Abstract
Mitochondrial energy production decreases while fatigability increases with age. Genes associated with energy metabolism may contribute to fatigability. Using Long Life Family Study (LLFS), ...we initially assessed variants (SNPs) in 272 candidate autosomal genes involved in energy metabolism (previously associated with mitochondrial dysfunction disease) with perceived physical fatigability. Two generations of LLFS enrollees (N=2342, mean age=73.7, range 60-108 years) completed the Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater fatigability) at Visit 2 (2014-2017). Physical fatigability prevalence was 42.1% (PFS≥15). Generalized linear mixed models assessed the association of each SNP with continuous PFS (GENESIS R package) adjusted for age, sex, field center, and family relatedness. We found no associations with perceived physical fatigability, all p>2.5E-7 (Bonferroni multiple comparison corrected p-value). Next steps will examine variants in the mitochondrial genome and BTBD3, another promising candidate gene recently discovered. Genetic biomarker(s) may identify individuals susceptible to greater fatigability to target for early intervention.
Abstract
Although measures of physical function such as walking speed and time to complete chair-rises are highly heritable, the genetic architecture underlying these phenotypes remains poorly ...defined. To identify potentially novel genes and pathways underlying physical performance in older adults, we conducted a genome-wide association meta-analysis of the short physical performance battery (SPPB) (Score 0-12) and one of its components, chair-rise time (seconds) in 24,033 Caucasian adults aged 60+ from 13 cohorts (mean cohort age 66.2 ± 5.3 to 84.3 ± 4.1 years; 56.5% women). Cohorts had a genome wide scan imputed to either the Haplotype Reference Consortium or Trans-Omics for Precision Medicine imputation panels. Single nucleotide polymorphism (SNPs) with a minor allele frequency ≥0.1% and imputation quality score ≥0.7 were included (range 7.5-10.5 million per cohort). Analyses were adjusted for age, sex, height, and population substructure. Meta-analysis was performed using a fixed-effects model. Although no genome-wide significant loci were identified, 67 and 60 suggestive loci (p< 5*10-5) were detected for SPPB score and chair-rises time, respectively. Pathway-based analyses indicated significant enrichment of genes affecting negative regulation of calcium channel activity (Bonferroni corrected p-value < 0.05). Sex-stratified gene-based analyses identified clathrin vesicle-associated sec14 protein 1 (CLVS1), significantly associated with chair-rise time in women (p= -1.5*10-7). CLVS1 is highly expressed in the cerebellum, which is involved in postural and motor function control. A larger sample size is needed to confirm and extend our findings, but our results potentially implicate a novel pathway and locus for physical performance in older women.
Abstract
Objective
Skeletal muscle adiposity (SMA) increases with aging and is recognized as a major risk factor for cardiometabolic diseases, disability, and mortality among older adults. Obesity is ...related to dementia and cognitive decline yet the relationship between SMA and cognition remains ill defined. The objective of this study was to assess SMA and cognitive function among African Caribbean women.Design and
Methods
Cross-sectional analysis of 448 African Caribbean women in the Tobago Health Study (mean age, 55 years; range, 39-84 years). Cognition was assessed by the Digit Symbol Substitution Test (DSST), a test of information processing speed with a range of 0-90; higher scores suggest better cognitive function (faster information processing speed). Calf SMA (muscle density) was assessed with computed tomography (Stratec XCT-2000). Linear regression was used to assess the association of SMA with DSST adjusted for age, education, muscle area, waist circumference, alcohol intake, smoking, physical activity, diabetes, and hypertension.
Results
Participants had a BMI of 30.7 kg/m2. Mean (SD) DSST scores and SMA were 39.2 (13.1) and 71.7 (5.3) mg/cm3, respectively. After full adjustment, we found that one SD greater skeletal muscle adiposity was associated with a 1.40 lower DSST score (p-value=0.025).
Conclusions
Our findings suggest that in African Caribbean women, greater SMA is associated with slower information processing speed, an early indicator of future dementia risk. Future studies using an expanded battery of cognitive tests and longitudinal follow-up should further advance our understanding of the role of SMA and dementia risk among African ancestry populations.
Abstract
Gait speed is a predictor of overall health and mortality in older adults. Metabolomics may provide insights into biological mechanisms underlying gait speed. Herein, we examined the ...association between 193 lipid metabolites with gait speed in 1,717 adults (52.1% women) aged 82.0 ± 14.5. Lipidomic analysis was performed using liquid chromatography-mass spectrometry. Gait speed was measured over 4-meters and slowness was defined as <0.8m/s. Logistic regression, adjusted for age, sex, field center, height, fasting-duration and familial-relatedness, were used to examine the association between log-transformed metabolites with slowness. A false discovery rate (FDR) of p<0.05 was employed to account for multiple comparisons. Gait speed was 0.83 ± 0.32 and 53.4% had slowness. Three lipid metabolites were significantly associated with lower odds of slowness: an acylcarnitine, sphingomyelin and a ceramide non-hydroxy fatty acid-sphingosine. Our results potentially link lipids involved with mitochondrial beta-oxidation and nerve signal transduction to gait speed in older adults.
