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Among people with peripheral artery disease (PAD), perceived change in walking difficulty over time, compared with people without PAD, is unclear. Among people reporting no change in walking difficulty over time, differences in objectively measured change in walking performance between people with and without PAD are unknown. A total of 1289 participants were included. Eight hundred seventy-four participants with PAD (aged 71.1 ± 9.1 years) were identified from noninvasive vascular laboratories and 415 without PAD (aged 69.9 ± 7.6 years) were identified from people with normal vascular laboratory testing or general medical practices in Chicago. The Walking Impairment Questionnaire and 6-minute walk were completed at baseline and 1-year follow-up. The Walking Impairment Questionnaire assessed perceived difficulty walking due to symptoms in the calves or buttocks on a Likert scale (range, 0-4). Symptom change was determined by comparing difficulty reported at 1-year follow-up to difficulty reported at baseline. At 1-year follow-up, 31.9% of participants with and 20.6% of participants without PAD reported walking difficulty that was improved (P <.01), whereas 41.2% vs 55%, respectively, reported walking difficulty that was unchanged (P <.01). Among all reporting no change in walking difficulty, participants with PAD declined in 6-minute walk, whereas participants without PAD improved (−10 vs +15 meters; mean difference, −25; 95% confidence interval, −38 to −13; P <.01). Most people with PAD reported improvement or no change in walking difficulty from calf or buttock symptoms at one-year follow-up. Among all participants who perceived stable walking ability, those with PAD had significant greater declines in objectively measured walking performance, compared with people without PAD. [ABSTRACT FROM AUTHOR]

A genome-wide association study is conducted for the identification of the novel common variants that are associated with the circulating carotenoid levels and known lipid variants associated with [alpha]-tocopherol levels. The common variation taking place in the [beta]-carotene 15,15'-monooxygenase 1 gene is shown to affect the circulating levels of carotenoids.

Background Diet quality may be protective of physical function and muscle strength during aging. Objectives We aimed to investigate associations of the Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay (MIND) diet with physical function and grip strength. Methods Data were obtained from men and women in the Baltimore Longitudinal Study of Aging (mean ± SD age: 68 ± 14 y at first diet visit; n  = 1358). Diet was assessed by FFQ. MIND diet score was calculated from 15 food groups, with a higher score indicating better diet quality; tertile categories of averaged MIND score across visits were used. Physical function was assessed using the Short Physical Performance Battery (SPPB), with a score < 10 indicative of impaired function, and the Health, Aging and Body Composition Physical Performance Battery (HABCPPB). The highest value of grip strength over 3 trials was used. Multivariable logistic and linear mixed-effects models were examined with repeated measurements of physical function and grip strength, respectively. Results MIND score was inversely associated with physical function impairment (per 1-point increment: OR: 0.81; 95% CI: 0.71, 0.93; P  < 0.01), and with each SPPB component, over a median 6 y of follow-up. Participants in the highest compared with the lowest tertile of MIND diet score had 57% lower odds of functional impairment (OR: 0.43; 95% CI: 0.25, 0.73; P  < 0.01), and slower decline by the HABCPPB. Men and women in the highest compared with the lowest tertiles of MIND score had 1.86-kg (95% CI: 0.33, 3.40 kg; P  < 0.05) and 1.24-kg (95% CI: 0.04, 2.45 kg; P  < 0.05) greater grip strength, respectively. Conclusions Adherence to the MIND dietary pattern was associated with lower odds of physical function impairment and decline, and with better muscle strength, indicating that the MIND dietary pattern may be protective of physical functional health in older adults. [ABSTRACT FROM AUTHOR]

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRS L274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-R KT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-R KT /ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-R KT to promote proliferation and subsequent muscle resilience during CR. [Display omitted] • Short-term caloric restriction (CR) drastically alters the liver-derived plasma proteome • Circulating plasminogen increases with CR, which is necessary for satellite cell expansion • During CR, plasminogen signals to the satellite cell via the plasminogen receptor Plg-R KT • Loss of Plg-R KT prevents CR-induced SC expansion and associated regenerative enhancements Short-term caloric restriction (CR) has been shown to expand the muscle satellite cell pool and accelerate the early phase of muscle regeneration. Bareja et al. report robust changes in the liver-derived plasma proteome during CR and identify plasminogen as a contributing factor to the satellite cell expansion, signaling through Plg-R KT. [ABSTRACT FROM AUTHOR]

