Evidence of association between higher cardiorespiratory fitness and higher cerebral myelination in aging.

Emerging evidence suggests that altered myelination is an important pathophysiologic correlate of several neurodegenerative diseases, including Alzheimer and Parkinson's diseases. Thus, improving myelin integrity may be an effective intervention to prevent and treat age-associated neurodegenerative pathologies. It has been suggested that cardiorespiratory fitness (CRF) may preserve and enhance cerebral myelination throughout the adult lifespan, but this hypothesis has not been fully tested. Among cognitively normal participants from two well-characterized studies spanning a wide age range, we assessed CRF operationalized as the maximum rate of oxygen consumption (VO2max) and myelin content defined by myelin water fraction (MWF) estimated through our advanced multicomponent relaxometry MRI method. We found significant positive correlations between VO2max and MWF across several white matter regions. Interestingly, the effect size of this association was higher in brain regions susceptible to early degeneration, including the frontal lobes and major white matter fiber tracts. Further, the interaction between age and VO2max exhibited i) a steeper positive slope in the older age group, suggesting that the association of VO2max with MWF is stronger at middle and older ages and ii) a steeper negative slope in the lower VO2max group, indicating that lower VO2max levels are associated with lower myelination with increasing age. Finally, the nonlinear pattern of myelin maturation and decline is VO2max-dependent with the higher VO2max group reaching the MWF peak at later ages. This study provides evidence of an interconnection between CRF and cerebral myelination and suggests therapeutic strategies for promoting brain health and attenuating white matter degeneration.

Longitudinal and Cross-Sectional Association Between Gait Speed, Ankle Proprioception, and LE Numbness-Results From the Baltimore Longitudinal Study of Aging.

Mobility declines in older adults can be determined through monitoring longitudinal changes in gait speed. We examined longitudinal changes [in] ankle proprioception among those with and without baseline lower extremity numbness to develop a better understanding of mobility declines in healthy older adults. Participants included 568 adults (52.8% women) aged 60-98 years from the Baltimore Longitudinal Study of Aging. Larger ankle proprioception decreases during plantar flexion were found in the participants with lower extremity numbness compared with those without numbness (p = .034). Among participants with lower extremity numbness, slower baseline speeds from both usual and fast pace gait were associated with performance decline in ankle proprioception measured during ankle dorsiflexion (p = .039 and p = .004, respectively). Assisting older adults, especially those with lower extremity numbness, to maintain and improve ankle proprioception may help prevent mobility declines that have previously been considered age related.

N-terminal truncations of human bHLH transcription factor Twist1 leads to the formation of aggresomes.

In the cell, misfolded proteins are processed by molecular chaperone-mediated refolding or through ubiquitin-mediated proteosome system. Dysregulation of these mechanisms facilitates the aggregation of misfolded proteins and forms aggresomes in the juxta nuclear position of the cell which are removed by lysosome-mediated autophagy pathway in the subsequent cell division. Accumulation of misfolded proteins in the cell is hallmark of several neurological disorders and other diseases including cancer. However, the exact mechanism of aggresome formation and clearance is not thoroughly understood. Reports have shown that several proteins including p300, p53, TAU, α-synuclein, SOD, etc. contain intrinsically disordered region (IDR) which has the tendency to form aggresome. To study the nature of aggresome formation and stability of the aggresome, we have chosen Twist1 as a model protein since it has IDR regions. Twist1 is a bHLH transcription factor which plays a major role in epithelial mesenchymal transition (EMT) and shown to interact with HAT domain of p300 and p53. In the present study, we generated several deletion mutants of human Twist1 with different fluorescent tags and delineated the regions responsible for aggresome formation. The Twist1 protein contains two NLS motifs at the N-terminal region. We showed that the deletions of regions spanning the amino acids 30-46 (Twist1Δ30-46) which lacks the first NLS motif form larger and intense aggregates while the deletion of residues from 47 to 100 (Twist1Δ47-100) which lacks the second NLS motif generates smaller and less intense aggregates in the juxta nuclear position. This suggests that both the NLS motifs are needed for the proper nuclear localization of Twist1. The aggresome formation of the Twist1 deletion mutants was confirmed by counterstaining with known aggresome markers: Vimentin, HDAC6, and gamma tubulin and further validated by MG-132 treatment. In addition, it was found that the aggresomes generated by the Twist1Δ30-46 construct are more stable than the aggresome produced by the Twist1Δ47-100 construct as well as the wild-type Twist1 protein. Taken together, our data provide an important understanding on the role of IDR regions on the formation and stability of aggresomes.

