bluuebunny/crossref_metadata_2025 huggingface dataset:
CONFORMAL PREDICTION OF RESIDUAL COGNITION IN AGING AND ALZHEIMER’S DISEASE
Authors: Essien Ime , McDaniel Laura , Walston Jeremy , Bennett David , Abadir Peter , Chellappa Rama
Published: January 2025

Cognitive reserve (CR) and resilience in aging and Alzheimer’s disease (AD) have gained significant attention in recent research. We explore cognitive resilience by examining how individuals maintain cognitive function despite neuropathological burden, particularly in the context of AD in Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Our approach involves modeling residual cognition, defined as the difference between observed cognitive function and expected function based on neuropathological burden. Conformal prediction is applied to generate prediction intervals for global cognitive scores based on beta-amyloid and tau protein levels and demographic data. This provides a valid measure of uncertainty to derive our residual cognition. This method allows us to identify cases where beta-amyloid and tau protein levels are misaligned with final cognitive diagnoses, providing valuable feature interpretability. The study stratifies participants using the Clinical consensus diagnosis of cognitive status at time of death into control, asymptomatic AD (AsymAD), and AD groups to investigate cognitive maintenance in the presence of AD-associated neuropathological changes. By comparing residuals across different diagnostic groups, we gain insights into factors contributing to cognitive resilience. We use the clinical diagnosis of cognitive status as a validation measure to examine how well our residual cognition measure predicts clinical outcomes. Our research builds upon previous work on CR measurement, including decomposition approaches, the Alzheimer’s Disease Cognitive Resilience Score, and the residual reserve index. The findings will help inform interventions to promote cognitive health in aging populations.
DAILY CONSUMPTION OF KETONE ESTER, BIS-OCTANOYL (R)-1,3-BUTANEDIOL, IS SAFE AND TOLERABLE IN HEALTHY OLDER ADULTS
Authors: Senadheera Chatura , Blonquist Traci , Stubbs Brianna , Diaz Stephanie Roa , Peralta Sawyer , Stephens Elizabeth , Newman John
Published: January 2025

Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this pilot study was to assess tolerability and safety of KE ingestion in older adults. We carried out a randomized, placebo-controlled, double-blinded, parallel-arm trial (NCT05585762) with community-dwelling, independent older adults in stable health. N=30 (M=15, F=15; age=76y, range 65 –90y) were randomized and n=23 completed. Participants were randomly allocated to consume either KE (25g bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched canola oil placebo (PLA) daily for 12 weeks. Tolerability was assessed using a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events. There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n=2 (14.3% [90% CI=2.6–38.5]);PLA n=1 (7.1% [90% CI=0.4–29.7]). Dropouts numbered four in the PLA group and two in the KE group. More symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2–12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group.
DETERMINANTS OF AGE AT NATURAL MENOPAUSE AMONG POSTMENOPAUSAL GHANAIAN WOMEN IN OKAIKWEI NORTH DISTRICT, GHANA
Authors: Kontor Okyere , Nyarko Veneranda , Botwe Paul
Published: January 2025

