Specifically, total testosterone and estradiol were associated with abdominal muscle area, while only total testosterone was associated with muscle radiodensity and SHBG was inversely associated with muscle radiodensity.Clinical Trial: NCT00005487.

A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS).

Glycated hemoglobin (HbA1c) indicates average glucose levels over three months and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal changes in HbA1c (ΔHbA1c) are also associated with aging processes, cognitive performance, and mortality. We analyzed ΔHbA1c in 1,886 non-diabetic Europeans from the Long Life Family Study to uncover gene variants influencing ΔHbA1c. Using growth curve modeling adjusted for multiple covariates, we derived ΔHbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis of this locus revealed a variant rs56340929 (explaining 27% of the linkage peak) in the ARHGAP44 gene that was significantly associated with ΔHbA1c. RNA transcription of ARHGAP44 was associated with ΔHbA1c. The Framingham Offspring Study data further supported these findings on the gene level. Together, we found a novel gene ARHGAP44 for ΔHbA1c in family members without T2D. Follow-up studies using longitudinal omics data in large independent cohorts are warranted.

Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.

OBJECTIVE: The aim of this study was to examine associations of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults. METHODS: Cross-sectional data from 829 adults ≥70 years of age were used. Abdominal, subcutaneous, and visceral AT and thigh muscle fat infiltration (MFI) were quantified by magnetic resonance imaging. SM mitochondrial energetics were characterized in vivo (31P-magnetic resonance spectroscopy; ATPmax) and ex vivo (high-resolution respirometry maximal oxidative phosphorylation [OXPHOS]). ActivPal was used to measure physical activity ([PA]; step count). Linear regression adjusted for covariates was applied, with sequential adjustment for BMI and PA. RESULTS: Independent of BMI, total abdominal AT (standardized [Std.] ß = -0.21; R2 = 0.09) and visceral AT (Std. ß = -0.16; R2 = 0.09) were associated with ATPmax (p < 0.01; n = 770) but not following adjustment for PA (p ≥ 0.05; n = 658). Visceral AT (Std. ß = -0.16; R2 = 0.25) and thigh MFI (Std. ß = -0.11; R2 = 0.24) were associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 609). Total abdominal AT (Std. ß = -0.19; R2 = 0.24) and visceral AT (Std. ß = -0.17; R2 = 0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 447). CONCLUSIONS: Skeletal MFI and abdominal visceral, but not subcutaneous, AT are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT and in vivo mitochondrial bioenergetics are attenuated by PA.

Sex differences in Alzheimer's disease blood biomarkers in a Caribbean population of African ancestry: The Tobago Health Study.

INTRODUCTION: Alzheimer's disease (AD) is increasing in the Caribbean, especially for persons of African ancestry (PAA) and women. However, studies have mostly utilized surveys without AD biomarkers. METHODS: In the Tobago Health Study (n = 309; 109 women, mean age 70.3 ± 6.6), we assessed sex differences and risk factors for serum levels of phosphorylated tau-181 (p-tau181), amyloid-beta (Aß)42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Blood samples were from 2010 to 2013 for men and from 2019 to 2023 for women. RESULTS: Women were more obese, hypertensive, and sedentary but reported less smoking and alcohol use than men (age-adjusted p < 0.04). Compared to men, women had worse levels of AD biomarkers, with higher p-tau181 and lower Aß42/40, independent of covariates (p < 0.001). In sex-stratified analyses, higher p-tau181 was associated with older age in women and with hypertension in men. GFAP and NfL did not differ by sex. DISCUSSION: Women had worse AD biomarkers than men, unexplained by age, cardiometabolic diseases, or lifestyle. Studying risk factors for AD in PAA is warranted, especially for women earlier in life.

Associations of Fecal Microbiota with Ectopic Fat in African Caribbean Men.

