Abstract
Grip strength declines with aging, is an indicator of overall health, and predicts mortality among older adults. Herein, we quantified the genetic contributions to grip strength among 4534 ...individuals, belonging to 574 families in the Long Life Family Study (age 70.3 ± 15.7, range 24–110 years; 56% women). Grip strength was measured using a handheld dynamometer, and the maximum value of two trials in the stronger hand was used. Quantitative trait linkage analysis was completed using pedigree-based maximum-likelihood methods with logarithm of the odds (LOD) scores >3.0 indicating genome-wide significance. Linkage analysis in the top 10% of families contributing to LOD scores was also performed to allow for heterogeneity among families (HLOD). All analyses were adjusted for age, sex, height and field center. Grip strength was lower per one year of older age (β: -0.34 ± 0.01kg, p <0.01), and overall: 24.3% of men and 19.3% of women had “low” grip strength according to European Working Group on Sarcopenia definitions. Grip strength was highly heritable (h2 = 0.37, p<0.05). We identified a potentially novel locus for grip strength on chromosome 18p (LOD 3.18) with 26 families contributing to this linkage peak (HLOD = 10.94). Deep sequencing of the chromosome 18 region may yield fundamental insight on the biology of muscle weakness with aging, and may help identify novel therapeutic targets for treatment and prevention of this common condition.
Abstract
Circulating levels of procollagen type III N-terminal peptide (P3NP) may reflect increased fibrosis of skeletal muscle and other tissues with aging. In the current study, we tested if P3NP ...levels were associated with baseline and 7-year change in physical function among adults aged 39-104. Participants (n=400) were from the Long Life Family Study, a study of exceptional familial longevity. Plasma P3NP concentration was measured using a sandwich enzyme-linked immunosorbent assay (inter-assay CVs <3%). At baseline and 7-year follow-up visits, physical function was measured using the Short Physical Performance Battery (score 0-12), which consists of gait speed, balance, and chair-rise tests. Grip strength was measured using a handheld dynamometer. The association between log-transformed P3NP and physical function was examined using Generalized Estimating Equations adjusted for familial relatedness, age, sex, height, weight, lifestyle characteristics, chronic disease prevalence and inflammatory cytokines. Participants were aged 73.1 ± 15.2 years, 54% female, had a BMI of 26.6 ± 4.3 kg/m2, and a gait speed of 1.0 ± 0.3 m/s. One standard deviation higher P3NP concentration was related to worse baseline SPPB score (β=-0.9points), gait speed (β=-0.05m/s), chair-rise time (β=8.34seconds), and grip strength (β=-2.0kg; all p<0.001). Higher P3NP concentration was also associated with greater declines in gait speed (β=-1.41, p<.001) and chair-rise performance (β=0.41, p<.001). Plasma P3NP concentration may be a strong, novel biomarker of current and physical function changes with aging. Future research is needed to extend our findings to a larger population, and determine the mechanisms underlying these associations.
Abstract
Skeletal muscle adipose tissue infiltration is hypothesized to lead to poorer muscle quality and function with aging. Indeed, skeletal muscle adiposity has emerged as a consistent, ...independent predictor of skeletal muscle strength, mobility, metabolic disorders, and survival among older adults. However, phenotypic features of skeletal muscle among the oldest-old remain poorly characterized. Herein, we evaluated the skeletal muscle characteristics of 54 nonagenarians and centenarians (mean age 98 years, range 90-110 years; 63% women) and 25 middle-aged individuals (mean age 54 years, range 40-59 years; 36% women) belonging to the Long Life Family Study (LLFS), an international, multicenter cohort of families with a clustering of longevity. Ultrasonography was used to measure echo intensity of the sternocleidomastoid muscle, which has a similar fiber type distribution to the rectus femoris. Greater echo intensity is indicative of lower muscle quality (greater adipose and fibrotic tissue). Current smoking, alcohol intake, and BMI were similar between the age groups. Nonagenarians and centenarians had lower grip strength (16.3 vs. 39 kg) and were less physically active (22.2% vs 66.7% exercised 1+ times per week) compared to younger individuals (P<0.001 for all). Mean±SE echo intensity, adjusted for gender, field center, BMI and physical activity was 52.1±1.7 among nonagenarians and centenarians compared to 44.2±2.4 among younger individuals (P=0.0098). Our preliminary findings suggest that nonagenarians and centenarians may have substantially lower skeletal muscle quality and strength compared to their younger aged counterparts. Additional research is needed to better understand the mechanisms leading to poorer muscle characteristics of the oldest-old.