The age at natural menopause, influenced by genetic and modifiable factors is linked to the risk of certain chronic conditions. While menopause has been studied extensively in other countries, there is limited data on its determinants among women in developing countries like Ghana, creating a theory gap for investigations. This study aims to assess post-menopausal women’s knowledge of menopause, determine the average age at natural menopause, and identify factors influencing this age among postmenopausal Ghanaian women in the Okaikwei North Municipality of Ghana. A cross-sectional study design with a quantitative approach was used. Consecutive sampling selected 296 post-menopausal women attending Achimota Hospital’s (municipal referral hospital) outpatient clinic. Data were collected via a structured questionnaire and analyzed using Stata version 16. Descriptive statistics, bivariate analysis (Chi-square and Fisher’s exact test) and multiple logistic regression (crude and adjusted odds ratios) were used, with statistical significance set at p < 0.05. The study found that 48.3% of participants had adequate knowledge about menopause. Most women experienced the “expected” natural menopause, 46-55 years (93.2%), with early menopause (40-45 years) at 3.7% and late menopause (>55 years) at 3.1%. The average age at natural menopause was 49.5 years (±0.17 SD). Significant factors associated with natural menopausal age included age at menarche, age at first pregnancy and contraceptive use. The study highlighting low knowledge about menopause among the participants therefore recommends an enhanced practical education, cost-effective health care, and women’s empowerment to better prepare women for menopause, particularly those approaching this transition.
DIETARY METHIONINE RESTRICTION STARTED LATE IN LIFE IMPROVES NEUROMUSCULAR FUNCTION AND PROMOTES HEALTHY AGING
Authors: Parkhitko Andrey , Arciga Ulalume Hernandez , Stamenkovic Ceda , Yadav Shweta , Ables Gene , Sacco Alessandra , Jurczak Michael , Rizzo Stacey J Sukoff
Published: January 2025

Methionine metabolism is negatively affected by aging and restricting methionine consumption (MetR) extends lifespan across diverse species. Similarly, levels of enzymes in the tyrosine degradation pathway (TDP) increase with age, the targeting of which extends Drosophila lifespan. However, we have limited information on the effects of either metabolic manipulation when started late in life in mice, and we lack information on the effects of dietary MetR on the aging process in humans. To investigate the efficacy of targeting either methionine metabolism or the TDP for healthspan improvement in advanced age, we initiated long-term dietary MetR or treatment with the TDP inhibitor, nitisinone, in 18-mo male and female C57BL/6J mice. Our data demonstrate multiple healthspan benefits of dietary MetR started late in life with the strongest improvements observed in neuromuscular function, metabolic health, lung function, and frailty. By contrast, we observed no such signal of benefit with nitisinone treatment. Using single-nucleus RNA and ATAC sequencing of muscle tissues, we identified subtype-specific processes and transcription factors activated by dietary MetR. Epigenetic clocks can be used to evaluate longevity interventions across different species including humans. Surprisingly, dietary MetR did not significantly affect the mouse epigenetic clock. An analysis of human samples obtained from a randomized clinical trial (NCT04701346) examining an 8-week dietary MetR intervention also did not reveal a significant MetR-dependent effect on the epigenetic clocks. These findings establish beneficial effects of MetR started late in life and provide translational rationale to develop MetR mimetics as an anti-aging intervention in humans.
DIFFERENTIAL EFFECT OF SIRT1 ON MITOCHONDRIAL FUNCTION: INSIGHTS INTO MITOCHONDRIAL RESPIRATORY COMPLEXES
Authors: Zhang Xiaomin , Shrivastava Jyotsna , Patyal Pankaj , Verma Ambika , Sharma Shakshi , Azhar Gohar , Wei Jeanne Y
Published: January 2025

Sirtuin-1 gene (SIRT1) regulates various cellular functions that influence metabolic homeostasis and aging. SIRT1 dysfunction has been implicated in cardiovascular diseases and mitochondrial dysfunction. However, mechanism of SIRT1 in the regulation of cellular respiration, metabolic homeostasis, and mitochondrial respiratory complexes is not well-known. We tested whether SIRT1 gene knockout (KO) in HEK293T affects mitochondrial respiratory complex function and expression profiles of associated genes compared with wildtype (WT) HEK293T cells. Oxygen consumption rate (OCR, assayed by XFe96 Analyzer and Oxygraph-O2K) was reduced (p < 0.001 and p < 0.05, respectively) in HEK293T SIRT1-KO cells compared to WT. Basal extracellular acidification rate (ECAR) was also reduced in SIRT1-KO cells relative to WT (p < 0.001), with higher levels of ATP in SIRT-1 KO (p < 0.01). SIRT1-KO significantly reduced the expression of glycolytic genes, including Phosphofructokinase P (p < 0.01), Hexokinase 2 (p < 0.05), and Phosphofructokinase Mv4 relative to WT (p < 0.05). Mitochondrial respiratory complexes are vital for ATP production through oxidative phosphorylation. Complex IV is crucial for the final step of electron transport chain. Compared to WT, significantly reduced OCR for complex IV in SIRT1-KO cells indicated mitochondrial dysfunction and impaired energy production (p < 0.05). SIRT1-KO also repressed the expression of mitochondrial respiratory complex I genes (NDUFAB1, NDUFV1, and NDUFV2), essential for efficient cellular respiration. This repression suggests compromised mitochondrial bioenergetics and metabolic homeostasis. Interestingly, SIRT1-KO also downregulated mitofusin-1, a key protein in maintaining mitochondrial morphology and size. Our data highlights that SIRT1 is crucial for regulating mitochondrial respiration, metabolism, and bioenergetics.
E3 UBIQUITIN LIGASE2 SIAH2 MAY REGULATE AGE-ASSOCIATED LIPID TURNOVER IN ADIPOSE TISSUE MACROPHAGES
Authors: Ghosh Bhaswati
Published: January 2025