Background: Although diets rich in carotenoids are associated with reduced risks of cardiovascular disease, age-related macular degeneration, disability, and other adverse aging outcomes, the underlying biological mechanisms are not fully elucidated.Objectives: To characterize the plasma proteome fingerprint associated with circulating carotenoid and retinol concentrations in older adults.Methods: In 728 adults ≥65 y participating in the Invecchiare in Chianti (InCHIANTI) Study, plasma α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene were measured using HPLC. The SOMAscan assay was used to measure 1301 plasma proteins. Multivariable linear regression models were used to examine the relationship of individual carotenoids and retinol with plasma proteins. A false discovery rate approach was used to deal with multiple comparisons using a q-value < 0.05.Results: Plasma β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene were associated with 85, 39, 4, 2, and 5 plasma proteins, respectively, in multivariable linear regression models adjusting for potential confounders (q < 0.05). No proteins were associated with α-carotene or retinol. Two or more carotenoids were positively associated with ferritin, 6-phosphogluconate dehydrogenase (decarboxylating), hepcidin, thrombospondin-2, and choline/ethanolamine kinase. The proteins associated with circulating carotenoids were related to energy metabolism, sirtuin signaling, inflammation and oxidative stress, iron metabolism, proteostasis, innate immunity, and longevity.Conclusions: The plasma proteomic fingerprint associated with elevated circulating carotenoids in older adults provides insight into the mechanisms underlying the protective role of carotenoids on health. [ABSTRACT FROM AUTHOR]

Body weight changes reflect and impact several health conditions in older age, but little is known about its relationship with multimorbidity. We aimed to study the association of long-terms trajectories of body mass index (BMI) with contemporaneous changes in multimorbidity −and multimorbidity type− development in a population-based cohort of older adults. Twelve-year BMI trajectories (2001–2013) were identified in subjects aged 60+ years from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) using growth mixture models (N = 2189). Information on 60 chronic diseases and multimorbidity was ascertained based on clinical examinations, lab tests, medications, and inpatient and outpatient medical records. Linear mixed models were used to study the association between BMI trajectories and the speed of chronic disease accumulation, in general and by groups of cardiovascular and neuropsychiatric diseases. Eighty percent of the study population was included in what we defined a stable BMI trajectory, 18% in a slow-decline trajectory with an accelerated BMI decline from age 78 onwards, and 2% in a fast-decline trajectory that reached underweight values before age 85. A significantly higher yearly rate of chronic disease accumulation was observed in the fast-decline versus stable trajectory (β = 0.221, 95% CI 0.090–0.352) after adjusting the model for age cohort, sex, education and time to death. Subjects in the slow-decline trajectory showed a significantly higher yearly rate of cardiovascular disease accumulation (β = 0.016, 95% CI 0.000–0.031); those in the fast-decline trajectory showed a faster accumulation of both cardiovascular (β = 0.020, 95% CI -0.025, 0.064) and neuropsychiatric diseases (β = 0.102, 95% CI 0.064–0.139), even if the former association did not reach statistical significance. Our results provide further evidence of the importance of carefully monitoring older adults with sustained weight loss, which is an early indicator of accelerated health deterioration, reflected in our study by a faster accumulation of chronic −especially neuropsychiatric− diseases. [ABSTRACT FROM AUTHOR]

Background Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20–30 ng/mL) for skeletal health. Objectives We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults' physical function. Methods Using 5 large prospective, population-based studies—Age, Gene/Environment Susceptibility-Reykjavik (n  = 4858, Iceland); Health, Aging, and Body Composition (n  = 2494, United States); Invecchiare in Chianti (n  = 873, Italy); Osteoporotic Fractures in Men (n  = 2301, United States); and Study of Osteoporotic Fractures (n  = 5862, United States)—we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged ≥65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women <0.8 m/s; men <0.825 m/s) and secondary outcomes (gait speed, incident self-reported mobility, and stair climb impairment) at median 3.0-y follow-up. We identified sex-specific 25(OH)D thresholds that best discriminated incident slow gait using machine learning in training data (2/3 cohort-stratified random sample) and validated using the remaining (validation) data and secondary outcomes. Results Mean age in the cohorts ranged from 74.4 to 76.5 y in women and from 73.3 to 76.6 y in men. Overall, 1112/6123 women (18.2%) and 494/3937 men (12.5%) experienced incident slow gait, 1098/7011 women (15.7%) and 474/3962 men (12.0%) experienced incident mobility impairment, and 1044/6941 women (15.0%) and 432/3993 men (10.8%) experienced incident stair climb impairment. Slow gait was best discriminated by 25(OH)D <24.0 ng/mL compared with 25(OH)D ≥24.0 ng/mL in women (RR: 1.29; 95% CI: 1.10, 1.50) and 25(OH)D <21.0 ng/mL compared with 25(OH)D ≥21.0 ng/mL in men (RR: 1.43; 95% CI: 1.01, 2.02). Most associations between 25(OH)D and secondary outcomes were modest; estimates were similar between validation and training datasets. Conclusions Empirically identified and validated sex-specific threshold 25(OH)D concentrations for physical function for older adults, 24.0 ng/mL for women and 21.0 ng/mL for men, may inform candidate reference concentrations or the design of vitamin D intervention trials. [ABSTRACT FROM AUTHOR]