OBJECTIVE: The gut microbiome has been associated with visceral fat (VAT) in European and Asian populations; however, associations with VAT and with ectopic fats among African-ancestry individuals are not known. Our objective was to investigate cross-sectional associations of fecal microbiota diversity and composition with VAT and ectopic fat, as well as body mass index (BMI), among middle-aged and older African Caribbean men. METHODS: We included in our analysis n = 193 men (mean age = 62.2 ± 7.6 years; mean BMI = 28.3 ± 4.9 kg/m2) from the Tobago Health Study. We assessed fecal microbiota using V4 16s rRNA gene sequencing. We evaluated multivariable-adjusted associations of microbiota features (alpha diversity, beta diversity, microbiota differential abundance) with BMI and with computed tomography-measured VAT and ectopic fats (pericardial and intermuscular fat; muscle and liver attenuation). RESULTS: Lower alpha diversity was associated with higher VAT and BMI, and somewhat with higher pericardial and liver fat. VAT, BMI, and pericardial fat each explained similar levels of variance in beta diversity. Gram-negative Prevotellaceae and Negativicutes microbiota showed positive associations, while gram-positive Ruminococcaceae microbiota showed inverse associations, with ectopic fats. CONCLUSIONS: Fecal microbiota features associated with measures of general adiposity also extend to metabolically pernicious VAT and ectopic fat accumulation in older African-ancestry men.

Associations of Abdominal Muscle Density and Area and Incident Cardiovascular Disease, Coronary Heart Disease, and Stroke: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Muscle density is inversely associated with all-cause mortality, but associations with cardiovascular disease (CVD) risk are not well understood. This study evaluated the association between muscle density and muscle area and incident total CVD, coronary heart disease (CHD), and stroke in diverse men and women. METHODS AND RESULTS: Adult participants (N=1869) in the Multi-Ethnic Study of Atherosclerosis Ancillary Body Composition Study underwent computer tomography scans of the L2-L4 region of the abdomen. Muscle was quantified by density (Hounsfield units) and area in cm2. Sex-stratified Cox proportional hazard models assessed associations between incident total CVD, incident CHD, and incident stroke across sex-specific percentiles of muscle area and density, which were entered simultaneously into the model. Mean age for men and women at baseline were 64.1 and 65.1 years, respectively, and median follow-up time was 10.3 years. For men, associations between muscle density and incident CVD were inverse but not significant in fully adjusted models (P trend=0.15). However, there was an inverse association between density and CHD (P trend=0.02; HR, 0.26 for 95th versus 10th percentile), and no association with stroke (P trend=0.78). Conversely, for men, there was a strong positive association between muscle area and incident CVD (HR, 4.19 for 95th versus 10th percentile; P trend<0.001). Associations were stronger for CHD (HR, 6.18 for 95th versus 10th percentile; P trend<0.001), and null for stroke (P trend=0.67). Associations for women were mostly null. CONCLUSIONS: For men, abdominal muscle density is associated with lower CHD risk, whereas greater muscle area is associated with markedly increased risk of CHD.

Sex Hormones and Abdominal Muscle Area and Radiodensity in Men: The Multi-Ethnic Study of Atherosclerosis.

Information on the associations of testosterone levels with abdominal muscle volume and quality in men is limited, while the role of estradiol and SHBG on these muscle characteristics are unclear. To investigate the association between fasting serum sex hormones and CT-derived abdominal muscle area and radiodensity in adult men. Cross sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis. A community-based sample of 907 men aged 45-84 years; 878 men with complete data were included in the analysis. CT scans of the abdomen were interrogated for muscle characteristics. Multivariable linear regressions were used to test the associations. After adjustment, higher levels of both total testosterone and estradiol were associated with higher abdominal muscle area (1.79, 0.1-3.4, & 1.79, 0.4-3.2, respectively). In the final analyses, levels of total testosterone showed a positive association, while an inverse relationship was observed for SHBG with abdominal muscle radiodensity (0.3, 0.0-0.6, & -0.34, -0.6 - -0.1, respectively). Our results indicate a complex association between sex hormones and abdominal muscle characteristics in men. Specifically, total testosterone and estradiol were associated with abdominal muscle area, while only total testosterone was associated with muscle radiodensity and SHBG was inversely associated with muscle radiodensity.