OBJECTIVE:African ancestry individuals are at high risk for hypertensive cardiovascular disease (CVD) and could benefit from early detection of arterial stiffening. We tested the association between ...the 2017 ACC/AHA hypertension categorizations, which include new blood pressure (BP) cutoffs and a definition for elevated BP, and arterial stiffness in 772 Afro-Caribbean men aged 50+ years (mean 64 years).
METHODS:Arterial stiffness was assessed by brachial–ankle pulse-wave velocity (PWV) using a waveform analyzer. Hypertension groups were based on the 2017 ACC/AHA guidelines and by pharmacologic control status. Multiple linear/logistic regression was used to determine the association of PWV with BP and hypertension.
RESULTS:Mean (SD) PWV was 1609 (298) cm/s and was independently correlated with age, SBP, pulse, diabetes, height, and alcohol intake (all P < 0.02). After adjusting for these, in men aged at least 65 years, those with stage 1 or uncontrolled stage 2 hypertension had significantly greater PWV than all other groups (all P < 0.05). Men with controlled hypertension had similar PWV to those with elevated BP (P = 0.7); however, this was significantly greater than men with normal BP (all P < 0.05). Patterns were similar, but with smaller effect sizes, in men aged less than 65 years (all P < 0.05 except controlled hypertension versus elevated or normal BP were not significant).
CONCLUSION:In these high-risk Afro-Caribbeansstage 1 hypertension is associated with increased PWV, which supports the new guidelines; and, pharmacologic control appears to partially protect men from increased PWV. Longitudinal studies are needed to determine optimal PWV and timing of antihypertensive treatment for preventing future CVD.
Abstract
Diabetes has been linked to accelerated muscle strength decline with aging. However, the association between glucose metabolism and muscle strength decline among individuals without diabetes ...is less clear. We tested whether fasting plasma markers of glucose and insulin metabolism (glucose, insulin, hemoglobin A1c, and soluble receptor for advanced glycation end products (sRAGE)) are associated with grip strength decline among 1415 non-diabetic offspring of exceptionally long-lived individuals who have a low diabetes risk (age range 36-88; mean age ± SD = 60 ± 8 years; mean BMI ± SD = 27 ± 4.7 kg/m2; 57% women). Grip strength was assessed using a hand-held dynamometer at two clinic visits over an average of 7.9 years. Multiple linear mixed models were adjusted for age, sex, field center, lifestyle, comorbidities, body weight, height, weight change, and family relatedness. Each standard deviation higher fasting insulin (7.3 mIU/L) was related to greater grip strength decline (-0.38 ± 0.16 kg; p=0.016), while each standard deviation higher fasting sRAGE (430 pg/mL) was related to slower grip strength decline (0.36 ± 0.18 kg; p=0.04). Our findings suggest that even among non-diabetic individuals from families with a clustering of “healthier” metabolic profiles - insulin metabolism and advanced glycation end products may be important biomarkers of muscle strength decline with aging. Potential mechanisms, including genetic and metabolic mediators underlying the observed associations, warrant further investigation.
Abstract
Atherosclerotic occlusion of peripheral arteries is a major contributor to morbidity and mortality in older adults. Our aim was to describe the epidemiology of peripheral artery disease ...(PAD) and other peripheral vascular disease (OPD) in the LLFS. 3248 individuals from 509 families (1182 probands, mean age 89; 2066 offspring, mean age 60) had doppler ankle-brachial index (ABI) assessment. Measures were performed twice for each posterior tibial artery and minimum of the mean ABI was used. PAD was defined as any ABI<0.9. OPD was defined as any ABI >1.4 or ≥1 non-compressible artery. Stepwise linear or logistic regression determined significant independent clinical and demographic predictors (P<0.05) after adjustment for age, sex, study center, and familial relatedness. Overall, ABI had a median of 1.2 with 7.4% PAD (18.1% probands, 1.2% offspring; P<0.001). OPD prevalence was 10.6% and was more common than PAD in offspring (8.1%). Age-adjusted OPD was higher in men (13.3%) than women (8.3%, P<0.001), while age-adjusted PAD did not did not differ by sex (P=0.45). Predictors of PAD included greater age and systolic blood pressure, lower diastolic blood pressure, prevalent kidney disease, antihypertensive use, and current smoking. Predictors of OPD included greater age, male sex, and current smoking. In these exceptionally long-lived families, PAD was low compared to other epidemiologic studies. However, OPD including non-compressible arteries, a marker of arterial stiffness, was more prevalent than PAD. These findings in long-lived families highlight a need for more epidemiologic research in other peripheral vascular disease in adults from the general population.