Relationships of GDF8 and 11 and Their Antagonists With Decline of Grip Strength Among Older Adults in the Baltimore Longitudinal Study of Aging.

Although growth/differentiation factor 11 (GDF11), growth/differentiation factor 8 (GDF8), and their circulating antagonists, which include GDF11 and GDF8 propeptides, follistatin (FST), WAP, Follistatin/Kazal, Immunoglobulin, Kunitz And Netrin Domain Containing (WFIKKN)1, and WFIKKN2, have been shown to influence skeletal muscle and aging in mice, the relationship of these circulating factors with human phenotypes is less clear. This study aimed to characterize the relationship between plasma GDF8, GDF11, FST, WFIKKN1, and WFIKKN2 concentrations with the decline of grip strength in 534 adults, ≥65 years, who participated in the Baltimore Longitudinal Study of Aging and had grip strength measured over time. Plasma GDF8 and GDF11 mature proteins, GDF8 and GDF11 propeptides, FST (isoform FST315 and cleaved form FST303), WFIKKN1, and WFIKKN2 concentrations were measured using selected reaction monitoring-tandem mass spectrometry at baseline. Grip strength was measured at baseline and at follow-up visits (median follow-up 8.87 years). Mean (standard deviation) grip strength declined in men and women by -0.84 (2.45) and -0.60 (1.32) kg/year, respectively. Plasma GDF8 and GDF11 mature proteins, GDF8 and GDF11 propeptides, FST315, FST303, WFIKKN1, and WFIKKN2 concentrations were not independently predictive of the decline of grip strength in men or women in multivariable linear regression analyses that adjusted for potential confounders. In conclusion, circulating GDF8, GDF11, and their antagonists do not appear to influence the decline of grip strength in older men or women.

Lower Myelin Content Is Associated With Lower Gait Speed in Cognitively Unimpaired Adults.

Mounting evidence indicates that abnormal gait speed predicts the progression of neurodegenerative diseases, including Alzheimer's disease. Understanding the relationship between white matter integrity, especially myelination, and motor function is crucial to the diagnosis and treatment of neurodegenerative diseases. We recruited 118 cognitively unimpaired adults across an extended age range of 22-94 years to examine associations between rapid or usual gait speeds and cerebral myelin content. Using our advanced multicomponent magnetic resonance relaxometry method, we measured myelin water fraction (MWF), a direct measure of myelin content, as well as longitudinal and transverse relaxation rates (R1 and R2), sensitive but nonspecific magnetic resonance imaging measures of myelin content. After adjusting for covariates and excluding 22 data sets due to cognitive impairments or artifacts, our results indicate that participants with higher rapid gait speed exhibited higher MWF, R1, and R2 values, that is, higher myelin content. These associations were statistically significant within several white matter brain regions, particularly the frontal and parietal lobes, splenium, anterior corona radiata, and superior fronto-occipital and longitudinal fasciculus. In contrast, we did not find any significant associations between usual gait speed and MWF, R1, or R2, which suggests that rapid gait speed may be a more sensitive marker of demyelination than usual gait speed. These findings advance our understanding on the implication of myelination in gait impairment among cognitively unimpaired adults, providing further evidence of the interconnection between white matter integrity and motor function.

Investigation of the association between central arterial stiffness and aggregate g-ratio in cognitively unimpaired adults.

Stiffness of the large arteries has been shown to impact cerebral white matter (WM) microstructure in both younger and older adults. However, no study has yet demonstrated an association between arterial stiffness and aggregate g-ratio, a specific magnetic resonance imaging (MRI) measure of axonal myelination that is highly correlated with neuronal signal conduction speed. In a cohort of 38 well-documented cognitively unimpaired adults spanning a wide age range, we investigated the association between central arterial stiffness, measured using pulse wave velocity (PWV), and aggregate g-ratio, measured using our recent advanced quantitative MRI methodology, in several cerebral WM structures. After adjusting for age, sex, smoking status, and systolic blood pressure, our results indicate that higher PWV values, that is, elevated arterial stiffness, were associated with lower aggregate g-ratio values, that is, lower microstructural integrity of WM. Compared to other brain regions, these associations were stronger and highly significant in the splenium of the corpus callosum and the internal capsules, which have been consistently documented as very sensitive to elevated arterial stiffness. Moreover, our detailed analysis indicates that these associations were mainly driven by differences in myelination, measured using myelin volume fraction, rather than axonal density, measured using axonal volume fraction. Our findings suggest that arterial stiffness is associated with myelin degeneration, and encourages further longitudinal studies in larger study cohorts. Controlling arterial stiffness may represent a therapeutic target in maintaining the health of WM tissue in cerebral normative aging.