Among people with lower extremity peripheral artery disease (PAD), little is known about variation in response to supervised exercise therapy (SET). Clinical characteristics associated with greater responsiveness to SET have not been identified. Data from participants with PAD in two randomized clinical trials comparing SET vs nonexercising control were combined. The exercise intervention consisted of three times weekly supervised treadmill exercise. The control groups received lectures on health-related topics. Of 309 unique participants randomized (mean age, 67.9 years [standard deviation, 9.3 years]; 132 [42.7%] women; 185 [59.9%] black), 285 (92%) completed 6-month follow-up. Compared with control, those randomized to SET improved 6-minute walk distance by 35.6 meters (95% confidence interval, 21.4-49.8; P <.001). In the 95 (62.1%) participants who attended at least 70% of SET sessions, change in 6-minute walk distance varied from −149.4 to +356.0 meters. Thirty-four (35.8%) had no 6-minute walk distance improvement. Among all participants, age, sex, race, body mass index, prior lower extremity revascularization, and other clinical characteristics did not affect the degree of improvement in 6-minute walk distance after SET relative to the control group. Participants with 6-minute walk distance less than the median of 334 meters at baseline had greater percentage improvement in 6-minute walk distance compared with those with baseline 6-minute walk distance above the median (+20.5% vs +5.3%; P for interaction =.0107). Among people with PAD, substantial variability exists in walking improvement after SET. Shorter 6-minute walk distance at baseline was associated with greater improvement after SET, but other clinical characteristics, including age, sex, prior lower extremity revascularization, and disease severity, did not affect responsiveness to exercise therapy. [ABSTRACT FROM AUTHOR]

Randomized trials of people with peripheral artery disease (PAD) and intermittent claudication have traditionally used maximal treadmill walking distance as the primary outcome, but the 6-minute walk test is increasingly used as a primary outcome in randomized trials of PAD. This study compared relative changes in maximal treadmill walking distance versus 6-minute walk distance in response to a therapeutic intervention or control in randomized trials of participants with PAD. Data from four randomized trials of therapeutic interventions in participants with PAD that measured both 6-minute walk and treadmill walking performance at baseline and the 6-month follow-up were combined. Two trials studied supervised treadmill exercise, one studied home-based walking exercise, and one studied resveratrol. Of 467 participants (mean age, 69.8; standard deviation, 9.7), the mean ankle-brachial index was 0.66 (standard deviation, 0.17). At the 6-month follow-up, participants with PAD randomized to control or placebo significantly declined in 6-minute walk distance (−10.2 m; 95% confidence interval, −18.2 to −2.2; P =.013), but improved maximal treadmill walking distance (+25.7 m; 95% CI, +6.0 to +45.3 m; P =.010; difference between change in 6-minute walk versus maximal treadmill walking distance: −37.3 m; 95% CI, −56.4 to −18.2; P <.001). Home-based exercise improved the 6-minute walk distance by 43.2 m (95% CI, +28.4 to +57.9), and supervised treadmill exercise improved the 6-minute walk distance by 25.0 m (95% CI, +14.7 to +35.2; mean difference, +18.2 m favoring home-based exercise [95% CI, +0.2 to +36.2 m; P =.048]). Among all participants, the presence (vs absence) of treadmill exercise training was associated with a 141.3-m greater improvement in maximal treadmill walking distance compared to 6-minute walk distance (95% CI, 88.2-194.4; P <.001), suggesting a benefit from treadmill training on the treadmill outcome. Maximal treadmill walking distance and the 6-minute walk distance are not interchangeable outcomes in participants with PAD. Participants with PAD randomized to control groups improved treadmill walking distance but simultaneously meaningfully declined in 6-minute walk distance. Supervised treadmill exercise training amplified improvement in treadmill walking distance because of a training to the outcome measure phenomenon. [ABSTRACT FROM AUTHOR]

PUFA intake is associated with reduced cardiovascular and all-cause mortality in the general population; however, evidence about this association in older adults is controversial. The objective of this study was to evaluate the relationship between PUFA intake and serum concentration, and the association of these variables with all-cause and cardiovascular mortality. in this cohort study, we selected 927 community dwelling adults aged ≥65 years enrolled in the InCHIANTI study from 1998 to 2000 and followed-up for 9 years. The association between PUFA intake and serum concentration was evaluated using scatterplot and Pearson correlation test; all-cause and cardiovascular mortality was analyzed using the Kaplan-Meier method and Cox regressions adjusted for potential confounders. mean age of the population was 75 years (SD 7.3), 55% were women. There was no association between overall PUFAs, linolenic and linoleic acid intake and their serum concentration. There was no association between quartiles (Q) of PUFA intake and all-cause mortality: compared to Q1 of PUFA intake, the adjusted HR (95% CI) for overall mortality were: 1.05 (0.74–1.50) in Q2, 1.10 (0.76–1.58) in Q3, and 0.98 (0.68–1.41) in Q4; this lack of association was confirmed for cardiovascular mortality. Compared to Q1, participants in the fourth quartile of PUFA serum concentration had lower risk of all-cause mortality (adjusted HR [95%CI]: Q2 1.10 [0.79–1.53], Q3 0.84 [0.60–1.19], Q4 0.66 [0.44–0.995]), no association was found for cardiovascular mortality. In our sample of community-dwelling older adults, PUFA intake is not associated with PUFA serum concentration. Interventions to modulate PUFA concentration based on dietary intake may not be effective in preventing mortality in this population. [ABSTRACT FROM AUTHOR]

