[Show abstract][Hide abstract] ABSTRACT: Associations of collateral vessels and lower extremity plaque with functional decline are unknown. Among people with peripheral artery disease (PAD), we determined whether greater superficial femoral artery (SFA) plaque burden combined with fewer lower extremity collateral vessels was associated with faster functional decline, compared to less plaque and/or more numerous collateral vessels. A total of 226 participants with ankle-brachial index (ABI) <1.00 underwent magnetic resonance imaging of lower extremity collateral vessels and cross-sectional imaging of the proximal SFA. Participants were categorized as follows: Group 1 (best), maximum plaque area < median and collateral vessel number ≥6 (median); Group 2, maximum plaque area < median and collateral vessel number <6; Group 3, maximum plaque area > median and collateral vessel number ≥6; Group 4 (worst), maximum plaque area > median and collateral vessel number <6. Functional measures were performed at baseline and annually for 2 years. Analyses adjust for age, sex, race, comorbidities, and other confounders. Annual changes in usual-paced walking velocity were: Group 1, +0.01 m/s; Group 2, -0.02 m/s; Group 3, -0.01 m/s; Group 4, -0.05 m/s (p-trend=0.008). Group 4 had greater decline than Group 1 (p<0.001), Group 2 (p=0.029), and Group 3 (p=0.010). Similar trends were observed for fastest-paced 4-meter walking velocity (p-trend=0.018). Results were not substantially changed when analyses were repeated with additional adjustment for ABI. However, there were no associations of SFA plaque burden and collateral vessel number with decline in 6-minute walk. In summary, a larger SFA plaque burden combined with fewer collateral vessels is associated with a faster decline in usual and fastest-paced walking velocity in PAD.
Vascular medicine (London, England). 07/2014; 19(4):281-288.
[Show abstract][Hide abstract] ABSTRACT: Although the accumulation of highly-differentiated and granzyme B (GrB)-expressing CD8(+)CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques and mice and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+)CD8(+) T cells by presenting endogenous antigens and utilizing the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and their capacity to evoke the generation of GrB(+)CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4-1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly.
[Show abstract][Hide abstract] ABSTRACT: Anxiety and other psychological dispositions are thought to be associated with blood pressure. This study tests whether personality traits have long-term associations with masked and white-coat effects.
[Show abstract][Hide abstract] ABSTRACT: Our objective is to report prevalence of motoric cognitive risk syndrome (MCR), a newly described predementia syndrome characterized by slow gait and cognitive complaints, in multiple countries, and its association with dementia risk.METHODS: Pooled MCR prevalence analysis of individual data from 26,802 adults without dementia and disability aged 60 years and older from 22 cohorts from 17 countries. We also examined risk of incident cognitive impairment (Mini-Mental State Examination decline ≥4 points) and dementia associated with MCR in 4,812 individuals without dementia with baseline Mini-Mental State Examination scores ≥25 from 4 prospective cohort studies using Cox models adjusted for potential confounders.RESULTS: At baseline, 2,808 of the 26,802 participants met MCR criteria. Pooled MCR prevalence was 9.7% (95% confidence interval [CI] 8.2%-11.2%). MCR prevalence was higher with older age but there were no sex differences. MCR predicted risk of developing incident cognitive impairment in the pooled sample (adjusted hazard ratio [aHR] 2.0, 95% CI 1.7-2.4); aHRs were 1.5 to 2.7 in the individual cohorts. MCR also predicted dementia in the pooled sample (aHR 1.9, 95% CI 1.5-2.3). The results persisted even after excluding participants with possible cognitive impairment, accounting for early dementia, and diagnostic overlap with other predementia syndromes.CONCLUSION: MCR is common in older adults, and is a strong and early risk factor for cognitive decline. This clinical approach can be easily applied to identify high-risk seniors in a wide variety of settings.
[Show abstract][Hide abstract] ABSTRACT: Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.
[Show abstract][Hide abstract] ABSTRACT: Many biodemographic studies use biomarkers of inflammation to understand or predict chronic disease and aging. Inflamm-aging, i.e. chronic low-grade inflammation during aging, is commonly characterized by pro-inflammatory biomarkers. However, most studies use just one marker at a time, sometimes leading to conflicting results due to complex interactions among the markers. A multidimensional approach allows a more robust interpretation of the various relationships between the markers. We applied principal component analysis (PCA) to 19 inflammatory biomarkers from the InCHIANTI study. We identified a clear, stable structure among the markers, with the first axis explaining inflammatory activation (both pro- and anti-inflammatory markers loaded strongly and positively) and the second axis innate immune response. The first but not the second axis was strongly correlated with age (r=0.56, p<0.0001, r=0.08 p=0.053), and both were strongly predictive of mortality (hazard ratios per PCA unit (95% CI): 1.33 (1.16-1.53) and 0.87 (0.76-0.98) respectively) and multiple chronic diseases, but in opposite directions. Both axes were more predictive than any individual markers for baseline chronic diseases and mortality. These results show that PCA can uncover a novel biological structure in the relationships among inflammatory markers, and that key axes of this structure play important roles in chronic disease.