Sex Differences in Longitudinal Determinants of Carotid Intima Medial Thickening With Aging in a Community-Dwelling Population: The Baltimore Longitudinal Study on Aging.

Background Common carotid intima medial thickness (IMT) increases with aging. However, the longitudinal association between IMT and other age-associated hemodynamic alterations in men and in women are not fully explored. Methods and Results We analyzed repeated measures of IMT, blood pressure, and carotid-femoral pulse wave velocity over a 20-year period in 1067 men and women of the Baltimore Longitudinal Study on Aging; participants were ages 20 to 92 years at entry and free of overt cardiovascular disease. Linear mixed-effects models were used to calculate the individual rates of change (Change) of IMT, pulse pressure, mean arterial pressure, and pulse wave velocity, among other covariates. Multivariate regression analysis was used to examine the association of IMTChange with baseline and rates of change of hemodynamic parameters and cardiovascular risk factors. IMT increased at accelerating rates from 0.02 mm/decade at age 50 years to 0.05 mm/decade at age 80 years greater rates in men than in women. IMTChange was positively associated with baseline low-density lipoprotein, low-density lipoproteinChange, and baseline systolic blood pressure and systolic blood pressureChange, but inversely with baseline diastolic blood pressure and diastolic blood pressureChange. When blood pressure was expressed as pulse pressure and MAP, IMTChange was positively associated with baseline pulse pressure and pulse pressureChange and inversely with baseline mean arterial pressure and mean arterial pressureChange. In sex-specific analysis, these associations were observed in women, but not in men. Conclusions In summary, our analyses showed that IMT increases at accelerating rates with aging. Age-associated changes in IMT were modulated by concurrent changes of low-density lipoprotein in both sexes, and of pulsatile and mean blood pressure in women but not men.

Identification of a novel leukemic-specific splice variant of DNMT3B and its stability.

DNA methyltransferases make use of alternative splicing mechanism to generate various splice variants, but their role(s) in modulating DNA methylation patterns in the cells is unclear. Notably, DNMT3B alone contains nearly 40 different splice variants. In this study, we have identified a novel splice variant of DNMT3B, which lacks exon 7 and 10 from leukemic cell lines which we termed as DNMT3B9. The exon 7 codes for the major part of PWWP domain, and exon 10 inclusion serves as a pluripotent marker. By quantitative RT-PCR using exon-exon junction-specific primers, we showed higher level of DNMT3B9 transcripts in several leukemic cell lines. However, DNMT3B9 expression was less in other tested cancer cell lines indicating that DNMT3B9 might serve as a leukemic-specific biomarker. Surprisingly, endogenous protein for DNMT3B9 was not detected in leukemic cells suggesting the unidentified RNA-related function(s) for DNMT3B9. In addition, we showed that DNMT3B9 protein lacks PWWP domain is less stable compared to other DNMT3B variants which contain PWWP domain through computational predictions and by cycloheximide half-life experiment. Taken together, we demonstrated the existence of novel leukemic-specific splice variant of DNMT3B and provide the evidence for the role of PWWP domain in the stability of DNMT3B. The findings reported here have relevance in epigenetic therapy, which is aimed to target the DNMT3B in cancer cells.

State- and trait-dependent associations of vitamin-D with brain function during aging.

We investigated whether (1) serum levels of 25-hydroxyvitamin D [25(OH)D] and single nucleotide polymorphisms (SNPs) in the group-specific component (GC) gene-regulating serum 25(OH)D levels are associated with cognition in older individuals; and (2) whether causal relationships exist between 25(OH)D and cognition during aging. Data from 1207 participants in the Baltimore Longitudinal Study of Aging were analyzed (mean follow-up, 10.4 years) to test associations between serum 25(OH)D and cognition. Two GC SNPs were used to derive a composite genetic risk score associated with lower 25(OH)D concentrations. Lower serum 25(OH)D and higher GC composite scores were associated with lower executive function at baseline. Mendelian randomization analyses suggested a causal relationship between lower serum 25(OH)D and poorer executive function and psychomotor speed. The SNP score was also associated with lower performance on measures of visuospatial abilities at baseline but with attenuated declines over time in visuospatial abilities and executive function. Widespread associations between vitamin-D regulatory SNPs and cognition suggest a mechanistic basis for the relationship between serum 25(OH)D levels and cognition during aging.