Background and Aims: Increased uric acid levels correlate with cardiovascular disease and cardiovascular/overall mortality. To identify a uric acid threshold above which cardiovascular mortality rises, we studied the relationship between uric acid concentration and overall/cardiovascular mortality.Methods and Results: We analyzed data from the InCHIANTI study, a cohort study of Italian community-dwelling people with 9 years of follow-up. We selected a sample of 947 individuals over 64 years of age, free from cardio-cerebrovascular disease and with available uric acid measurement at baseline. The sample was divided according to plasma uric acid tertiles. The Hazard ratio (HR) for mortality was calculated by multivariate Cox proportional hazard model. Mean age of participants was 75.3 ± 7.3 years; the mean value of uric acid was 5.1 ± 1.4 mg/dl. Over 9-years of follow-up, 342 (36.1%) participants died, 143 deaths (15.1%) were due to cardiovascular disease. Subjects with higher uric acid concentrations presented a higher cardiovascular mortality [II (4.6-5.5 mg/dl) vs I (1.8-4.5 mg/dl) tertile HR: 1.98, 95%C.I. 1.22-3.23; III (≥5.6 mg/dl) vs I tertile HR: 1.87, 95%C.I. 1.13-3.09]. We found a non-linear association between uric acid concentrations and cardiovascular mortality with the lowest mortality for values of about 4.1 mg/dl and a significant risk increment for values above 4.3 mg/dl.Conclusion: In community-dwelling older individuals free from cardio-cerebrovascular events, the lowest 9-year cardiovascular mortality was observed for uric acid values far below current target values. If confirmed, these data might represent the background for investigating the efficacy of uric acid levels reduction in similar populations. [ABSTRACT FROM AUTHOR]

The relation between liver fibrosis scores and health outcomes in older people has been barely investigated. We aimed to evaluate the association of four liver fibrosis scores (fibrosis-4 -FIB-4-, NAFLD fibrosis score -NFS-, BARD and aspartate aminotransferase/alanine aminotransferase ratio -AST/ALT-) with mortality and incident disability at 6 years in an older population. We studied 962 individuals aged ≥65 (mean age 74.4; female 55.5%) with a mean follow-up of 95.7 months, enrolled in the InCHIANTI study. The relationship between liver fibrosis scores and mortality and disability was assessed through Cox and log-binomial regressions. NFS and FIB-4 were associated with higher overall (aHR ranging 1.38–1.78 for intermediate risk of fibrosis and 1.60–2.02 for high risk) and cardiovascular (aHR ranging 1.76–2.90 for intermediate and 2.22–2.42 for high risk) mortality. AST/ALT and BARD were only associated with overall mortality. Only NFS and FIB-4 high risk classes were associated with incident disability (aRR ranging 1.93–2.76). Despite poor sensitivity, all scores showed high specificity (ranging 0.88–0.95). Higher risk of liver fibrosis is associated with higher risk of poor health outcomes. Liver fibrosis scores may help to stratify the risk and, mainly, identify elderly patients with favorable prognosis. [ABSTRACT FROM AUTHOR]

Sarcopenia, the progressive loss of muscle mass, strength, and physical performance that occurs during aging, is highly prevalent among the elderly. Sarcopenia increases the risk of falls, disability, and death. The biological basis for sarcopenia is not well understood. There are no specific preventive or therapeutic strategies for sarcopenia except exercise. The elucidation of biological pathways and identification of therapeutic targets for treating or preventing sarcopenia remain a high priority in aging research. Mitochondria play a critical role in skeletal muscle by providing energy in the form of ATP, regulation of signaling, calcium homeostasis, autophagy, and other functions. Cardiolipin, a unique dimeric phospholipid specific to mitochondria and an essential component of mitochondrial membranes, is involved in mitochondrial protein transport, maintaining structural organization of mitochondrial membranes, cellular signaling, regulating enzymes involved in β-oxidation of fatty acids, and facilitating normal electron transport chain (ETC) function and generation of ATP. The fatty acid species composition of cardiolipin is critical to mitochondrial bioenergetics, as cardiolipin affects membrane biophysical properties, binds and stabilizes ETC protein complexes, and shapes the curvature of the mitochondrial cristae. Tetra-linoleoyl cardiolipin (18:2)4 comprises ∼80% of cardiolipin in mitochondria in normal human skeletal and cardiac muscle and is optimal for effective ETC function and ATP generation. Aging is associated with a decrease in cardiolipin content, decrease in tetra-linoleoyl cardiolipin (18:2)4 and replacement of linoleic acid (18:2) with other fatty acids in cardiolipin composition, decline of ETC function, and increased generation of reactive oxygen species in muscle. Together, these findings from the literature prompt the hypothesis that depletion of the cardiolipin (18:2)4 species may be at the root of mitochondrial dysfunction with aging, in turn leading to sarcopenia. Corroboration of the tetra-linoleoyl cardiolipin depletion hypothesis suggests new leads for the prevention and treatment of sarcopenia by enhancing the biosynthesis, accretion, and integrity of tetra-linoleoyl cardiolipin. [ABSTRACT FROM AUTHOR]