[Show abstract][Hide abstract] ABSTRACT: Motivated by aging research, we propose an estimator of the effect of a time-varying exposure on an outcome in longitudinal studies with dropout and truncation by death. We use an inverse-probability weighted (IPW) estimator to derive a doubly robust augmented inverse-probability weighted (AIPW) estimator. IPW estimation involves weights for the exposure mechanism, dropout, and mortality; AIPW estimation additionally involves estimating data-generating models via regression. We demonstrate that the estimators identify a causal contrast that is a function of principal strata effects under a set of assumptions. Simulations show that AIPW estimation is unbiased when weights or outcome regressions are correct, and that AIPW estimation is more efficient than IPW estimation when all models are correct. We apply the method to a study of vitamin D and gait speed among older adults.
[Show abstract][Hide abstract] ABSTRACT: Although metabolic syndrome (MS) is a typical condition of middle-aged/older person, the association between MS and mortality risk has not been confirmed in people over 65 years. We hypothesized that while in the elderly MS phenotype might lose its value in predicting mortality risk, the two core factors of MS, i.e. insulin resistance (IR) and low grade systemic inflammation (LGSI) would not.
[Show abstract][Hide abstract] ABSTRACT: Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
[Show abstract][Hide abstract] ABSTRACT: -Omega-6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.
-To elucidate undiscovered biologic pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with five plasma n6 PUFAs in 8,631 Caucasian adults (55% female) across five prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linoleic acid (DGLA), arachidonic acid (AA), and adrenic acid (AdrA) were expressed as % of total fatty acids. We performed linear regression with robust standard errors to test for SNP-fatty acid associations, with pooling using inverse-variance weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118, p-value = 8.1x10(-9); near NRBF2); on chromosome 16 with LA, GLA, DGLA, and AA (rs16966952, p-value = 1.2x10(-15), 5.0x10(-11), 7.6x10(-65), and 2.4x10(-10), respectively; NTAN1); and on chromosome 6 with AdrA following adjustment for AA (rs3134950, p-value = 2.1x10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and AA, and further observed novel genome-wide significant association of this cluster with GLA, DGLA, and AdrA (p-value = 2.3x10(-72), 2.6x10(-151), and 6.3x10(-140), respectively).
-Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anticancer effects in humans and is related to longevity in some lower organisms. OBJECTIVE To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans. DESIGN Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study ("Aging in the Chianti Region"), 1998 to 2009 conducted in 2 villages in the Chianti area in a population-based sample of 783 community-dwelling men and women 65 years or older. EXPOSURES Twenty-four-hour urinary resveratrol metabolites. MAIN OUTCOMES AND MEASURES Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]) and prevalent and incident cancer and cardiovascular disease. RESULTS Mean (95% CI) log total urinary resveratrol metabolite concentrations were 7.08 (6.69-7.48) nmol/g of creatinine. During 9 years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P = .67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% CI, 0.54-1.17) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF, prevalent or incident cardiovascular disease, or cancer. CONCLUSIONS AND RELEVANCE In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study.
JAMA Internal Medicine 05/2014; · 10.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is a J-shaped relationship between body mass index (BMI) and cardiovascular outcomes in elderly patients (obesity paradox). Whether low BMI correlates with aortic calcification (AC) and whether this association is accounted for by bone demineralization is uncertain.
[Show abstract][Hide abstract] ABSTRACT: Age-related declines in physical activity are commonly observed in human and animal populations, but their physiologic bases are not fully understood. The authors hypothesize that a lack of available energy contributes to low levels of activity in older persons.
Cross-sectional analyses of relationships between physical activity level and energy availability were performed in 602 community-dwelling volunteers aged 45-91 yrs from the Baltimore Longitudinal Study of Aging. Energy expenditure was measured at rest and during a maximal 400-m walk for calculation of "available energy." Overall and vigorous physical activity levels were assessed using standardized questionnaires. General linear regression models were used to assess the relationships between available energy and general and vigorous physical activity, and stratified analyses were used to analyze the possible differential association between available energy and physical activity across high and low (peak sustained walking oxygen consumption per unit time, <18.3 ml of oxygen per kilogram per minute) levels of aerobic fitness.
Low available energy was associated with low levels of total physical activity (β = 64.678, P = 0.015) and vigorous activity (β = 9.123, P < 0.0001). The direct relationship between available energy and physical activity was particularly strong in persons categorized as having low aerobic fitness between available energy and physical activity with both total (β = 119.783, P = 0.022) and vigorous activity (β = 10.246, P = 0.015) and was independent of body composition and age.
