bluuebunny/crossref_metadata_2025_split huggingface dataset:
GREATER DOPAMINERGIC SIGNALING IN PUTAMEN IS RELATED TO BETTER GAIT QUALITY IN ADULTS WITHOUT PARKINSON’S DISEASE
Authors: Gil-Silva Mauricio , Rosano Caterina , Bohnen Nicolaas , Kritchevsky Stephen , Halilaj Eni , Bohlke Kayla , Rosso Andrea 
Published: January 2025

Abstract
Gait quality aspects beyond pace like walking smoothness (harmonic ratio), regularity (entropy rate), and complexity (Lempel-Ziv complexity) may be useful in capturing the motor control strategies important in successful everyday walking. Dopaminergic signaling in the central nervous system plays a crucial role in motor function. Age-related declines in dopamine within the putamen may contribute to concurrent declines in gait quality in older adults without Parkinson’s. We investigated the relationship between putamen DA signaling and gait quality and hypothesized that lower DA signaling was associated with poorer gait quality. In 199 participants (Age: 75.00 (4.63), Sex: 123 F (61.81%) BMI: 28.22 (5.41)), (+)-[11C] (DTBZ) PET imaging estimated the striatal binding site density of the type 2 Vesicular Monoamine Transporter (VMAT2). Accelerometers on the L3 segment of the lumbar spine during walking over 15 meters measured entropy rate, Lempel-Ziv complexity, wavelet entropy, and harmonic ratio of the signal in the medial/lateral, anterior/posterior, and vertical anatomical directions. Multiple linear regression estimated the cross-sectional association between the posterior putamen and each gait measure, adjusted for age, sex, BMI, race, education, and hours walking per week. Lower posterior putamen DA binding site density was associated with both greater vertical wavelet entropy (-0.243 [-0.425, -0.060]) and greater medial/lateral Lempel-Ziv complexity (-0.045 [-0.083, -0.007]). Positive trending associations (p=&lt; 0.10) for posterior putamen DA binding site density were found in medial/lateral entropy rate (0.072 [-0.010, 0.155]) and medial/lateral wavelet entropy (0.256 [-0.059, 0.571]). These results suggest that dynamic complex gait functions are more stable with higher putaminal DTBZ binding.
INTER-RELATIONSHIPS OF CIRCULATING PLASMA METABOLITES, INTERMUSCULAR FAT, AND PROCESSING SPEED: HEALTH ABC STUDY
Authors: Xu Richard , Marron Megan , Yao Shanshan , Kim Seyoung , Shah Ravi , Murthy Venkatesh , Newman Anne , Rosano Caterina 
Published: January 2025

Abstract
Higher intermuscular fat (IMF) is associated with worse processing speed, measured by the digit symbol substitution test (DSST) in older adults. However, the underlying biological mechanisms are not well understood. Since muscles and the brain are both highly metabolically active, we sought to identify metabolites that would explain the IMF-DSST association. We assessed 613 known plasma metabolites in 2388 participants from the Health, Aging and Body Composition Study (average age ± standard deviation: 74.7 ± 2.9 years, 50% men, 63% white), using liquid chromatography-mass spectrometry. Using linear regression, we first identified metabolites associated with both IMF and DSST, and then used mediation analyses to assess to what extent these metabolites explained the IMF-DSST association. Higher IMF was associated with worse DSST scores (standardized beta (95% CI): -0.08 (-0.12, -0.03), p&lt; 0.001) adjusting for age, sex, and race. Adjusting for covariates and multiple comparisons, 66 metabolites were associated with both IMF and DSST and 24 of these significantly attenuated the IMF-DSST association. Four attenuated the association by ≥10-14%: higher levels of adrenic acid (omega-6 polyunsaturated fatty acid), and lower levels of maslinic acid, 1-methylnicotinamide (myokine derived from vitamin B3), and C20:5 lysophosphatidylcholine (lysophospholipid containing omega-3 fatty acid) were associated with higher IMF and worse DSST. Prior studies suggested adrenic acid may have pro-inflammatory effects, while the other three metabolites have neuroprotective, anti-inflammatory, and antioxidant effects. This study provides hypothesis-generating evidence that metabolites related to myokines, fatty acids, and phospholipids may partially explain the negative association of intermuscular fat with processing speed.
MARKERS OF INFLAMMATION ARE MODIFIED BY SEX, FRAILTY AND EXERCISE IN A HEAD-DOWN TILT BEDREST STUDY
Authors: Howlett Susan , Hodgins Maddison L , Godin Judith , Rockwood Kenneth , Grandy Scott 
Published: January 2025