Cancer incidence substantially increases with ageing in both men and women, although the reason for this increase is unknown. In this Series paper, we propose that age-associated changes in gut commensal microbes, otherwise known as the microbiota, facilitate cancer development and growth by compromising immune fitness. Ageing is associated with a reduction in the beneficial commensal microbes, which control the expansion of pathogenic commensals and maintain the integrity of the intestinal barrier through the production of mucus and lipid metabolites, such as short-chain fatty acids. Expansion of gut dysbiosis and leakage of microbial products contributes to the chronic proinflammatory state (inflammaging), which negatively affects the immune system and impairs the removal of mutant and senescent cells, thereby enabling tumour outgrowth. Studies in animal models and the importance of commensals in cancer immunotherapy suggest that this status can be reversible. Thus, interventions that alter the composition of the gut microbiota might reduce inflammaging and rejuvenate immune functions to provide anticancer benefits in frail elderly people. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Changes in the composition of body tissues are major aging phenotypes, but they have been difficult to study in depth. Here we describe age-related change in abdominal tissues observable in computed tomography (CT) scans. We used pattern recognition and machine learning to detect and quantify these changes in a model-agnostic fashion.Materials and Methods: CT scans of abdominal L4 sections were obtained from Baltimore Longitudinal Study of Aging (BLSA) participants. Age-related change in the constituent tissues were determined by training machine classifiers to differentiate age groups within male and female strata ("Younger" at 50-70 years old vs "Older" at 80-99 years old). The accuracy achieved by the classifiers in differentiating the age cohorts was used as a surrogate measure of the aging signal in the different tissues.Results: The highest accuracy for discriminating age differences was 0.76 and 0.72 for males and females, respectively. The classification accuracy was 0.79 and 0.71 for adipose tissue, 0.70 and 0.68 for soft tissue, and 0.65 and 0.64 for bone.Conclusions: Using image data from a large sample of well-characterized pool of participants dispersed over a wide age range, we explored age-related differences in gross morphology and texture of abdominal tissues. This technology is advantageous for tracking effects of biological aging and predicting adverse outcomes when compared to the traditional use of specific molecular biomarkers. Application of pattern recognition and machine learning as a tool for analyzing medical images may provide much needed insight into tissue changes occurring with aging and, further, connect these changes with their metabolic and functional consequences. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to describe associations of the presence of lipid-rich necrotic core (LRNC) in the proximal superficial femoral artery (SFA) with lower extremity peripheral artery disease (PAD) event rates and systemic cardiovascular event rates. Background LRNC in the coronary and carotid arteries is associated with adverse outcomes but has not been studied previously in lower extremity arteries. Methods Participants with ankle-brachial index (ABI) values <1.00 were identified from Chicago medical centers and followed annually. Magnetic resonance imaging was used to characterize SFA atherosclerotic plaque at baseline. Medical records for hospitalizations and procedures after baseline were adjudicated for lower extremity revascularization, amputation, and critical limb ischemia and also for new coronary events, ischemic stroke, and mortality. Results Of 254 participants with PAD, 62 (24%) had LRNC and 149 (59%) had calcium in the SFA at baseline. Cox regression analyses were adjusted for age, sex, race, comorbidities, baseline ABI, and other confounders. SFA LRNC was associated with an increased incidence of the combined outcome of lower extremity amputation, critical limb ischemia, ABI decline >0.15, and revascularization at 47-month follow-up (hazard ratio: 2.18; 95% confidence interval: 1.27 to 3.75; p = 0.005). The association of SFA LRNC with PAD events was maintained even when this combined outcome excluded lower extremity revascularization (hazard ratio: 2.58; 95% confidence interval: 1.25 to 5.33; p = 0.01). LRNC in the SFA was not associated with all-cause mortality, acute coronary events, or stroke. Conclusions Among patients with PAD, LRNC in the SFA was associated with higher rates of clinical PAD events, and this association was independent of ABI. Further study is needed to determine whether interventions that reduce SFA LRNC prevent PAD events. [ABSTRACT FROM AUTHOR]

Background: For older groups, being overweight [body mass index (BMI; in kg/m²): 25 to, 30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to, 25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life. Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD). Design: This study followed 130,473 UK Biobank participants aged 60-69 y (baseline 2006-2010) for ≤8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were, 0.91 and ≥0.96 for men and, 0.79 and ≥0.85 for women, respectively. Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality. Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life. [ABSTRACT FROM AUTHOR]

