Serum Proteomic Signatures of Common Health Outcomes among Older Adults.

INTRODUCTION: In aging populations, the coexistence of multiple health comorbidities represents a significant challenge for clinicians and researchers. Leveraging advances in omics techniques to characterize these health conditions may provide insight into disease pathogenesis as well as reveal biomarkers for monitoring, prognostication, and diagnosis. Researchers have previously established the utility of big data approaches with respect to comprehensive health outcome measurements in younger populations, identifying protein markers that may provide significant health information with a single blood sample. METHODS: Here, we employed a similar approach in two cohorts of older adults, the Baltimore Longitudinal Study of Aging (mean age = 76.12 years) and InCHIANTI Study (mean age = 66.05 years), examining the relationship between levels of serum proteins and 5 key health outcomes: kidney function, fasting glucose, physical activity, lean body mass, and percent body fat. RESULTS: Correlations between proteins and health outcomes were primarily shared across both older adult cohorts. We further identified that most proteins associated with health outcomes in the older adult cohorts were not associated with the same outcomes in a prior study of a younger population. A subset of proteins, adiponectin, MIC-1, and NCAM-120, were associated with at least three health outcomes in both older adult cohorts but not in the previously published younger cohort, suggesting that they may represent plausible markers of general health in older adult populations. CONCLUSION: Taken together, these findings suggest that comprehensive protein health markers have utility in aging populations and are distinct from those identified in younger adults, indicating unique mechanisms of disease with aging.

Evidence of association between obesity and lower cerebral myelin content in cognitively unimpaired adults.

BACKGROUND: Myelin loss is a central feature of several neurodegenerative diseases, including Alzheimer's disease (AD). In animal studies, a link has been established between obesity and impairment of oligodendrocyte maturation, the cells that produce and maintain myelin. Although clinical magnetic resonance imaging (MRI) studies have revealed microstructural alterations of cerebral white matter tissue in subjects with obesity, no specific myelin vs. obesity correlation studies have been performed in humans using a direct myelin content metric. OBJECTIVES: To assess the association between obesity and myelin integrity in cerebral white matter using advanced MRI methodology for myelin content imaging. METHODS: Studies were performed in the clinical unit of the National Institute on Aging on a cohort of 119 cognitively unimpaired adults. Using advanced MRI methodology, we measured whole-brain myelin water fraction (MWF), a marker of myelin content. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between MWF and obesity, measured using the body mass index (BMI) or waist circumference (WC), in various white matter brain regions. RESULTS: MWF was negatively associated with BMI or WC in all brain regions evaluated. These associations, adjusted for sex, ethnicity, and age, were statistically significant in most brain regions examined (p < 0.05), with higher BMI or WC corresponding to lower myelin content. Finally, in agreement with previous work, MWF exhibited a quadratic, inverted U-shaped, association with age; this is attributed to the process of myelination from youth through middle age, followed by demyelination afterward. CONCLUSIONS: These findings suggest that obesity was significantly associated with white matter integrity, and in particular myelin content. We expect that this work will lay the foundation for further investigations to clarify the nature of myelin damage in neurodegeneration, including AD, and the effect of lifestyle factors such as diet and physical activity on myelination.

Blood Metabolite Signature of Metabolic Syndrome Implicates Alterations in Amino Acid Metabolism: Findings from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS).

Rapid lifestyle and dietary changes have contributed to a rise in the global prevalence of metabolic syndrome (MetS), which presents a potential healthcare crisis, owing to its association with an increased burden of multiple cardiovascular and neurological diseases. Prior work has identified the role that genetic, lifestyle, and environmental factors can play in the prevalence of MetS. Metabolomics is an important tool to study alterations in biochemical pathways intrinsic to the pathophysiology of MetS. We undertook a metabolomic study of MetS in serum samples from two ethnically distinct, well-characterized cohorts-the Baltimore Longitudinal Study of Aging (BLSA) from the U.S. and the Tsuruoka Metabolomics Cohort Study (TMCS) from Japan. We used multivariate logistic regression to identify metabolites that were associated with MetS in both cohorts. Among the top 25 most significant (lowest p-value) metabolite associations with MetS in each cohort, we identified 18 metabolites that were shared between TMCS and BLSA, the majority of which were classified as amino acids. These associations implicate multiple biochemical pathways in MetS, including branched-chain amino acid metabolism, glutathione production, aromatic amino acid metabolism, gluconeogenesis, and the tricarboxylic acid cycle. Our results suggest that fundamental alterations in amino acid metabolism may be central features of MetS.