Abstract
Prolonged bedrest can induce physiological stress thereby exacerbating frailty and inflammation. We explored whether Head-Down Tilt (HDT) bedrest with or without exercise would alter inflammatory markers implicated in frailty. Twenty 55-65-year-old males (baseline frailty index (FI)=0.02±0.02) and females (FI=0.03±0.03) were subjected to HDT bedrest (2-weeks). Half were randomly assigned to a high-intensity interval/aerobic/strength training exercise intervention for 60 minutes/day (Control: n=4 males, 5 females; Exercise n=5 males, 6 females). FI and serum inflammatory cytokines were measured (multiplex assay) during bedrest (days 0,1,3,7,14), and recovery (days 0,4,32). Data were analyzed with linear mixed models. Proinflammatory marker levels (interleukin (IL)-6, IL-8) increased during bedrest in all groups but were higher in males than females (IL-6: ß=8.87, IL-8: ß=12.93; p&lt; 0.01). IL-8 declined during recovery in all groups, although IL-8 and IL-6 remained higher in males (IL-6: ß=9.32, IL-8: ß=2.85, p&lt; 0.01). The anti-inflammatory cytokine IL-10 was higher in males than females during bedrest, declined in recovery and remained highest in males. During bedrest proinflammatory cytokines (IL-1ß, IL-12) increased as frailty increased in all participants (IL- ß: ß=0.01, IL-12: ß=0.02, p&lt; 0.05) whereas monocyte chemoattractant protein-1 levels declined (ß =-20.54, p&lt; 0.05). The anti-inflammatory protein IL-1ra increased with frailty throughout bedrest in all, especially those who exercised (ß=3.15, p&lt; 0.01). In older adults, inflammatory markers increased during bedrest, declined during recovery and were higher in males than females. Some inflammatory markers increased in parallel with frailty during bedrest. Exercise also increased IL-1ra levels, which may help reduce inflammation in older adults during prolonged bedrest.
MECHANISMS OF GUT MICROBIOTA IN FRAILTY: FINDINGS FROM MENDELIAN RANDOMIZATION AND MOUSE MODEL STUDIES
Authors: Xu Ting , Song Shulin , Zhao Dan , Zheng Yaguang , Qi Xiang , Ji Minghui , Xu Qin , Wu Bei 
Published: January 2025

Abstract
Frailty is a prevalent syndrome among older adults, and recent evidence suggests a connection between gut microbiota and frailty. However, the underlying mechanisms remain unclear. This study aimed to investigate the relationship between gut microbiota and frailty, with a focus on how serum metabolites and inflammatory markers might mediate the association. We used a combination of Mendelian randomization and animal models in our approach. Mice frailty was induced via chronic inflammation and assessed by the frailty index based on mice model. We used high-throughput 16S rDNA sequencing to identify alterations in gut microbiota. Differences between groups were examined through Wilcoxon rank-sum tests. We then used spearman correlation analysis to examine the association between gut microbiota changes and frailty-related indicators and metabolites. MR methods, including inverse variance weighted, MR-Egger, and weighted median approaches were used to estimate causal effects. Our animal experiments revealed gut microbiota dysbiosis in frail mice, notably a reduction in Ruminococcus. We found a positive correlation between Ruminococcus abundance and frailty scores (⍴ = 0.716, p &lt; 0.001) and inflammatory markers. Through metabolomic profiling, we identified several key metabolites potentially involved in frailty, including S-Methyl-5’-thioadenosine, L-anserine, and indoleacetic acid. Further analysis using MR methods confirmed a causal relationship between Ruminococcus obeum abundance and frailty index (p = 0.004, OR = 1.035, 95% CI: [1.011, 1.059]), underscoring the role of inflammatory proteins and metabolites as incomplete mediation. This study provides insights into how gut microbiota contribute to frailty and highlights potential biomarkers and therapeutic targets to support healthy aging.
MEETING THE CHALLENGE: NEURAL RESPONSE ASSOCIATED WITH MINIMAL DUAL-TASK COST IN AGING
Authors: Schneider Claudia , Molholm Sophie , Foxe John , Wagner Johanna , De Sanctis Pierfilippo 
Published: January 2025