Abstract
Grip strength is a robust indicator of overall health, is moderately heritable and predicts longevity in older adults. Using genome-wide linkage analysis, we identified a novel locus on ...chromosome 18p linked to grip strength in 4534 individuals from 582 families (age 70.0 ± 15.8, range 24–110 years; 54% women). DNA sequencing was completed to identify single nucleotide variants (SNVs) in the 3.44 – 4.04 mega-basepair region on chromosome 18p. Using the sequencing data, we performed association analyses between the 7312 SNVs in the region and grip strength in families exhibiting evidence for linkage. Models were adjusted for age, age2, sex, height, field center and population substructure. There were 23 families (263 individuals) that contributed to the linkage peak (cumulative logarithm of the odds LOD score = 12.4). Six families (112 individuals) accounted for most of the linkage signal (LOD = 6.4). In these 6 families, we found highly significant associations between SNVs in the Disks Large-associated Protein 1 (DLGAP1) gene and grip strength (lead SNV: β= -0.75kg ± 0.15, p-value= 4.3*10-6). Correcting for the top SNV in DLGAP1 reduces the LOD by 72% in these families. Further, the effect allele frequency is much higher in these 6 families (39.7%) compared with both the NHLBI’s Trans-OMICs for Precision Medicine (23.5%) and 1000Genomes (28.0%) references panels. The DLGAP1 gene plays an important role in post-synaptic density of neurons; thus, it is a novel positional and biological candidate gene for follow-up studies aimed at uncovering genetic determinants of muscle strength.
Abstract
Gait speed is a heritable, robust predictor of longevity in older adults. Using genome-wide linkage analysis in 2379 individuals from 509 families (64±12 years; 45% men), we identified a ...locus on chromosome 16p linked to gait speed change over 7±1 years (logarithm of the odds score LOD=4.2). Gait speed change was calculated using a two-stage growth curve mixed-model. DNA sequencing was completed to identify single nucleotide variants (SNVs) in the linkage region. Association analyses between the 24039 SNVs in the ~1.6mBP region (3.7-5.3mBP) and gait speed change were performed adjusting for age, age2, sex, height, field center, familial relatedness and population substructure. Eleven families (188 individuals) accounted for most of the linkage signal (LOD=6.06). Associations between SNVs flanking the Mesothelin (MSLN) gene and gait speed change were identified (lead SNV rs56850119: β = -0.5±0.1, p = 6.4*10-7). Thus, MSLN is a potential positional candidate gene for mobility decline with aging.
Abstract Background and aims There is strong evidence that fat accumulating in non-adipose sites, “ectopic fat”, is associated with cardiovascular disease (CVD), including vascular calcification. ...Most previous studies of this association have assessed only a single ectopic fat depot. Therefore, our aim was to assess the association of total, regional, and ectopic fat with abdominal aorto-illiac calcification (AAC) and coronary artery calcification (CAC) in 798 African ancestry men. Methods Participants (mean age 62) were from the Tobago Bone Health Study cohort. Adiposity was assessed via clinical examination, dual x-ray absorptiometry, and computed tomography (CT). Ectopic fat depots included: abdominal visceral adipose tissue (VAT), liver attenuation, and calf intermuscular adipose tissue (IMAT). Vascular calcification was assessed by CT and quantified as present versus absent. Associations were tested using multiple logistic regression adjusted for traditional cardiovascular risk factors. Models of ectopic fat were additionally adjusted for total body fat and standing height. Results All adiposity measures, except VAT, were associated with AAC. Lower liver attenuation or greater calf IMAT was associated with 1.2–1.3-fold increased odds of AAC ( p < 0.03 for both), though calf IMAT was a stronger predictor than liver attenuation ( p < 0.001) when entered in a single model. No ectopic fat measure was associated with CAC. Conclusions Greater adiposity in the skeletal muscle and liver, but not in the visceral compartment, was associated with increased odds of AAC in African ancestry men. These results highlight the potential importance of both quantity and location of adiposity accumulation throughout the body.