Vitamin D deficiency and airflow limitation in the Baltimore Longitudinal Study of Ageing.

BACKGROUND: Vitamin D deficiency is common in patients with chronic obstructive pulmonary disease (COPD) and has also been linked to comorbidities often present in COPD. AIM: The aim of this study was to investigate whether vitamin D deficiency was related specifically to airflow limitation or whether vitamin D deficiency was determined by conditions that frequently coexist with COPD: insulin resistance, hypertension, anaemia, obesity and hypercholesterolaemia. METHODS: For this cross-sectional analysis, we included 897 subjects from the Baltimore Longitudinal Study of Aging. Subjects taking vitamin D supplements were excluded. Airflow limitation was defined as FEV1 /FVC < lower limit of normal. Logistic regression was used to assess the association between vitamin D deficiency (25-hydroxy vitamin D < 20 ng/mL) and possible determinants. RESULTS: Vitamin D deficiency was not specific for subjects with airflow limitation. Body mass index (BMI) (OR: 1.05, P < 0.03) and obesity (BMI > 30 kg/m(2)) (OR: 1.9, P < 0.002) were significantly associated with vitamin D deficiency in the adjusted multivariate regression analysis. Physical activity was associated with a decreased risk of vitamin D deficiency. CONCLUSIONS: Airflow limitation was not an independent determinant of vitamin D deficiency. The effect of weight loss and increased physical activity on vitamin D levels should be investigated further in intervention studies.

Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging.

To define metrics of phenotypic aging, it is essential to identify biological and environmental factors that influence the pace of aging. Previous attempts to develop aging metrics were hampered by cross-sectional designs and/or focused on younger populations. In the Baltimore Longitudinal Study of Aging (BLSA), we collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration/neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging and demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity and shorter survival. These associations are more robust compared with the use of phenotypic and epigenetic measurements at a single time point. Estimation of these metrics required repeated measures of multiple phenotypes over time but may uniquely facilitate the identification of mechanisms driving phenotypic aging and subsequent age-related functional decline.

Midlife anticholinergic drug use, risk of Alzheimer's disease, and brain atrophy in community-dwelling older adults.

INTRODUCTION: We examined how long-term anticholinergic (AC) drug use beginning at midlife affects risk of Alzheimer's disease (AD) and rates of brain atrophy in cognitively normal older adults. METHODS: We followed 723 individuals (mean baseline age 52.3 years; mean follow-up interval 20.1 years) in the Baltimore Longitudinal Study of Aging. The AC drug exposure was defined using the Anticholinergic Cognitive Burden Scale: Nonusers (n = 404), as well as participants exposed to medications with AC activity but without known clinically relevant negative cognitive effects (i.e., "possible AC users"; n = 185) and those exposed to AC drugs with established and clinically relevant negative cognitive effects (i.e., "definite AC users"; n = 134). The neuroimaging sample included 93 participants who remained cognitively normal through follow-up and underwent serial magnetic resonance imaging (n = 93, 724 brain scans, mean follow-up interval 8.2 years, and baseline age 68.6 years). RESULTS: Possible AC users, but not definite AC users, showed increased risk of incident AD compared with nonusers (hazard ratio, 1.63; 95% confidence interval, 1.02-2.61; P = .04) and greater rates of atrophy in total cortical gray matter volume compared with nonusers (ß = -0.74, P = .018). Faster rates of brain atrophy were also observed among possible AC users in the right posterior cingulate, as well as right middle frontal and left superior temporal gyri. Data on frequency and duration of medication use were available in only approximately half of the sample. Among these participants, definite AC users had both shorter duration and lower frequency of medication use relative to possible AC users. DISCUSSION: Long-term exposure to medications with mild AC activity during midlife is associated with increased risk of AD and accelerated brain atrophy.

Telomere Shortening, Inflammatory Cytokines, and Anti-Cytomegalovirus Antibody Follow Distinct Age-Associated Trajectories in Humans.