Abstract
Walking while engaged in a cognitively challenging task is a common daily activity that becomes harder as we grow older. The cost associated with performing two tasks simultaneously, called dual-task cost (DTC), can predict fall risk and cognitive decline. However, findings are mixed and predictive validity is modest. This study aims to define a neural marker of DTC that, when combined with a behavioral measure, could provide a more robust predictor. To this end, we acquired event-related potentials (ERP) in 36 healthy individuals aged 65 years and older who performed a cognitive Go/NoGo response inhibition task while sitting (i.e., single task) or walking (i.e., dual-task). To determine a neural marker of DTC, we considered differences in DTC between participants. Guided by findings in young adults showing a link between low behavioral DTC and reduction in NoGo-ERP amplitude during walking, we tested this prediction in individuals aged 65 years and older. Participants experienced dual-task cost when performing the Go/NoGo task while walking. They also exhibited a reduced ERP amplitude performing the Go/NoGo task during walking compared to sitting. When participants were split into two equal groups defined by their Go/NoGo performance, however, only the group with minimal DTC revealed a NoGo-ERP modulation during walking. Our data suggest that low DTC is linked to walking-related change in neurocognitive processing (i.e., NoGo-ERP amplitude reduction). The NoGo-ERP may serve as neural DTC marker to help improve early prediction of fall risk and cognitive decline in aging.
MF-300 (15-PGDH ENZYME INHIBITOR) REVERSES AGE-RELATED MUSCLE WEAKNESS IN MICE BY RESTORING MUSCLE QUALITY
Authors: Webster Micah , Martin Jennifer , Fahr Bruce , Khairallah Ramzi 
Published: January 2025

Abstract
Sarcopenia is an age-related disease that causes muscle weakness and reduced muscle quality with disproportionate impact on fast-twitch muscle. Gene expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that metabolizes prostaglandins including PGE2, is elevated in older adult muscle and may contribute to sarcopenia. The study tested whether MF-300, a 15-PGDH inhibitor, could improve muscle quality (force per unit of mass, defined as specific force) in an ageing mouse model. C57BL/6J mice, aged 90-92 weeks, were stratified on body weight and muscle force into groups that were administered oral MF-300 (10, 30 or 60mg/kg every other day) or vehicle (control). A group of 39-54 week-old mice administered vehicle served as a younger adult comparator. Nerve evoked force production of the plantar flexors was measured and normalized to muscle mass to assess muscle specific force. Aged-vehicle mice had lower absolute and specific force relative to the adult-vehicle group. After 12 weeks of treatment, MF-300 10mg/kg significantly increased maximal muscle force (p&lt; 0.0001) and specific force (p=0.02) in aged animals compared to vehicle. MF-300 10 mg/kg showed a significant increase in absolute (p=0.0003) and specific muscle force (p=0.02), as well as contraction rate (p=0.0068), of the extensor digitorum longus (a fast-twitch muscle) compared to the aged-vehicle group. This experiment demonstrates that MF-300 enhances the intrinsic properties of aged fast twitch muscle fibers independently of muscle mass. These findings suggest that MF-300 holds potential as therapeutic strategy for restoring muscle quality and strength in sarcopenia.
MICRORNA BIOMARKERS AND POTENTIAL MECHANISMS ASSOCIATED WITH VO2PEAK VARIATION IN OLDER ADULTS
Authors: Karere Genesio , Hsu Fang-Chi , Cawthon Peggy , Zhang Xiping , Esser Karyn , Cox Laura , Kritchevsky Stephen 
Published: January 2025

Abstract
Peak oxygen consumption during exercise (VO2peak) is an indicator of cardiorespiratory and overall fitness. However, some older adults are intolerant to exercise, impeding VO2peak measurement and necessitating development of alternative methods to screen patients for VO2peak and define pathways that accompany VO2peak variation. We used RNA sequencing to identify expressed microRNAs (miRNAs) and mRNAs in serum and skeletal muscle from 72 participants (70-91 years old; females=53%) in the Study of Muscle, Mobility and Aging, with low (11-14.7 ml/kg/min) or high (28.3-39.4) VO2peak (N=18/group) as well as 36 random samples spanning the entire spectrum of VO2peak. We analyzed samples discordant for VO2peak using the Linear Models for Microarray/RNAseq Data analysis package and identified five serum miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) that discriminate individuals with low or high VO2peak (adjusted p&lt; 0.05). In muscle, 14 miRNAs also displayed differential expression in low and high VO2peak samples. We identified sex differences in expression of 8 miRNAs in muscle (adjusted p&lt; 0.05). Ten differentially expressed (DE) miRNAs, predicted to regulate 50 DE miRNAs, showed an inverse expression pattern in muscle, consistent with direct participation in gene regulation and VO2peak variation. We used Weighted Gene Co-expression Network Analysis and Ingenuity Pathway Analysis tools and identified ME Cyan as the top-most gene module correlated with VO2peak (r=0.7, p=4e-12). Pathways enriched with the module genes included nitric oxide synthesis and signaling. In conclusion, we identified a panel of potential circulating and tissue miRNA biomarkers of VO2peak in older adults and potential pathways that associate with VO2peak variation.
MODULATING CELLULAR SENESCENCE AND MTOR PATHWAY: THE THERAPEUTIC POTENTIAL OF FINGOLIMOD IN NPC DISEASE
Authors: Abyadeh Morteza , Kaya Alaattin 
Published: January 2025