Background: Choline is an essential nutrient for cell structure, cell signaling, neurotransmission, lipid transport, and bone formation. Choline can be irreversibly converted to betaine, a major source of methyl groups. Trimethylene N-oxide (TMAO), a proatherogenic molecule, is produced from the metabolism of dietary choline by the gut microbiome. The relation between serum choline and its closely related metabolites with linear growth in children is unknown. Objective: The aim was to characterize the relation between serum choline and its closely related metabolites, betaine and TMAO, with linear growth and stunting in young children. Design: We measured serum choline, betaine, and TMAO concentrations by using liquid chromatography isotopic dilution tandem mass spectrometry in a cross-sectional study in 325 Malawian children, aged 12-59 mo, of whom 62% were stunted. Results: Median (25th, 75th percentile) serum choline, betaine, and TMAO concentrations were 6.4 (4.8, 8.3), 12.4 (9.1, 16.3), and 1.2 (0.7, 1.8) µmol/L, respectively. Spearman correlation coefficients of age with serum choline, betaine, and TMAO were 20.57 (P, 0.0001), 20.26 (P < 0.0001), and 20.10 (P = 0.07), respectively. Correlation coefficients of height-for-age z score with serum choline, betaine-to-choline ratio, and TMAO-to-choline ratio were 0.31 (P < 0.0001), 20.24 (P < 0.0001), and 20.29 (P < 0.0001), respectively. Serum choline concentrations were strongly and significantly associated with stunting. Children with and without stunting had median (25th, 75th percentile) serum choline concentrations of 5.6 (4.4, 7.4) and 7.3 (5.9, 9.1) mmol/L (P < 0.0001). Conclusions: Linear growth failure in young children is associated with low serum choline and elevated betaine-to-choline and TMAO-to-choline ratios. Further work is needed to understand whether low dietary choline intake explains low circulating choline among stunted children living in low-income countries and whether increasing choline intake may correct choline deficiency and improve growth and development. This trial was registered in the ISRCTN registry (www.isrctn.com) as ISRCTN14597012. [ABSTRACT FROM AUTHOR]

Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression. Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation. Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium. Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 x 1021). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 x 1018) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05). Conclusion: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation. [ABSTRACT FROM AUTHOR]

Background: Resveratrol may play a protective role against the frailty syndrome (FS) because of its antioxidant and anti-inflammatory properties. Objective: We prospectively evaluated the association between habitual dietary resveratrol exposure and the development of FS after 3-, 6-, and 9-y follow-up periods in a community-dwelling older population. Design: We conducted a longitudinal analysis with the use of data from 769 participants aged $65 y from the Invecchiare in Chianti (Aging in Chianti) study. Total dietary resveratrol (TDR) intake was estimated at baseline with the use of a validated food-frequency questionnaire, which was developed to assess participants' usual food intakes over the previous year, and an ad hoc resveratrol database. Total urinary resveratrol (TUR) was analyzed with the use of liquid chromatography-tandem mass spectrometry with a previous solid-phase extraction at baseline. The combination of both measures [total dietary resveratrol plus total urinary resveratrol (TDR +TUR)] was computed with the use of the Howe's method. FS was assessed at baseline and at 3-, 6-, and 9-y of follow-up and was defined as the presence of ≥3 of the following 5 criteria: shrinking, exhaustion, sedentariness, slowness, and weakness. Results: TDR+TUR concentrations were inversely associated with FS risk over 3-y of follow-up (OR for comparison of extreme tertiles: 0.11; 95% CI: 0.03, 0.45; P-trend = 0.002) but not after 6- and 9-y of follow-up in multinomial logistic regression models adjusted for baseline frailty status and potential confounders. These results did not differ when analyses were further adjusted for inflammatory markers. Conclusion: Higher habitual dietary resveratrol exposure was associated with lower risk of older community dwellers developing FS during the first 3 y of follow-up but not after longer follow-up periods. [ABSTRACT FROM AUTHOR]

Summary: Background & aims: Metabolic syndrome (MetS) is associated with incident disability in middle-aged subjects. We evaluated the association of MetS with functional ability in an older population. Methods: We enrolled 1155 participants aged 65+, derived from the InCHIANTI study, and followed for 3 years. MetS was diagnosed according to the National Cholesterol Education Program's ATP-III criteria. Functional ability was estimated using the Katz's activities of daily living (ADLs), and the Lawton and Brody for the instrumental activities of daily living (IADLs) scales. The association between disability and MetS at baseline and after follow-up was assessed by logistic regression. Results: At baseline, MetS was associated with reduced probability of ADLs disability among participants aged 74+ (OR = .33, 95% CI = .14–.77; p = .010), but not in younger (5.08, 95% CI = .88–29.24; p = .069). Also, MetS was associated with reduced probability of incident ADLs disability (OR = .61, 95% CI .41–.91; p = .016), but neither with prevalent, nor incident IADLs disability. Conclusions: In older persons, MetS is associated with reduced probability of prevalent and incident ADLs disability. Whether older persons with MetS should receive treatment and whether the current diagnostic criteria for MetS apply to older individuals need further investigation. [Copyright &y& Elsevier]