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Background:
Emerging evidence indicates that ectopic fat, such as that in the visceral depot or muscle fat infiltration, may be associated with diabetes, independent of general ...obesity.Very little is known about the health effects of fat density, an emerging novel indicator of fat quality. Existing studies have focused on visceral or pericardial fat density. There is currently no information on muscle fat density and its associations with diabetes or other cardio-metabolic disorders.
Methods:
The aim of this preliminary study was to investigate whether visceral (VAT) or intermuscular (IMAT) adipose tissue density was associated with measures of glucose and insulin homeostasis independent of fat depot volume. We hypothesized that adipose tissue characterized by higher density would be associated with lower glucose and insulin fasting serum levels, and lower homeostasis model assessment of insulin resistance (HOMA-IR). Adipose tissue volume (cm3) and density (Hounsfield units) were measured in the abdomen and thigh from computed tomography scans in 193 non-diabetic black men aged 50 to 87 years (mean age 61 years, mean BMI 27 kg/m2). All measures were transformed to normal distribution and partial Pearson correlation coefficients were calculated.
Results:
In models adjusted for age and corresponding fat volume, thigh IMAT density and abdominal paraspinal IMAT density were inversely associated with fasting insulin (=-0.15 and r=-0.16, respectively; both p<0.05) and HOMA-IR (r=-0.18 and r=-0.19, respectively; both p<0.05). These associations were only slightly attenuated after additional adjustment for BMI (p for all <0.07). In contrast, VAT density was not associated with fasting insulin or HOMA-IR after adjustment for VAT volume or BMI. No fat density measure was associated with fasting serum glucose in any model.
Conclusion:
We found a novel correlation between lower intermuscular fat density and hyperinsulinemia and insulin resistance among non-diabetic black men. These results suggest that muscle fat quality may be a novel predictor of diabetic risk even independent of overall and ectopic fat volume.
Abstract
Body composition changes vary by age and ethnicity and have a major impact on health and physical function. However, little is known about the magnitude, tempo and patterns of these changes ...in African-ancestry populations, particularly outside the U.S. Thus, we examined age-specific rates-of-change in lean and fat mass in a unique population-based, longitudinal cohort study of 2621 African-ancestry men on the Caribbean island of Tobago (age: 62.0±11.8 years, range: 32-99 years). Body composition was measured with DXA at study entry and after an average of 4 and 9 years. Annualized rates of change and 95% confidence intervals were calculated using all 3 time-points with Generalized Estimating Equations stratified by 5-year baseline age-groups. Lean mass declined at a fairly constant rate in age-strata up through age ≤64 years (-0.72; -0.76, -0.67%/yr), but accelerated to -0.92 %/yr (-1.02, -0.82 %/yr) among those aged 65-69, and to -1.16 %/yr (-1.30, -1.03 %/yr) among those aged 70-74 years – plateauing in those aged 75+. This pattern of age acceleration was observed in arm but not leg lean mass. The age-specific rates of decline in lean mass in this cohort of African Caribbean men appear to be lower than those reported in older African American men. In contrast to lean mas, fat mass increased by 2.93 %/yr (2.72, 3.15 %/yr) and this rate of increase was fairly uniform across the lifespan. Additional research is needed to better define the lifestyle, medical and biological factors contributing to body composition changes across the lifespan in African-ancestry populations.