The findings from this study support the hypothesis that available energy promotes the maintenance of physical activity in older persons. The findings also run counter to the perception that age-related declines in physical activity are primarily societally or behaviorally driven.
American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 05/2014; · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Measuring physiological dysregulation during aging could be a key tool both to understand underlying aging mechanisms and to predict clinical outcomes in patients. However, most existing indices are either circular or hard to interpret biologically. Recently, we showed that statistical distance of 14 common blood biomarkers (a measure of how strange an individual's biomarker profile is) was associated with age and mortality in the WHAS II data set, validating its use as a measure of physiological dysregulation. Here, we extend the analyses to other data sets (WHAS I and InCHIANTI) to assess the stability of the measure across populations. We found that the statistical criteria used to determine the original 14 biomarkers produced diverging results across populations; in other words, had we started with a different data set, we would have chosen a different set of markers. Nonetheless, the same 14 markers (or the subset of 12 available for InCHIANTI) produced highly similar predictions of age and mortality. We include analyses of all combinatorial subsets of the markers and show that results do not depend much on biomarker choice or data set, but that more markers produces a stronger signal. We conclude that statistical distance as a measure of physiological dysregulation is stable across populations in Europe and North America.
[Show abstract][Hide abstract] ABSTRACT: This analysis sought to determine the associations of the Foundation for the National Institutes of Health Sarcopenia Project criteria for weakness and low lean mass with likelihood for mobility impairment (gait speed ≤ 0.8 m/s) and mortality. Providing validity for these criteria is essential for research and clinical evaluation.
Among 4,411 men and 1,869 women pooled from 6 cohort studies, 3-year likelihood for incident mobility impairment and mortality over 10 years were determined for individuals with weakness, low lean mass, and for those having both. Weakness was defined as low grip strength (<26kg men and <16kg women) and low grip strength-to-body mass index (BMI; kg/m(2)) ratio (<1.00 men and <0.56 women). Low lean mass (dual-energy x-ray absorptiometry) was categorized as low appendicular lean mass (ALM; <19.75kg men and <15.02kg women) and low ALM-to-BMI ratio (<0.789 men and <0.512 women).
Low grip strength (men: odds ratio [OR] = 2.31, 95% confidence interval [CI] = 1.34-3.99; women: OR = 1.99, 95% CI 1.23-3.21), low grip strength-to-BMI ratio (men: OR = 3.28, 95% CI 1.92-5.59; women: OR = 2.54, 95% CI 1.10-5.83) and low ALM-to-BMI ratio (men: OR = 1.58, 95% CI 1.12-2.25; women: OR = 1.81, 95% CI 1.14-2.87), but not low ALM, were associated with increased likelihood for incident mobility impairment. Weakness increased likelihood of mobility impairment regardless of low lean mass. Mortality risk patterns were inconsistent.
These findings support our cut-points for low grip strength and low ALM-to-BMI ratio as candidate criteria for clinically relevant weakness and low lean mass. Further validation in other populations and for alternate relevant outcomes is needed.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2014; 69(5):576-83. · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Weakness is common and contributes to disability, but no consensus exists regarding a strength cutpoint to identify persons at high risk. This analysis, conducted as part of the Foundation for the National Institutes of Health Sarcopenia Project, sought to identify cutpoints that distinguish weakness associated with mobility impairment, defined as gait speed less than 0.8 m/s.
In pooled cross-sectional data (9,897 men and 10,950 women), Classification and Regression Tree analysis was used to derive cutpoints for grip strength associated with mobility impairment.
In men, a grip strength of 26-32 kg was classified as "intermediate" and less than 26 kg as "weak"; 11% of men were intermediate and 5% were weak. Compared with men with normal strength, odds ratios for mobility impairment were 3.63 (95% CI: 3.01-4.38) and 7.62 (95% CI 6.13-9.49), respectively. In women, a grip strength of 16-20 kg was classified as "intermediate" and less than 16 kg as "weak"; 25% of women were intermediate and 18% were weak. Compared with women with normal strength, odds ratios for mobility impairment were 2.44 (95% CI 2.20-2.71) and 4.42 (95% CI 3.94-4.97), respectively. Weakness based on these cutpoints was associated with mobility impairment across subgroups based on age, body mass index, height, and disease status. Notably, in women, grip strength divided by body mass index provided better fit relative to grip strength alone, but fit was not sufficiently improved to merit different measures by gender and use of a more complex measure.
Cutpoints for weakness derived from this large, diverse sample of older adults may be useful to identify populations who may benefit from interventions to improve muscle strength and function.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2014; 69(5):559-66. · 4.31 Impact Factor