When food is heated to high temperatures, the characteristic ''browning'' generates advanced glycation end products (AGEs). AGEs are associated with an increased risk of cardiovascular disease, diabetes, and other adverse outcomes. Whether dietary AGEs are absorbed and are harmful to human health remains highly controversial. The objective of this study was to compare the effects of a diet high or low in AGEs on endothelial function, circulating AGEs, inflammatory mediators, and circulating receptors for AGEs in healthy adults. A randomized, parallel-arm, controlled dietary intervention was conducted for 6 wk with 24 healthy adults, aged 50-69 y, that compared isocaloric, food-equivalent diets that were prepared at either high or mild temperatures. Peripheral arterial tonometry, serum and urine carboxymethyl-lysine (CML), inflammatory mediators (interleukin-6, C-reactive protein, vascular adhesion molecule-1, and tumor necrosis factor-Α receptors I and II), soluble receptor for AGEs, and endogenous secretory receptor for AGEs were measured at baseline and after 6 wk of dietary intervention. In the low-AGE diet group, the following changed from baseline to 6 wk (mean ± SE): serum CML from 763 ± 24 to 679 ± 29 ng/mL (P = 0.03) and urine CML from 1.37 ± 1.47 to 0.77 ± 2.01 µg/mL creatinine (P = 0.02). There were no significant changes in serum and urinary CML concentrations from baseline to follow-up in the high-AGE diet group. A high-or low-AGE diet had no significant impact on peripheral arterial tonometry or any inflammatory mediators after 6 wk of dietary intervention. In healthy middle-aged to older adults, consumption of a diet high or low in AGEs for 6 wk had no impact on endothelial function and inflammatory mediators, 2 precursors of cardiovascular disease. This trial was registered at clinicaltrials.gov as NCT01402973. [ABSTRACT FROM AUTHOR]

Among modifiable lifestyle factors, diet may affect cognitive health. Cross-sectional and longitudinal associations may exist between dietary exposures [e.g., caffeine (mg/d), alcohol (g/d), and nutrient adequacy] and cognitive performance and change over time. This was a prospective cohort study, the Baltimore Longitudinal Study of Aging (n = 628-1305 persons depending on the cognitive outcome; ~2 visits/person). Outcomes included 10 cognitive scores, spanning various domains of cognition. Caffeine and alcohol intakes and a nutrient adequacy score (NAS) were estimated from 7-d food diaries. Among key findings, caffeine intake was associated with better baseline global cognition among participants with a baseline age (Agebase) of ≥70 y. A higher NAS was associated with better baseline global cognition performance (overall, women, Agebase <70 y), better baseline verbal memory (immediate and delayed recall, Agebase ≥70 y), and slower rate of decline or faster improvement in the attention domain (women). For an Agebase of <70 y, alcohol consumption was associated with slower improvement on letter fluency and global cognition over time. Conversely, for an Agebase of ≥70 y and among women, alcohol intake was related to better baseline attention and working memory. In sum, patterns of diet and cognition associations indicate stratum-specific associations by sex and baseline age. The general observed trend was that of putative beneficial effects of caffeine intake and nutrient adequacy on domains of global cognition, verbal memory, and attention, and mixed effects of alcohol on domains of letter fluency, attention, and working memory. Further longitudinal studies conducted on larger samples of adults are needed to determine whether dietary factors individually or in combination are modifiers of cognitive trajectories among adults. [ABSTRACT FROM AUTHOR]

Abstract: Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD. [Copyright &y& Elsevier]

Rationale and Objectives: Separate quantification of abdominal subcutaneous and visceral fat regions is essential to understand the role of regional adiposity as risk factor in epidemiological studies. Fat quantification is often based on computed tomography (CT) because fat density is distinct from other tissue densities in the abdomen. However, the presence of intestinal food residues with densities similar to fat may reduce fat quantification accuracy. We introduce an abdominal fat quantification method in CT with interest in food residue removal. Materials and Methods: Total fat was identified in the feature space of Hounsfield units and divided into subcutaneous and visceral components using model-based segmentation. Regions of food residues were identified and removed from visceral fat using a machine learning method integrating intensity, texture, and spatial information. Cost-weighting and bagging techniques were investigated to address class imbalance. Results: We validated our automated food residue removal technique against semimanual quantifications. Our feature selection experiments indicated that joint intensity and texture features produce the highest classification accuracy at 95%. We explored generalization capability using k-fold cross-validation and receiver operating characteristic (ROC) analysis with variable k. Losses in accuracy and area under ROC curve between maximum and minimum k were limited to 0.1% and 0.3%. We validated tissue segmentation against reference semimanual delineations. The Dice similarity scores were as high as 93.1 for subcutaneous fat and 85.6 for visceral fat. Conclusions: Computer-aided regional abdominal fat quantification is a reliable computational tool for large-scale epidemiological studies. Our proposed intestinal food residue reduction scheme is an original contribution of this work. Validation experiments indicate very good accuracy and generalization capability. [Copyright &y& Elsevier]

Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy. TUP concentrations were measured at enrolment (1998-2000) using the Folin-Ciocalteau assay after a solid-phase extraction. TDPs were also estimated at baseline throughout a validated food frequency questionnaire and using our database based on USDA and Phenol-Explorer databases. We modeled associations using Kaplan-Meier survival and Cox proportional hazards models, with adjustment for potential confounders. During the 12-y follow-up, 274 participants (34%) died. At enrollment, TUP excretion adjusted for age and sex tended to be greater in participants who survived [163 ± 62 mg gallic acid equivalents (GAE)/d)] than in those who died (143 ± 63 mg GAE/d) (P = 0.07). However, no significant differences were observed for TDPs. In the multivariable Cox model, participants in the highest tertile of TUP at enrolment had a lower mortality rate than those in the lowest tertile [HR = 0.70 (95% Ch 0.49-0.99); P-trend = 0.045], whereas no significant associations were found between TDP and overall mortality. TUP is an independent risk factor for mortality among community-dwelling older adults, suggesting that high dietary intake of polyphenols may be associated with longevity. [ABSTRACT FROM AUTHOR]

Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. Objective: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. Design: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10-8) were tested for association with CAD in 31,400 cases and 92,927 controls. Results: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with they concentrations, including 6 novel loci in or near MMACHC (2.1 x 10-9), SLC17A3 (1.0 10-8), GTPB10 (1.7 x 10-8), CUBN (7.5 x 10-10), HNF1A (1.2 x 10-12), and FUT2 (6.6 x 10-9), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-µmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 x 10-36). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). Conclusions: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD. [ABSTRACT FROM AUTHOR]

Objectives: We studied associations of magnetic resonance imaging (MRI)-measured superficial femoral artery (SFA) occlusions with functional performance, leg symptoms, and collateral vessel number in peripheral artery disease (PAD). We studied associations of collateral vessel number with functional performance in PAD. Background: Associations of MRI-detected SFA occlusion and collateral vessel number with functional performance among individuals with PAD have not been reported. Methods: A total of 457 participants with an ankle brachial index (ABI) <1.00 had MRI measurement of the proximal SFA with 12 consecutive 2.5-μm cross-sectional images. An occluded SFA was defined as an SFA in which at least 1 segment was occluded. A nonoccluded SFA was defined as absence of any occluded slices. Collateral vessels were visualized with magnetic resonance angiography. Lower extremity functional performance was measured with the 6-min walk, 4-m walking velocity at usual and fastest pace, and the Short Physical Performance Battery (SPPB) (0 to 12 scale, 12 = best). Results: Adjusting for age, sex, race, comorbidities, and other confounders, the presence of an SFA occlusion was associated with poorer 6-min walk performance (1,031 vs. 1,169 feet, p = 0.006), slower fast-paced walking velocity (1.15 vs. 1.22 m/s, p = 0.042), and lower SPPB score (9.07 vs. 9.75, p = 0.038) compared with the absence of an SFA occlusion. More numerous collateral vessels were associated with better 6-min walk performance (0 to 3 collaterals—1,064 feet, 4 to 7 collaterals—1,165 feet, ≥8 collaterals—1,246 feet, p trend = 0.007), faster usual-paced walking speed (0 to 3 collaterals—0.84 m/s, 4 to 7 collaterals—0.88 m/s, ≥8 collaterals—0.91 m/s, p trend = 0.029), and faster rapid-paced walking speed (0 to 3 collaterals—1.17 m/s, 4 to 7 collaterals—1.22 m/s, ≥8 collaterals—1.29 m/s, p trend = 0.002), adjusting for age, sex, race, comorbidities, ABI, and other confounders. Conclusions: Among PAD participants, MRI-visualized occlusions in the proximal SFA are associated with poorer functional performance, whereas more numerous collaterals are associated with better functional performance. (Magnetic Resonance Imaging to Identify Characteristics of Plaque Build-Up in People With Peripheral Arterial Disease; NCT00520312) [Copyright &y& Elsevier]

Abstract: Objective: To identify a standard physical performance test, which can predict 3-year incident mobility disability independent of demographics. Design: Longitudinal cohort study. Setting: Population-based middle-aged and older adult cohort assessment performed at a local geriatric clinical center. Participants: Community-living middle-aged and older persons (age, 50–85y) without baseline mobility disability (N=622). Interventions: Not applicable. Main Outcome Measures: Mobility disability was ascertained at baseline and at 3-year follow-up using an established self-report method: self-reported inability to walk a quarter mile without resting or inability to walk up a flight of stairs unsupported. Physical performance tests included self-selected usual gait speed, time required to complete 5 times sit-to-stand (5TSTS), and 400-m brisk walking. Demographic variables age, sex, height, and weight were recorded. Results: Overall, 13.5% participants reported 3-year incident mobility disability. Usual gait speed <1.2m/s, requiring >13.6 seconds to complete 5TSTS, and completing 400m at <1.19m/s walking speed were highly predictive of future mobility disability independent of demographics. Conclusions: Inability to complete 5TSTS in <13.7 seconds can be a clinically convenient guideline for monitoring and for further assessment of middle-aged and older persons, in order to prevent or delay future mobility disability. [Copyright &y& Elsevier]