The global adult population with obesity is rapidly increasing. One of the aging hallmarks is accumulation of pro-inflammatory cells, which disrupts the balance between lipid storage and lipolysis leading to adipose tissue (AT) expansion and obesity-related insulin resistance. The primary inflammatory contributors in AT are adipose tissue macrophages (ATMs). As in obesity, ATM accumulation increases with aging. Notably, the ubiquitin-proteasome system, the non-lysosomal degradative machinery that maintains protein homeostasis, tightly regulates inflammation and declines with age. We hypothesized that aging downregulates proteasomal activity in ATMs resulting in dysfunctional lipid metabolism. We previously showed the E3-ubiquitin ligase Seven-in-Absentia mammalian homolog2 (Siah2) is crucial for promoting adipogenesis in pre-adipocytes and regulates obesity-mediated AT inflammation. Recently we found Siah2 is present in immune cells including macrophages. Here, we generated a macrophage-specific Siah2 knockout (SKM) mouse model to investigate the role of Siah2 in ATM lipid metabolism. We co-cultured primary SKM-bone marrow-derived macrophages (SKM-BMDMs) or wild-type-bone marrow-derived macrophages (WT-BMDMs) in presence of gonadal white adipose tissue from lean mice as a model of bone marrow-derived ATMs. Interestingly, SKM-ATMs accumulate more, and larger lipid droplets than WT-ATMs via increased lipid uptake. Furthermore, Siah2KO in ATMs suppresses lysosomal delivery of lipid droplets, and the SKM-ATM lysosomes are enlarged compared to WT-ATMs. Consistently, SKM-BMDMs are pro-inflammatory and show decreased oxygen consumption rate indicative of a switch to glycolytic metabolism. Altogether, our findings indicate Siah2 functions as a critical lipid sensor in ATMs, raising the possibly that aging downregulates Siah2 activity in ATMs leading to declined lipid turnover.
EARLY DIAGNOSIS OF ALZHEIMER’S DISEASE USING A SIMPLE AND SENSITIVE NANOBIOSENSOR
Authors: Xia Xiaohu
Published: January 2025