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Introduction:
Cardiovascular disease (CVD) is the leading cause of death throughout the world and age-adjusted rates of CVD mortality in Trinidad and Tobago are estimated to be ~2x ...those of the US. Given the drastic differences in culture and urbanization between Tobago and the US, we started the Tobago Heart Health Study to evaluate several aspects of subclinical CVD within a sample of men from an existing longitudinal study on the island.
Hypothesis:
We assessed the hypothesis that subclinical CVD burden in adult Afro-Caribbean men would be low overall, but that the burden would be substantially greater in the oldest men.
Methods:
We have preliminary data on subclinical CVD measures from 140 men, including carotid plaque from B-mode ultrasound, coronary artery calcification (CAC) and pericardial fat from computed tomography, and ankle-brachial index (ABI) and brachial-ankle pulse-wave velocity (baPWV) from automated waveform analysis. To assess the burden of multiple adverse measures, we calculated a subclinical CVD score (range 0-5) by summing the prevalence of the following: any carotid plaque, any CAC, highest quintile of pericardial fat, lowest quintile of ABI, or highest quintile of baPWV. For all subclinical variables of interest, we calculated means(SD) or frequencies, as appropriate, and identified age trends by testing for linear trends with age grouped as <60 years (n=56), 60-69 years (n=59) or ≥70 years (n=30).
Results:
The men were aged 53-88 years (mean(SD): 64(9) years) and the prevalence of hypertension, diabetes, smoking, moderate alcohol intake, and sedentary behavior were 64%, 26%, 5%, 18% and 52%, respectively. Sixteen percent of men had any carotid plaque and 25% had any CAC. Mean ABI was 1.1(0.1), mean baPWV was 1696(388)cm/s and mean pericardial fat was 41.4(27.6)cm3. Only 56% had ≥1 adverse subclinical CVD measure (23% with 1, 21% with 2, 10% with 3, 2% with 4, 0 with 5). Men in the oldest age group had significantly more carotid plaque, more CAC, lower ABI, higher baPWV and more pericardial fat compared to the younger age groups (all p<0.05). Mean(SD) subclinical CVD score was 0.6(0.8) in men <60 years, 0.8(0.9) in men aged 60-69 years, and 2.2(1.0) in men aged ≥70 years (p<0.001). Greater age remained a significant predictor of subclinical CVD score after adjustment for hypertension, diabetes, smoking, alcohol intake and physical activity (p<0.001).
Conclusions:
Subclinical CVD burden was low in this sample of 140 Afro-Caribbean men from Tobago. However, prevalence of adverse subclinical CVD measures greatly increased over the age of 70. It will be important to assess the impact of this aging-related subclinical burden on clinical CVD and cardiovascular mortality risks in adult Afro-Caribbean men in future studies.
Abstract
Gait speed is an indicator of health and function with aging. The potential genetic contributions to gait speed and its decline with aging are not well characterized. We sought to better ...quantify the genetic contributions to and identify potential genes and genetic variants underlying change in gait speed among older adults. To accomplish these aims, we used data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30–110 years; 45% men). Gait-speed was measured over 4 meters at baseline and after an average of 7±1.1 years. Quantitative trait linkage analyses were completed using pedigree-based maximum-likelihood methods with logarithm of the odds (LOD) scores > 3.3 indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height and field center. At baseline, 26.9% of individuals had “low” gait-speed <1.0 m/s (mean: 1.1±0.2 m/s) and gait speed declined at a rate of -0.02±0.03 m/s per year (p<0.0001). Baseline and change in gait-speed were significantly heritable (h2 = 0.24-0.32, p<0.05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a potentially novel locus for change in gait speed on chromosome 16p (LOD 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Sequence analysis of the chromosome 16 region may yield new insight on the biology of age-related mobility decline.
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