Associations between muscle quality and N-terminal pro-B-type natriuretic peptide (NT-proBNP): The multi-ethnic study of atherosclerosis.

INTRODUCTION: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is widely used in clinical settings to identify cardiac stress, diagnose, and manage heart failure (HF). We explored the associations between NT-proBNP and both muscle area and density. METHODS: A cross-sectional analysis including 1,489 participants from the MESA. Plasma NT-proBNP concentrations and inflammatory biomarkers and health history questionnaires were analyzed. Computed tomography quantified abdominal body composition. Separate multivariable linear regression models were used to assess the associations between both muscle (MA) area and density (MD) and NT-proBNP. RESULTS: In models adjusted for sociodemographic characteristics, risk factors for cardiovascular disease, anthropometric variables, and subcutaneous and visceral adiposity, NT-proBNP was inversely associated with total abdominal and psoas MAs. Adjustment for inflammatory markers and MD attenuated these associations to the null. Stabilization MA and NT-proBNP were not significantly associated. Analyses per quartiles of MA confirmed lack of a consistent association between stabilization and total abdominal MAs and NT-proBNP. While the third and fourth quartiles of psoas MA were inversely associated with NT-proBNP, adding inflammation biomarkers and MD to the model attenuated the association to the null. Conversely, after full adjustment, NT-proBNP was inversely and significantly associated with total abdominal, stabilization and psoas MDs. For psoas MD, but not the other muscle density variables, the addition of MA to the model attenuated the association to the null. The quartiles of MD were consistently inversely associated with NT-proBNP, where higher MDs showed larger estimates of the association compared to the lowest quartiles, for all muscle groups investigated. CONCLUSION: Muscle density is inversely associated with NT-proBNP, while muscle area is not after adjustment for inflammation and muscle density.

Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.

Objective: Examine the association of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults. Methods: Cross-sectional data from 829 older adults ≥70 years was used. Total abdominal, subcutaneous, and visceral AT; and thigh muscle fat infiltration (MFI) was quantified by MRI. SM mitochondrial energetics were characterized using in vivo 31 P-MRS (ATP max ) and ex vivo high-resolution respirometry (maximal oxidative phosphorylation (OXPHOS)). ActivPal was used to measure PA (step count). Linear regression models adjusted for covariates were applied, with sequential adjustment for BMI and PA. Results: Independent of BMI, total abdominal (standardized (Std.) ß=-0.21; R 2 =0.09) and visceral AT (Std. ß=-0.16; R 2 =0.09) were associated with ATP max ( p <0.01), but not after further adjustment for PA (p≥0.05). Visceral AT (Std. ß=-0.16; R 2 =0.25) and thigh MFI (Std. ß=-0.11; R 2 =0.24) were negatively associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA ( p <0.05). Total abdominal AT (Std. ß=-0.19; R 2 =0.24) and visceral AT (Std. ß=-0.17; R 2 =0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p<0.05). Conclusions: Skeletal MFI and abdominal visceral, but not subcutaneous AT, are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT and in vivo mitochondrial bioenergetics are attenuated by PA.

Skeletal muscle adiposity is a novel risk factor for poor cognition in African Caribbean women.