Abstract
Niemann-Pick type C (NPC) disease is a genetically-driven neurodegenerative disorder with no effective treatment. Neurodegeneration, particularly in the cerebellum, is a key pathological feature. Fingolimod phosphate (FTY720), initially approved for multiple sclerosis, functions mainly as an immunomodulator but shows potential in treating neurodegenerative conditions. This study investigates FTY720’s therapeutic potential in mitigating cellular senescence and neurodegeneration in NPC using both in vitro and in vivo models. Our findings reveal that FTY720 pretreatment reduces cellular senescence in fibroblasts, delays muscle mass decline, and improves motor neuron function in NPC mouse models, as evidenced by performance in balance beam and vertical screen tests. Omics analyses indicate that FTY720 exerts anti-inflammatory and anti-aging effects by modulating mTOR signaling and complement coagulation pathways. Importantly, FTY720’s effects were sex-specific, with greater efficacy observed in male mice. Immunohistopathological studies further confirmed FTY720’s protective effects, showing more pronounced benefits in males. In conclusion, FTY720 demonstrates significant promise as a treatment for NPC, particularly in males, by delaying disease symptoms through its protective effects against cellular senescence and inflammation.
MOUSE SKELETAL MUSCLE OVEREXPRESSION OF TFEB: AN EXERCISE MIMETIC PROMOTING BRAIN HEALTH INDEPENDENT OF AHN
Authors: Hakian Mia , Matthews Ian , Cai Catherine , Cortes Constanza 
Published: January 2025

Abstract
Adult hippocampal neurogenesis (AHN), which forms new neurons in the dentate gyrus of the hippocampus, is important for cognition and decreases with age. This reduction in AHN can be reversed with voluntary wheel running in mice, increasing the expression of Transcription Factor E-B (TFEB) within skeletal muscle. TFEB regulates lysosomal and metabolic function through the expression of genes controlling mitochondrial oxidation, fatty acid oxidation, and oxidative phosphorylation. Our lab has recently shown that a transgenic mouse model that overexpresses TFEB only in skeletal muscle mimics many of the neuroprotective benefits of exercise during aging compared to the control, but the effect of TFEB on AHN was unknown. Therefore, we hypothesized that overexpression of TFEB in skeletal muscle has the potential to increase AHN in our exercise mimicking TFEB model. Levels of AHN were measured by using immunofluorescence approaches in hemibrain cryosections to quantify the number of doublecortin (DCX) positive cells, a marker for immature neurons, in the dentate gyrus of the hippocampus of 3-month-old control and muscle-TFEB overexpressing mice. If skeletal muscle-TFEB overexpression is an exercise mimetic, then we expect to see increased levels of AHN in the DG of the hippocampus in TFEB mice compared to the control. We found no significant difference of AHN in TFEB mice compared to the control. These results contradict our hypothesis, but are interesting because we show the maintenance of memory function in our old muscle TFEB mice. This suggests our muscle TFEB mice mimic exercise’s improvement of hippocampal function independent of AHN.
NOVEL PLASMA PROTEIN BIOMARKERS: A TIME-DEPENDENT PREDICTIVE MODEL FOR ALZHEIMER’S DISEASE
Authors: Zhuang Tianchi , Xu Ting , Qiu Xichenhui , Yang Yingqi , Qi Xiang , Xu Qin , Ji Minghui 
Published: January 2025