A number of biological parameters have been cited as hallmarks of immune aging. However, it is not clear whether these multiple biological changes are the result of common underlying aging processes and follow correlated trajectories, or whether the patterns of change for multiple parameters vary across individuals and reflect heterogeneity in the aging process. Here, we have studied parameters of immune system aging through longitudinal analysis of telomere length, inflammatory cytokines, and antibody titer to cytomegalovirus (CMV) in 465 subjects ranging in age from 21 to 88 years at the first visit, with an average of 13 years (7-19 years) follow-up. We observed a highly variable rate of change in telomere length of PBMCs with a relatively slow average rate of telomere shortening (-16 bp/year). Similarly, there were significant increases with age in vivo in three inflammation-related cytokines (interferon gamma, IL-6, and IL-10) and in anti-CMV IgG titer, which varied widely across individuals as well. We further observed positive correlative changes among different inflammatory cytokines. However, we did not find significant correlations among the rate of changes in telomere length, inflammatory cytokines, and anti-CMV IgG titers. Our findings thus reveal that age-related trajectories of telomere attrition, elevated circulating inflammatory cytokines, and anti-CMV IgG are independent and that aging individuals do not show a uniform pattern of change in these variables. Immune aging processes are complex and vary across individuals, and the use of multiple biomarkers is essential to evaluation of biological aging of the immune system.

Longitudinal trajectories of arterial stiffness and the role of blood pressure: the Baltimore Longitudinal Study of Aging.

Carotid-femoral pulse wave velocity (PWV), a marker of arterial stiffness, is an established independent cardiovascular risk factor. Little information is available on the pattern and determinants of the longitudinal change in PWV with aging. Such information is crucial to elucidating mechanisms underlying arterial stiffness and the design of interventions to retard it. Between 1988 and 2013, we collected 2 to 9 serial measures of PWV in 354 men and 423 women of the Baltimore Longitudinal Study of Aging, who were 21 to 94 years of age and free of clinically significant cardiovascular disease. Rates of PWV increase accelerated with advancing age in men more than women, leading to sex differences in PWV after the age of 50 years. In both sexes, not only systolic blood pressure (SBP) ≥140 mm Hg but also SBP of 120 to 139 mm Hg was associated with steeper rates of PWV increase compared with SBP<120 mm Hg. Furthermore, there was a dose-dependent effect of SBP in men with marked acceleration in PWV rate of increase with age at SBP ≥140 mm Hg compared with SBP of 120 to 139 mm Hg. Except for waist circumference in women, no other traditional cardiovascular risk factors predicted longitudinal PWV increase. In conclusion, the steeper longitudinal increase of PWV in men than women led to the sex difference that expanded with advancing age. Age and SBP are the main longitudinal determinants of PWV, and the effect of SBP on PWV trajectories exists even in the prehypertensive range.

Arterial stiffness and vitamin D levels: the Baltimore longitudinal study of aging.

CONTEXT: The importance of vitamin D for bone health has long been acknowledged. Recent evidence suggests that vitamin D can also play a role in reducing the risk of several other diseases, including cardiovascular disease. OBJECTIVE: The aim of this study is to test the hypothesis that 25-hydroxyvitamin D (25-OH D) is an independent cross-sectional correlate of central arterial stiffness in a normative aging study population. DESIGN AND SETTINGS: We conducted a cross-sectional analysis. SUBJECTS: We studied 1228 healthy volunteers (50% males; age, 70±12 yr) of the Baltimore Longitudinal Study of Aging. MAIN OUTCOME MEASURES: We measured carotid-femoral pulse wave velocity (PWV) and 25-OH D levels. RESULTS: We found a significant inverse association between PWV and 25-OH D levels (adjusted r2=0.27; ß=-0.43; P=0.001). After adjusting for age, gender, ethnicity, season of blood draw, estimated glomerular filtration rate, physical activity level, cardiovascular risk factors score (smoking, visceral obesity, hypercholesterolemia, hypertension, and diabetes), calcium/vitamin D supplementation, serum calcium, and PTH levels, the association between PWV and 25-OH D levels was only slightly reduced and remained statistically significant (adjusted r2=0.34; ß=-0.34; P=0.04). CONCLUSIONS: Vitamin D levels are inversely associated with increased arterial stiffness in a normative aging population, irrespective of traditional risk factor burden. Further research is needed to understand the mechanism of this association and to test the hypothesis that vitamin D supplementation can reduce arterial stiffness.