Existing diagnostic methods for Alzheimer’s disease (AD), such as PET/MRI imaging and cerebrospinal fluid tests, are invasive and/or costly. Recent studies have demonstrated that exosomes (nanoscale extracellular vesicles carrying specific biomarkers that can traverse blood-brain barrier) are ideal sources of AD biomarkers, which can be conveniently collected from peripheral body fluids like blood and saliva. Detection of AD exosomal biomarkers opens a new avenue for non-invasive diagnosis of AD. However, the concentrations of AD exosomal biomarkers in body fluids are extremely low. Therefore, highly sensitive analytical techniques such as mass spectrometry are required to measure the exosomal biomarkers accurately. Unfortunately, these sensitive techniques come with high costs and can be cumbersome, limiting their widespread use in clinical settings. In this research, we report a simple and low-cost nano-biosensor for ultrasensitive detection of AD exosomal biomarkers. The nano-biosensor relies on metal nanoparticles as labels or signal transducers. After conjugation of the metal nanoparticles with bioreceptors specific to AD exosomal biomarkers, the nanoparticle-bioreceptor conjugates can specifically catalyze the formation of colorimetric signal that can be conveniently quantified by an inexpensive spectrophotometer. The nano-biosensor is expected to be able to detect AD exosomal biomarkers from blood and/or saliva samples, representing a minimally invasive and accessible technology for early diagnosis of AD.
EFFECTS OF SPINELESS ON SURVIVAL AND REPRODUCTION IN DROSOPHILA MELANOGASTER
Authors: Swint Shelton , Hoffman Jessica
Published: January 2025

The aryl hydrocarbon receptor (AhR) is a widely conserved, ligand-activated mammalian transcription factor involved in numerous physiological processes, including maintaining stem cell pluripotency during development and regulating xenobiotic detoxification. One group of commonly studied activators of AhR are tryptophan and its downstream metabolites. Recent studies have shown that AhR-deficient mice display similar survival trends to control animals during early life (≤12 months) and then display a premature aging phenotype. As mice live for two to three years, we can advance our knowledge of AhR and aging using the fruit fly (D. melanogaster) as an alternative. Flies possess an ortholog of the mammalian AhR called spineless (ss), but the effects of ss on survival have yet to be shown. Additionally, many tryptophan-derived metabolites, like tryptamine, have been shown to decrease lifespan in control flies, potentially due to activation of AhR. We found that ss-deficient flies are shorter-lived than wildtype flies, and similar to trajectories in mice, ss flies have normal survival until around 40 days of age. The lifespan-shortening effects of tryptophan metabolites were reduced in ss-deficient flies, suggesting that the negative effects of tryptophan metabolites may be dependent on ss. Furthermore, oxidative stress assays showed that ss flies are more stress resistant, significantly outliving the wildtype flies at an early age. The effects of ss are also being investigated using a potential AhR-antagonist, cis-Jasmone. Overall, our work demonstrates that ss-deficient flies have reduced lifespan and altered responses to tryptophan metabolites, suggesting a conserved role of AhR in the aging process.
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

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=< 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

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< 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

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< 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< 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< 0.05) whereas monocyte chemoattractant protein-1 levels declined (ß =-20.54, p< 0.05). The anti-inflammatory protein IL-1ra increased with frailty throughout bedrest in all, especially those who exercised (ß=3.15, p< 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

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 < 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

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

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< 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

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< 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< 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

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

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

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<.001). All identified protein signatures were significantly associated with AD risk (P<.001) and time of onset (P<.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<.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

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

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< 0.01) and decreased odds of social isolation (OR=0.19 for $30,000-$70,000, OR=0.26 for $70,000+, p< 0.05) compared to income <$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< 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.
PATHWAYS LINKING ICT UTILIZATION TO CHRONIC DISEASES SELF-MANAGEMENT AMONG OLDER ADULTS IN CHINA
Authors: Chen Qingru , Chen Yan-Yan , Gong Ke , Zhang Xuefeng , Zhao Lirong
Published: January 2025