Abstract
The prediction of Alzheimer’s disease (AD) onset is crucial for the efficient disease and the management of its progression. While current diagnostic methods often rely on neuroimaging and cerebrospinal fluid (CSF) biomarkers, there is a growing need for less invasive and more accessible predictive tools. The study aimed to construct a risk predictive model for AD onset using novel plasma protein biomarkers. We analyzed data from 440 participants aged 60 and above from the Alzheimer’s Disease Neuroimaging Initiative cohort. Using a combination of Cox regression, LASSO regression, and cross-validation, we identified seven protein signatures (APOE, CGA, CRP, CCL26, CCL20, NRCAM, PYY) predictive of AD risk. Cox model demonstrated robust predictive performance in AD onset, with area under the curve (AUC) values of 0.77, 0.76, and 0.77 at 4, 6, and 8 years, respectively, and stable up to 12 years (AUC≥0.75). The model’s effectiveness was further validated using time-dependent ROC curves and Kaplan-Meier curves, which showed that low-risk individuals had significantly delayed AD onset compared to the high-risk group (P&lt;.001). All identified protein signatures were significantly associated with AD risk (P&lt;.001) and time of onset (P&lt;.01). However, we observed weak correlations between plasma and CSF protein levels, suggesting potential differences in peripheral and central nervous system biomarker profiles. Additionally, three proteins (APOE, CGA, CRP) showed lower expression in APOE ε4 carriers (P&lt;.05). These findings highlight the complex interplay between genetics and protein expression in AD pathogenesis and concludes that plasma protein signatures have potential as valuable predictors of AD risk.
NOVEL SERUM BIOMARKERS FOR SARCOPENIA: INSIGHTS FROM CLINICAL DATA AND STUDIES USING C2C12 MYOBLASTS
Authors: Huang Hsien-Hao 
Published: January 2025

Abstract

Introduction
Sarcopenia, the progressive loss of skeletal muscle mass and function, is a critical public health issue among older adults with underlying functional decline and increased risk of adverse health outcomes. While roles have been established for gut hormones in age-associated anorexia, their direct influence on sarcopenia remains unknown. We evaluated the associations between elevated glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) serum levels and sarcopenia and investigated their direct effects on myogenesis and muscle fusion.

Methods
Total 179 patients with sarcopenia were enrolled in this study. This study utilized clinical biomarkers, Bioelectrical Impedance Analysis (BIA), and comprehensive geriatric assessment. Concurrently, C2C12 myoblasts were treated with varying concentrations of GLP-1 and CCK (0, 1, 10, and 100 ng/mL) to examine their influence on myoblast differentiation and myocyte fusion, as assessed by myosin heavy chain (MYH1/2) expression using western blot, and fusion index using immunostaining. Results Patients with sarcopenia exhibit significantly elevated levels of GLP-1 and CCK. GLP-1 impedes the differentiation of myoblasts into mature myocytes in vitro, thereby potentially restricting myogenesis, and GLP-1 treatment negatively impacts myocyte fusion with myotubes. In contrast, CCK inhibits myocyte fusion, a crucial step in muscle formation, without altering the initial differentiation of myoblasts. These findings underscore the critical role of these hormones in muscle development and provide novel insights into their contribution to sarcopenia.

Conclusion
This study supports the use of GLP-1 and CCK as key biomarkers for sarcopenia, suggesting that their impact extends beyond metabolism and directly affects muscle integrity.
PARTICIPATION IN VALUED ACTIVITIES, RESTRICTION, AND SOCIAL ISOLATION IN DEMENTIA CAREGIVING
Authors: Won Sarah , Cotter Valerie , Budhathoki Chakra , Regier Natalie 
Published: January 2025

Abstract
This study investigated the associations between five indicators of social determinants of health (SDOH) and participation in valued activities, participation restriction, and social isolation among family and other unpaid caregivers of older adults with dementia. Data from the 2022 National Health and Aging Trends Study and National Study of Caregiving IV (Round 12) were analyzed. The sample comprised 757 caregivers of community-dwelling care recipients aged 65 and older with possible/probable dementia. SDOH indicators included household income, education level, health insurance coverage, and neighborhood characteristics (neighborhood physical disorder and social cohesion of care recipients). Multivariable logistic regression models examined associations between SDOH indicators and caregiver outcomes, adjusting for demographics (race/ethnicity, age, gender, and marital status), health conditions, and caregiving characteristics (relationship with the care recipient, duration of caregiving year, hours helped last month, and informal/formal social support). Higher household annual income was significantly associated with increased odds of participation in valued activities (OR=3.46 for $30,000-$70,000, OR=3.40 for $70,000+, p&lt; 0.01) and decreased odds of social isolation (OR=0.19 for $30,000-$70,000, OR=0.26 for $70,000+, p&lt; 0.05) compared to income &lt;$30,000. Higher education level (associate’s degree or above) was associated with significantly higher odds of participation in valued activities (OR=6.17, p&lt; 0.001) compared to high school or less. No significant associations were found between SDOH indicators and participation restriction. Household income and education level were crucial SDOH factors associated with participation and social isolation. These findings highlight the importance of considering SDOH factors in developing interventions and policies to support dementia caregiving.