OBJECTIVE: Skeletal muscle adiposity (myosteatosis) is recognized as a major risk factor for cardiometabolic diseases, and it increases with aging. The relationship of myosteatosis with cognitive impairment is unknown. METHODS: The association of calf myosteatosis (measured by computed tomography-derived skeletal muscle density; higher values indicate less myosteatosis) with cognitive function was examined among 626 African Caribbean women who were aged 40 to 84 years, a population highly vulnerable to increased myosteatosis. Cognition was assessed by the Digit Symbol Substitution Test (DSST), a test of information processing speed (higher scores indicate better performance). Linear regression was used to assess the association of muscle density with DSST. RESULTS: Adjusting for age, education, muscle area, BMI, hypertension, diabetes, cardiovascular event history, lifestyle factors, lipid-lowering medication use, and menopausal status, a one-SD lower muscle density was associated with a 1.69-point lower DSST score (p = 0.002). BMI, diabetes, and hypertension interactions were not statistically significant, suggesting that the main association was not moderated by overall obesity or cardiometabolic diseases. CONCLUSIONS: These findings suggest that greater myosteatosis is associated with slower information processing speed, an early indicator of cognitive impairment. Further studies are needed to establish this association in this and other populations using an expanded battery of cognitive tests with longitudinal follow-up and to identify the biological mechanisms underlying this relationship.

Increase in skeletal muscular adiposity and cognitive decline in a biracial cohort of older men and women.

BACKGROUND: Obesity and loss of muscle mass are emerging as risk factors for dementia, but the role of adiposity infiltrating skeletal muscles is less clear. Skeletal muscle adiposity increases with older age and especially among Black women, a segment of the US population who is also at higher risk for dementia. METHODS: In 1634 adults (69-79 years, 48% women, 35% Black), we obtained thigh intermuscular adipose tissue (IMAT) via computerized tomography at Years 1 and 6, and mini-mental state exam (3MS) at Years 1, 3, 5, 8 and 10. Linear mixed effects models tested the hypothesis that increased IMAT (Year 1-6) would be associated with 3MS decline (Year 5-10). Models were adjusted for traditional dementia risk factors at Year 1 (3MS, education, APOe4 allele, diabetes, hypertension, and physical activity), with interactions between IMAT change by race or sex. To assess the influence of other muscle and adiposity characteristics, models accounted for change in muscle strength, muscle area, body weight, abdominal subcutaneous and visceral adiposity, and total body fat mass (all measured in Years 1 and 6). Models were also adjusted for cytokines related to adiposity: leptin, adiponectin, and interleukin-6. RESULTS: Thigh IMAT increased by 4.85 cm2 (Year 1-6) and 3MS declined by 3.20 points (Year 6-10). The association of IMAT increase with 3MS decline was statistically significant: an IMAT increase of 4.85 cm2 corresponded to a 3MS decline of an additional 3.60 points (p < 0.0001), indicating a clinically important change. Interactions by race and sex were not significant. CONCLUSIONS: Clinicians should be aware that regional adiposity accumulating in the skeletal muscle may be an important, novel risk factor for cognitive decline in Black and White participants independent of changes to muscle strength, body composition and traditional dementia risk factors.

Associations Between Circulating Levels of Myostatin and Plasma ß-Amyloid 42/40 in a Biracial Cohort of Older Adults.

BACKGROUND: Myostatin, a cytokine produced by skeletal muscle, may influence Alzheimer's disease (AD) pathogenesis, but sparse evidence exists in humans. We assessed the association between circulating levels of myostatin at Year 1 and plasma levels of ß-amyloid 42/40 at Year 2, a marker of AD pathology, in a biracial cohort of older adults. METHODS: We studied 403 community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from Memphis, Tennessee, and Pittsburgh, PA. Mean age was 73.8 ± 3 years; 54% were female; and 52% were Black. Serum myostatin levels were measured at Year 1, plasma ß-amyloid 42/40 levels in Year 2 (higher ratio indicating lower amyloid load). Multivariable linear regression analyses tested the association of serum myostatin with plasma levels of ß-amyloid 42/40 adjusted for computed-tomography-derived thigh muscle cross-sectional area, demographics, APOe4 allele, and risk factors for dementia. We tested for 2-way.interactions between myostatin and race or sex; results were stratified by race and sex. RESULTS: In multivariable models, myostatin was positively associated with plasma levels of ß-amyloid 42/40 (standardized regression coefficient: 0.145, p = .004). Results were significant for white men and women (0.279, p = .009, and 0.221, p = .035, respectively) but not for Black men or women; interactions by race and gender were not statistically significant. CONCLUSIONS: Higher serum myostatin was associated with lower amyloid burden, independently of APOe4 alleles, muscle area and other established risk factors for dementia. The role of myostatin in AD pathogenesis and the influence of race should be further investigated.