The underlying mechanisms linking information and communication technology (ICT) utilization to self-management are currently unclear. This cross-sectional study aims to examine the mediating role of health literacy, self-efficacy, and social support in the relationship between ICT utilization and chronic disease self-management among older adults in China. A total of 590 older adults (≥60 years) with at least one chronic disease were recruited from a tertiary hospital in Shanghai between July 2023 and June 2024. Questionnaire data were recorded on self-reported socio-demographics, self-management, social support, health literacy, self-efficacy, ICT utilization. Pearson’s correlation analysis identified the relationship between these factors and self-management. Serial multiple mediation model was used to test the hypothesized relationships. The results show ICT utilization, health literacy, self-efficacy, social support, and chronic disease self-management were found significantly correlated (p< 0.001). ICT utilization not only has a direct positive impact (effect=0.2377; 95%CI=0.1826-0.2927) on chronic disease self-management, but also has an indirect impact on chronic disease self-management through the independent mediating role of health literacy (effect=0.0912; 95%CI=0.0608-0.1240) and social support (effect=0.0186; 95%CI=0.0048-0.0367) and the chain mediating role of health literacy and self-efficacy (effect=0.0223; 95%CI=0.0128-0.0342), the chain mediating role of health literacy and social support (effect=0.0104; 95%CI=0.0044-0.0187), the chain mediating role of health literacy, self-efficacy, and social support (effect=0.0020; 95%CI=0.0008-0.0036).These findings suggest that ICT utilization can enhance chronic disease self-management among older adults and indirectly affects it through increasing health literacy, self-efficacy while providing more social support.
PLASMA PROTEOMIC MEDIATORS LINKING INTERMUSCULAR FAT WITH PSYCHOMOTOR SPEED
Authors: Toshiko Tanaka , Huang Xianging , Khan Sadiya , Miljkovic Iva , Terry James Greg , Tian Teresa , Rosano Caterina , Ferrucci Luigi
Published: January 2025

Intermuscular fat (IMF), or muscular fat infiltration, has been inversely associated with measures of cognitive function. However, the mechanisms linking higher IMF and poor cognitive function are not fully understood. To explore this, we characterized plasma proteomic profile of IMF in Baltimore Longitudinal Study on Aging (BLSA, n=942), and validated the findings in the Coronary Artery Risk Development in Young Adults Study (CARDIA; n=2453) study. Plasma proteomics was measured using 7K SOMAscan, IMF was measured on CT scans of the thigh (BLSA) or abdomen (CARDIA), and processing speed was assessed with digit symbol substitution test (DSST). Associations between measures of IMF and proteins were assessed using linear regression adjusting for age, sex, education, self-reported race, and total muscle area. Of the 7268 plasma proteins tested, 718 proteins were significantly associated with IMF in both discovery and validation studies (FDR p<=0.05). Mediation analysis of the IMF -associated proteins, 28 proteins significantly mediated the inverse association between IMF and DSST. Pathway analyses show the biological process and molecular functions most enriched by these proteins were the synaptic structure and function (STLITRK3, CBLN2, NTRK3, EPHA4, C1QL3) pathway, and growth factor binding (HTRA1, IGFBP2, NTRK2, EGFR, IGFBP4, IGAFLS) pathways. These results suggest a unique proteomic signature of IMF that is consistent across two independent cohorts. Further, the association of higher IMF with lower cognitive processing speed may be at least partially mediated through dysregulation of synaptic functions and growth factors binding.
PREDICTIVE MODELING OF HEALTH STATUS OVER LIFESPAN BASED ON SENESCENCE BIOMARKERS
Authors: Tang Lingzi , Hladyshau Siarhei , Ross Allison , Nyrop Kirsten , Entwistle Amy , Muss Hyman , Tsygankov Denis
Published: January 2025

Cellular senescence is known to play a significant role in aging and the development of age-related diseases. However, the complex interplay between the accumulation and clearance of senescent cells and the relationship of these processes to the physiological decline during natural aging is not understood. Here, we report a study that explores the potential of cellular and immune senescence biomarkers (p16, p14, LAG3, CD28, and CD244) in predicting health metrics as determined by standard clinical assessments. Data were collected from a cohort of 250 healthy participants aged 25 to 85 years and included gene expression in T-cells from peripheral blood, comprehensive blood panels, quality of life (QOL) surveys, body composition analysis, and physical performance evaluations. A combination of computational techniques, including correlation analysis, unsupervised hierarchical clustering, and machine learning techniques (such as an ensemble of bagged decision trees), was employed to assess the predictive capabilities of the biomarkers relative to the health assessments and vice versa. Our findings indicate that blood and QOL assessments generate distinct participant clusters, both strongly associated with p16 expression. The highest accuracy in predicting p16 expression was achieved by integrating measurements across various assessments, suggesting a systemic role for this biomarker. Furthermore, our analysis led to a scoring system that produces integrative metrics strongly and specifically correlating with different senescence biomarkers, suggesting a simple, practical method to differentiate between varying levels of cellular and immune senescence in naturally aging individuals.
PREVALENCE AND PREDICTORS OF LONELINESS AMONG CAREGIVERS BY CARE RECIPIENT’S LEVEL OF COGNITIVE IMPAIRMENT
Authors: Couch Elyse , Howe Rebecca , Southerland Jodi L
Published: January 2025

