Frailty and walking ability as integrated markers of aging and their metabolomic signatures

Frailty and slowed gait become more prevalent with advanced age and predict major health outcomes. These complex phenotypes are influenced by multiple aspects of aging and multimorbidity, and may be manifestations of dysregulation in physiologic systems. Metabolomics, the large-scale study of small molecules that are intermediates or end-products of metabolism, can help us better understand aging-related metabolic changes that contribute to frailty and walking ability by capturing global metabolic profiles occurring most closely to the phenotypes. Here, I aimed to 1) identify metabolites and pathways associated with high versus low walking ability using a nested case-control study of 120 older adults matched on age, gender, race, and fasting time, 2) determine metabolites and pathways associated with frailty to vigor among 287 older black men, and 3) develop and validate a metabolite composite score to determine whether it explains the frailty-associated higher mortality. Regarding aim 1, I found 96 metabolites, mostly lipids/lipid-like molecules, especially triacylglycerols, associated with walking ability. Body composition partly explained associations between select metabolites and walking ability, though many remained independently associated. Triaclyglycerols containing mostly polyunsaturated fatty acids were higher, whereas triaclyglycerols containing mostly saturated or monounsaturated fatty acids were lower among those with high walking ability. Arginine and proline metabolism was a top pathway associated with walking ability. In aims 2 and 3, I found 37 metabolites associated with frailty to vigor and used those metabolites to develop a novel composite score. The metabolite composite score significantly predicted mortality and explained 56% of the higher mortality associated with frailty, where organic acids/derivatives (mostly amino acids) and lipids/lipid-like molecules accounted for almost all of the attenuation. The metabolite composite score also predicted mortality in a validation cohort. Differences in patterns of plasma lipids and amino acids were common classes of metabolites associated with these aging-related phenotypes. Knowledge on differences in these metabolites and metabolic pathways associated with frailty to vigor and walking ability is of public health interest because it provides a better characterization of these complex aging-related phenotypes that can inform points in their pathophysiology to intervene on to promote healthy aging and preserve independence throughout late-life

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Mortality in relation to changes in a Healthy Aging Index : the health, aging, and body composition study

Background Baseline scores on a Healthy Aging Index (HAI), including five key physiologic domains, strongly predict health outcomes. This study aimed to characterize 9-year changes in a HAI and explore their relationship to subsequent mortality. Methods Data are from the Health, Aging, and Body Composition study of well-functioning adults aged 70–79 years. A HAI, which ranges from 0 to 10, was constructed at years 1 and 10 of the study including systolic blood pressure, forced expiratory volume, digit symbol substitution test, cystatin C, and fasting glucose. The relationships between the HAI at years 1 and 10 and the change between years and subsequent mortality until year 17 were estimated from Cox proportional hazards models. Results Two thousand two hundred sixty-four participants had complete data on a HAI at year 1, of these 1,122 had complete data at year 10. HAI scores tended to increase (i.e. get worse) over 9-year follow-up, from (mean [SD]) 4.3 (2.1) to 5.7 (2.1); mean within-person change 1.5 (1.6). After multivariable adjustment, HAI score was related to mortality from year 1 (hazard ratio [95% confidence interval] = 1.17 [1.13–1.21] per unit) and year 10 (1.20 [1.14–1.27] per unit). The change between years was also related to mortality (1.08 [1.02–1.15] per unit change). Conclusions HAI scores tended to increase with advancing age and stratified mortality rates among participants remaining at year 10. The HAI may prove useful to understand changes in health with aging

Associations Between Lipoprotein Subfractions and Area and Density of Abdominal Muscle and Intermuscular Adipose Tissue: The Multi-Ethnic Study of Atherosclerosis.

Skeletal muscle quantity and quality decrease with older age, which is partly attributed to ectopic fat infiltration and has negative metabolic consequences. To inform efforts to preserve skeletal muscle with aging, a better understanding of biologic correlates of quantity and quality of muscle and intermuscular adipose tissue (IMAT) is needed. We used targeted lipidomics of lipoprotein subfractions among 947 Multi-Ethnic Study of Atherosclerosis participants to provide a detailed metabolic characterization of area and density of abdominal muscle and IMAT. Serum lipoprotein subfractions were measured at the first visit using 1H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm2) and density (Hounsfield units) were estimated at visit 2 or 3 using computed tomography of the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, rectus abdominis) muscles. We identified lipoprotein subfractions associated with body composition using linear regression adjusting for demographics, lifestyle, and multiple comparisons. Among 105 lipoprotein subfractions, 24 were associated with total muscle area (absolute standardized regression coefficient range: 0.07-0.10, p-values ≤ 0.002), whereas none were associated with total muscle density. When examining muscle subgroups, 25 lipoprotein subfractions were associated with stabilization muscle area, with associations strongest among the obliques. For total IMAT area, there were 27 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.09-0.13, p-values ≤ 0.002). Specifically, 27 lipoprotein subfractions were associated with stabilization IMAT area, with associations strongest among the oblique and rectus abdominis muscles. For total IMAT density, there were 39 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.10-0.19, p-values ≤ 0.003). Specifically, 28 and 33 lipoprotein subfractions were associated with IMAT density of locomotion and stabilization (statistically driven by obliques) muscles, respectively. Higher VLDL (cholesterol, unesterified cholesterol, phospholipids, triglycerides, and apolipoprotein B) and lower HDL (cholesterol and unesterified cholesterol) were associated with higher muscle area, higher IMAT area, and lower IMAT density. Several associations between lipoprotein subfractions and abdominal muscle area and IMAT area and density were strongest among the stabilization muscles, particularly the obliques, illustrating the importance of examining muscle groups separately. Future work is needed to determine whether the observed associations indicate a lipoprotein profile contributing to worse skeletal muscle with fat infiltration

Oxylipins Associated with D3-Creatine Muscle Mass/Weight and Physical Performance among Community-Dwelling Older Men

Poor physical function is highly prevalent with aging, and strongly associated with D3-creatine muscle mass/weight. Using metabolomics, we previously identified several triglycerides consisting mostly of polyunsaturated fatty acids that were higher in older adults with good mobility. Here, we sought to further investigate polyunsaturated fatty-acid-related metabolites, i.e., oxylipins, and their associations with D3-creatine muscle mass/weight, gait speed, grip strength, and the Short Physical Performance Battery among 463 older men from the Osteoporotic Fractures in Men Study (MrOS). Oxylipins were measured in fasting serum using liquid chromatography–mass spectrometry. Muscle mass was estimated using D3-creatine dilution and adjusted for body size. We used linear regression to determine oxylipins associated with D3-creatine muscle mass/weight and physical performance, while adjusting for age, education, physical activity, Western dietary pattern, fish oil supplementation, and multiple comparisons. Among 42 oxylipins, none were associated with grip strength and 3 were associated with the Short Physical Performance Battery. In contrast, 18 and 17 oxylipins were associated with D3-creatine muscle mass/weight and gait speed, respectively. A subset of associations between oxylipins and gait speed were partially attenuated by D3-creatine muscle mass/weight. Higher levels of fatty acid alcohol and ketone oxylipins tended to be most strongly associated with gait speed and D3-creatine muscle mass/weight, potentially reflecting anti-inflammatory activity from these select oxylipins in MrOS older men