Thigh and Calf Myosteatosis are Strongly Associated with Muscle and Physical Function in African Caribbean Men.

BACKGROUND: African Caribbeans have higher levels of myosteatosis than other populations; however, little is known about the impact of myosteatosis on physical function in African Caribbeans. Herein, we examined the association between regional myosteatosis of the calf, thigh, and abdomen versus physical function in 850 African-Ancestry men aged 64.2 ± 8.9 (range 50-95) living on the Caribbean Island of Tobago. METHODS: Myosteatosis was measured using computed tomography and included intermuscular adipose tissue (IMAT) and muscle density levels of the thigh, calf, psoas, and paraspinous muscles. Outcomes included grip strength, time to complete 5 chair-rises, and 4-meter gait speed. Associations were quantified using separate linear models for each myosteatosis depot and were adjusted for age, height, demographics, physical activity, and chronic diseases. Beta coefficients were presented per standard deviation of each myosteatosis depot. RESULTS: Higher thigh IMAT was the only IMAT depot significantly associated with weaker grip strength (ß = -1.3 ± 0.43 kg, p = .003). However, lower muscle density of all 4 muscle groups was associated with weaker grip strength (all p < .05). Calf and thigh myosteatosis (IMAT and muscle density) were significantly associated with both worse chair rise time and gait speed (all p < .05), whereas psoas IMAT and paraspinous muscle density were associated with gait speed. CONCLUSION: Myosteatosis of the calf and thigh-but not the abdomen-were strongly associated with grip strength and performance measures of physical function in African Caribbean men. However, posterior abdominal myosteatosis may have some utility when abdominal images are all that are available.

Replacing sedentary time with light activity was associated with less adiposity across several depots in African ancestry men.

OBJECTIVE: The aim of this study was to determine whether displacement of sedentary time with activity was cross-sectionally associated with less adiposity among Black Caribbean men in the Tobago Health Study. METHODS: Objectively assessed activity was categorized as sedentary (< 1.5 metabolic equivalents; METs), light (≥ 1.5 to < 3.0 METs), or moderate-to-vigorous (≥ 3.0 METs) using the SenseWear Pro armband. Computed tomography scans of the chest, abdomen, liver, and thigh were used to assess subcutaneous and ectopic adipose tissue. The isotemporal substitution framework paired with linear regression was used to examine associations between activity and adiposity adjusting for age, height, total awake time, and multiple comparisons. RESULTS: On average, participants (n = 271) were 63 years old with 11.2 h/d of sedentary behavior, 4.5 h/d of light activity, and 54 min/d of moderate-to-vigorous activity. Replacing sedentary time with light activity was cross-sectionally associated with lower volume and higher density of abdominal and thigh subcutaneous adiposity, visceral adiposity, abdominal and thigh intermuscular adiposity, and pericardial adiposity and higher liver attenuation (p values ≤ 0.0001). CONCLUSIONS: Displacement of sedentary time with light activity was associated with less adiposity among this Black Caribbean cohort. Interventions focused on increasing light activity may be easier to maintain than higher intensity interventions and thus may be more successful at reducing adiposity.

Physical Activity Type and Intensity Are Associated With Abdominal Muscle Area and Density: The Multiethnic Study of Atherosclerosis.