Loneliness is increasingly being recognized as a public health issue. However, little is known about the prevalence or predictors of loneliness among caregivers in the United States (US). This study aimed to assess the prevalence and predictors of loneliness among US caregivers by the care recipient’s level of cognitive impairment. We conducted a cross-sectional study of caregivers for Medicare beneficiaries in the US using data from the National Study of Caregiving (NSOC). Caregivers were divided into three groups by the care recipient’s level of cognitive impairment: non-dementia, MCI, and ADRD caregivers. Logistic regression models were used to identify predictors of severe loneliness (defined as feeling lonely every day or most days) among caregivers. Sample weights were applied to all analyses. Overall, 8.5% of caregivers reported feelings of severe loneliness, equating to over 750,000 caregivers when sample weights were applied. The prevalence of severe loneliness was higher in dementia caregivers (13%) compared to MCI (7.4%) and non-dementia (7.1%) caregivers. Adjusted logistic regression models found dementia caregiving, being without a current partner, and reporting emotional difficulties with the caregiving role were significantly associated with severe loneliness. Increasing age and caring for a parent/other relative (vs spouse) were associated with reduced odds of loneliness. There was no difference in odds of severe loneliness by gender or race. Dementia caregiving is associated with an increased risk of loneliness. Future research is needed to understand how loneliness affects caregiver health and wellbeing outcomes and to develop interventions to address caregiver loneliness, particularly for dementia caregivers.
PRO-INFLAMMATORY CYTOKINES IN OLDER AFRICAN AMERICAN WOMEN IN A PAIN AND DEPRESSION INTERVENTION
Authors: Bhansali Rebekah , Hladek Melissa , Clair Catherine , Szanton Sarah , Gill Jessica , Taylor Janiece
Published: January 2025

Aging, pain, and depression are interconnected health concerns that significantly impact older women. African American women face additional risks of comorbid pain and depression, severe depressive symptoms, and less frequent pain treatment. Pro-inflammatory cytokines and inflammatory mediators are associated with both conditions. The DAPPER (Depression and Pain Perseverance through Empowerment and Recovery) pilot study tailored nurse-led interventions to meet the needs of older African American women with chronic pain and depression. This pilot study assessed non-pharmacological interventions among African American women aged 50+ with chronic pain and depressive symptoms. The intervention consisted of eight nurse-led sessions. Participants were randomized into waitlist control and immediate intervention groups. Ten participants in the immediate intervention group completed the program and provided pre- and post-intervention saliva samples. Outcomes, including goal attainment, pain, depression, and stress, were measured using validated tools such as PROMIS-8 and PSS-14. Saliva samples were collected for cytokine analysis, including TNFα, IL-8, IL-6, and IL-1β. Although under-powered for direct conclusions, data shows a downward trend in psychosocial and pro-inflammatory biomarkers. Pre- to post-intervention mean levels of psychosocial and cytokine markers (TNFα, IL-8, IL-6, IL-1β) decreased in a subset of the immediate intervention group, supported by median sensitivity analyses. The DAPPER pilot study acknowledged the intersectionality of race, age, and gender to provide personalized care and considered the biochemical mechanisms involved in pain and depression. Further research is needed to explore the potential biochemical impact of nurse-led, home-based interventions, particularly for older African American women.