Abstract
We tested the association of lipid metabolites with ankle-brachial index (ABI) in the LLFS. Minimum ABI from doppler was used. Participants underwent phlebotomy after >8 hours fasting. ...Plasma metabolites were isolated via solid phase extraction. Lipid metabolites (N=193) were measured using RPLC-MS and corrected for batch effects in 948 participants. We used linear mixed models adjusted for age, sex, site, fasting, and relatedness. Twenty metabolites were associated with ABI (FDR P<0.05), of which 17/20 were triacyclglycerol (TAG) species, plus cholesterol ester (22:6), phosphatidylcholine (35:7), and phosphatidylethanolamine (38:7). After additional adjustment for traditional ABI risk factors, only two TAGs (50:1, 42:0) were significantly associated after multiple testing correction. While not significant in the base model, the metabolite lysophosphatidylcholine (18:3) demonstrated a marginally significant protective association after full adjustment (P=0.014). While triglycerides are known correlates of atherosclerotic deposition, these findings may identify novel metabolic correlates of peripheral vascular health in long-lived individuals.
Abstract only
Although obesity is a major driver of type 2 diabetes (T2D), many obese individuals do not develop T2D. Indeed, fat around and within non-adipose tissue organs (i.e., ectopic fat) is ...emerging as a strong risk factor for diabetes. The potential differential contribution of ectopic fat depots throughout the body on T2D risk is unclear because studies have mainly focused on visceral and/or liver fat. No study, to our knowledge, has addressed the potential independent association of visceral, liver, and skeletal muscle adiposity with T2D. Such studies are particularly needed among African ancestry populations, as generalized obesity and other risk factors do not appear to explain the high T2D burden in this population segment. To address this knowledge gap, we measured total body fat by DXA, and visceral, liver, and calf skeletal muscle adiposity by computed tomography in 490 Afro-Caribbean men, aged 50-91 years (mean age=64 years, mean BMI=27.5 kg/m
2
). The prevalence of T2D in this population was 22.3%. We employed multiple logistic regression using total body fat percent and ectopic fat depots as predictors (Table). We found that each 7.9 HU decrease in liver attenuation (indicative of greater liver adiposity) was associated with a 33% increased odds of T2D (p=0.011). Similarly, each 4.2 mg/cm
3
decrease in muscle attenuation (indicative of greater intra-muscular adiposity) was associated with a 31% increased odds of T2D (p=0.04). These associations were independent of total and visceral adiposity. Our results support the “ectopic fat syndrome” theory, as opposed to the “portal theory”, in the pathogenesis of diabetes among African ancestry men. Longitudinal studies are needed to clarify the exact role of specific ectopic fat depots in T2D, particularly in high-risk African ancestry populations.
Abstract only
Objective:
While ectopic adiposity is considered a risk factor for many chronic diseases, including cardiovascular disease, the extent to which this association is independent of total ...adiposity is yet to be established. Vascular calcification, which is associated with greater adiposity, is a subclinical marker of cardiovascular disease that may have varying etiology and clinical implications in different vascular beds. Therefore, our objective was to assess the potential independent associations of total, regional and ectopic adiposity measures with abdominal aorto-iliac calcification (AAC) and coronary artery calcification (CAC).
Methods:
Detailed health history, clinical exam, dual x-ray absorptiometry and computed tomography (CT) scans were obtained in 798 African ancestry men aged ≥40 years (mean(SD): 62.0(8.6)years) recruited without regard to health status from the Tobago Heart Health Study. Vascular calcification was measured by CT in the abdomen (AAC) and chest (CAC). Calcification was scored using the Agatston method and a score ≥10 was considered to be a prevalent calcification. Severity of calcification was modeled using continuous Agatston score in those with any calcification. Multivariable logistic and linear regression models were used to assess the cross-sectional association of adiposity measures with vascular calcification prevalence and severity. All models were adjusted for age, hypertension, diabetes, dyslipidemia, smoking, alcohol intake and sedentary lifestyle. In addition, models of ectopic adiposity (abdominal visceral adipose tissue, liver attenuation and calf skeletal muscle fat) were adjusted for total body fat.
Results:
AAC was present in 63% and CAC was present in 29% of men. After adjustment for traditional cardiovascular risk factors, 1SD greater total, trunk, or abdominal subcutaneous adiposity was associated with 1.3-1.5-fold increased odds of AAC (all p<0.05). After additional adjustment for total body fat, 1SD lower liver attenuation (indicative of greater liver adiposity) or 1SD greater skeletal muscle fat were each associated with a 1.2-1.3-fold increased odds of AAC. In fully adjusted models, only greater BMI or waist circumference was associated with increased odds of CAC (OR 1.2, p<0.05 for both). In fully adjusted linear models of calcification severity, no significant association was observed between any adiposity measure and AAC or CAC.
Conclusions:
Independent of total adiposity, measures of ectopic adiposity were associated with greater AAC, but not CAC, prevalence in African ancestry men. These results highlight potential differences in the adiposity-vascular disease relationship that may vary by ectopic fat depot and vascular bed location. Future vascular disease research should explore potential underlying biologic mechanisms for these findings.
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