BACKGROUND: Using data from a multiethnic cohort, the authors tested associations of multiple types and intensities of physical activity (PA) with abdominal muscle area and density. METHODS: 1895 Multiethnic Study of Atherosclerosis participants (mean age 64.6 [9.6] y) completed health history and PA questionnaires and computed tomography to quantify body composition and measurements of cardiovascular and inflammatory biomarkers. Analyses included multivariable regression. RESULTS: Compared with those not meeting PA guidelines for Americans, those meeting the guidelines had higher total abdominal muscle area (odds ratio, 95% confidence interval 1.60, 1.20 to 2.15), stability muscle area (1.68, 1.28 to 2.20), and stability muscle density (1.35, 1.03 to 1.76). After adjustment for relevant covariates, each SD increase in total moderate to vigorous PA was associated with a higher total abdominal (ß, 95% confidence interval = 0.068, 0.036 to 0.173), stability (0.063, 0.027 to 0.099), and locomotor (0.069, 0.039 to 0.099) muscle area and higher locomotor muscle density (0.065, 0.022 to 0.108, P < .01). Only intentional and conditioning exercise were associated with total abdominal and stability muscle density (P < .05). Light PA and walking were not associated with muscle area or density. CONCLUSIONS: Most types of PA are positively associated with abdominal muscle area and density across functional categories, independent of relevant covariates. These results provide additional evidence for promoting PA for healthy muscle aging.

CREBRF missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in Polynesian peoples living in Samoa and Aotearoa New Zealand.

INTRODUCTION: The minor allele of a missense variant, rs373863828, in CREBRF is associated with higher body mass index (BMI), lower fasting glucose, and lower odds of type 2 diabetes. rs373863828 is common in Pacific Island populations (minor allele frequency (MAF) 0.096-0.259) but rare in non-Pacific Island populations (MAF <0.001). We examined the cross-sectional associations between BMI and rs373863828 in type 2 diabetes and fasting glucose with a large sample of adults of Polynesian ancestries from Samoa, American Samoa, and Aotearoa New Zealand, and estimated the direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose. RESEARCH DESIGN AND METHODS: We regressed type 2 diabetes and fasting glucose on BMI and rs373863828 stratified by obesity, regressed type 2 diabetes and fasting glucose on BMI stratified by rs373863828 genotype, and assessed the effects of rs373863828 on type 2 diabetes and fasting glucose with path analysis. The regression analyses were completed separately in four samples that were recruited during different time periods between 1990 and 2010 and then the results were meta-analyzed. All samples were pooled for the path analysis. RESULTS: Association of BMI with type 2 diabetes and fasting glucose may be greater in those without obesity (OR=7.77, p=0.015 and ß=0.213, p=9.53×10-5, respectively) than in those with obesity (OR=5.01, p=1.12×10-9 and ß=0.162, p=5.63×10-6, respectively). We did not observe evidence of differences in the association of BMI with type 2 diabetes or fasting glucose by genotype. In the path analysis, the minor allele has direct negative (lower odds of type 2 diabetes and fasting glucose) and indirect positive (higher odds of type 2 diabetes and fasting glucose) effects on type 2 diabetes risk and fasting glucose, with the indirect effects mediated through a direct positive effect of rs373863828 on BMI. CONCLUSIONS: There may be a stronger effect of BMI on fasting glucose in Polynesian individuals without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from higher odds of type 2 diabetes.

Peripheral bone structure, geometry, and strength and muscle density as derived from peripheral quantitative computed tomography and mortality among rural south Indian older adults.

Multiple studies have observed a relationship of bone mineral density (BMD) measured by Dual energy X-ray absorptiometry (DXA) and mortality. However, areal BMD (aBMD) measured by DXA is an integrated measure of trabecular and cortical bone and does not measure the geometry of bone. Peripheral Quantitative Computed Tomography (pQCT) provides greater insights on bone structure, geometry and strength. To examine whether higher bone phenotypes and muscle density as measured by pQCT are associated with a lower all-cause mortality, we studied 245 men and 254 women (all age >60) recruited in the Mobility and Independent Living among Elders Study in rural south India. Cox proportional hazards models estimated hazard ratios (HR [95% Confidence Intervals]). After an average follow-up of 5.3 years, 73 men and 50 women died. Among men, trabecular volumetric bone mineral density (vBMD) of radius (HR per SD increase in parameter = 0.59 [0.43, 0.81]) and tibia (0.60[0.45, 0.81]), cortical vBMD of radius (0.61, [0.47, 0.79]) and tibia (0.62, [0.49, 0.79]), cortical thickness of radius (0.55, [0.42, 0.7]) and tibia (0.60, [0.47, 0.77]), polar strength strain index (SSIp) of tibia (0.73 [0.54, 0.98]), endosteal circumference of radius (1.63, [1.25, 2.12]) and tibia (1.54, [1.19, 1.98]) were associated with all-cause mortality. Muscle density (0.67, [0.51, 0.87]) was associated with lower mortality in men. Among women cortical vBMD of radius (0.64, [0.47, 0.87]) and tibia (0.60 [0.45, 0.79]), cortical thickness of radius (0.54, [0.37, 0.79]) and tibia (0.43, [0.30, 0.61]), SSIp of radius (0.70 [0.48,1.01]) and tibia (0.58 [0.37, 0.90]) and endosteal circumference of radius (1.33 [0.97, 1.82]) and tibia (1.83, [1.37, 2.45]) were associated with all-cause mortality. Among men, gait speed mediated the association of muscle density and mortality but there was no mediation for any bone parameters. Conclusion: pQCT bone measures and muscle density were independently associated with mortality among rural south Indian elders.

Low Risk for Developing Diabetes Among the Offspring of Individuals With Exceptional Longevity and Their Spouses.

Little is known about the risk of type 2 diabetes (T2D) among the offspring of individuals with exceptional longevity. We determined the incidence of and potential risk and protective factors for T2D among the offspring of probands and offspring's spouses (mean age=60 years, range 32-88 years) in the Long Life Family Study (LLFS), a multicenter cohort study of 583 two-generation families with a clustering of healthy aging and exceptional longevity. Incident T2D was defined as fasting serum glucose ≥126 mg/dl, or HbA1c of ≥6.5%, or self-reported with doctor diagnosis of T2D, or the use of anti-diabetic medication during a mean follow-up 7.9 ± 1.1 years. Among offspring (n=1105) and spouses (n=328) aged 45-64 years without T2D at baseline visit, the annual incident rate of T2D was 3.6 and 3.0 per 1000 person-years, respectively, while among offspring (n=444) and spouses (n=153) aged 65+ years without T2D at baseline, the annual incident rate of T2D was 7.2 and 7.4 per 1000 person-years, respectively. By comparison, the annual incident rate of T2D per 1000 person-years in the U.S. general population was 9.9 among those aged 45-64, and 8.8 among those aged 65+ years (2018 National Health Interview Survey). Baseline BMI, waist circumference, and fasting serum triglycerides were positively associated with incident T2D, whereas fasting serum HDL-C, adiponectin, and sex hormone binding globulin were protective against incident T2D among the offspring (all P<0.05). Similar associations were observed among their spouses (all P<0.05, except sex hormone binding globulin). In addition, we observed that among spouses, but not offspring, fasting serum interleukin 6 and insulin-like growth factor 1 were positively associated with incident T2D (P<0.05 for both). Our study suggests that both offspring of long-living individuals and their spouses, especially middle-aged, share a similar low risk for developing T2D as compared with the general population. Our findings also raise the possibility that distinct biological risk and protective factors may contribute to T2D risk among offspring of long-lived individuals when compared with their spouses. Future studies are needed to identify the mechanisms underlying low T2D risk among the offspring of individuals with exceptional longevity, and also among their spouses.