bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological Aging, Mortality, and Alzheimer’s Disease Related Biomarkers from Midlife to Old Age
Authors: Franz Carol , Buchholz Erik , Qin Amy Yongmei , Tu Xin , Kremen William 
Published: December 2021

Abstract
People age at different rates and in different biological systems that may differentially contribute to accelerated decline. Better understanding of biological aging may contribute to identification of better targets for intervention. In 1005 VETSA participants we created 3 indicators of biological age: physiological age (PA), frailty, and brain age. PA included hemoglobin, glucose, lipids, height, weight, waist, systolic and diastolic blood pressure, and age. PA was calculated using the Klemera and Doubal (2006) method. The frailty index summed 37 health deficits (Jiang et al. 2017). A machine learning algorithm was used to estimate brain age across cortical and subcortical regions (Liem et al, 2017); predicted brain age subtracted from chronological age comprised the predicted brain age difference score (PBAD). Frailty and PBAD were calculated at waves 1, 2 and 3 when participants were average age 56, 62, and 68, respectively. PA markers were only available at waves 2 and 3. Outcome measures included mortality by wave 3 and scores on AD-related plasma biomarkers—Neurofilament light (NFL), Tau, and AB40 and AB42 at wave 3. Frailty at wave 1 and 2 predicted mortality. Frailty at wave 1 was significantly associated with wave 3 NFL, AB42 and AB40. Wave 2 & 3 frailty was associated with all biomarkers. Neither PA nor PBAD predicted biomarkers or mortality. The results are striking given the relatively young age of the sample. Even as early as one’s 50s, frailty in a community-dwelling sample predicted accelerated decline and mortality when the outcome age was only 66-73.
Can We Simplify Aging?
Authors: Ukraintseva Svetlana , Yashin Anatoliy 
Published: December 2021

Abstract
Aging is indeed a complex process, but can it be simplified, so we could efficiently prioritize candidate anti-aging interventions and select those with largest impacts on key negative consequence of the aging, i.e., on increases in mortality risk and comorbidities with age? Here we argue that human aging and its negative consequences for health and lifespan are essentially driven by the interplay among three processes: (i) depletion of limited body reserves (e.g., of stem, immune, neural, muscle cells); (ii) inherent deficiency of cell/tissue repair mechanisms, which leads to accumulation of damage, allostatic load, and systems dysregulation; and (iii) general slowdown of physiological processes in the body (such as metabolism, proliferation and information processing) with age that results in slower responses to stressors and delayed recovery after damage (i.e., decline in resilience), which in turn contributes to increase in vulnerability to death with age. We show that the interplay among these processes can have ambivalent effects on health and longevity that should be taken into account to develop optimal anti-aging and pro-longevity strategies. In order to be efficient on the long-term, the anti-aging interventions may need to target the different causes of aging (reserve depletion, damage accumulation, and slowdown) simultaneously, to avoid undesirable trade-offs.
Effect of Combined Stressors on C. elegans Lifespan
Authors: Hull Bradford , Sutphin George 
Published: December 2021

Abstract
Cellular stress is a fundamental component of age-associated disease. Cells experience many forms of stress (oxidative, heavy metal, etc.), and as we age the burden of stress and resulting damage increases while our cells’ ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. By understanding how cells respond to stress we aim to slow age-associated deterioration and develop treatment targets for age-associated disease. The majority of past work has focused on understanding responses to individual stressors. In contrast, how pathology and stress responses differ in the presence of multiple stressors is relatively unknown; we investigate that here. We cultured worms on agar plates with different combinations of arsenic, copper, and DTT (which create oxidative/proteotoxic, heavy metal, and endoplasmic reticulum (ER) stress, respectively) at doses that result in 20% lifespan reduction individually and measured the effect on lifespan. We found that arsenic/copper and arsenic/DTT combinations created additive lifespan reductions while the copper/DTT combination created an antagonistic lifespan reduction when compared to controls (p&lt;0.05). This antagonistic toxicity suggests an interaction either between the mechanisms of toxicity or the cellular response to copper and DTT. We are now evaluating the impact of copper and DTT individually and in combination on unfolded protein and heavy metal response pathways to understand the underlying mechanism of the interaction. Additionally, we are continuing to screen stressors to identify combinations that cause non-additive (synergistic or antagonistic) toxicity to build a comprehensive model of the genetic stress response network in C. elegans.
MTOR Inhibition Alters miRNA Profile in Cultured Bone Marrow Mesenchymal Stem Cells
Authors: Stukenborg Lisa , Potnis Manali , Sell Christian 
Published: December 2021

Abstract
Progressive decline in adult stem cell function is a feature of aged tissues and contributes to multiple age-related diseases. Of particular interest are bone marrow mesenchymal stem cells, also known as bone marrow stromal cells (BMSCs), which are multipotent, and have significant therapeutic potential for age-related disease. BMSCs isolated from older individuals show decreased differentiation and characteristics of cell senescence. We and others find that inhibition of the mTOR pathway prevents senescence and extends BMSC proliferation. We have examined miRNA profiles in rapamycin-treated BMSCs to identify miRNAs that may be needed to maintain “stemness” and facilitate differentiation in this population in undifferentiated cell populations. The analysis reveals a distinct miRNA profile induced by rapamycin associated with enhanced differentiation capacity.
A Phase 2b Clinical Trial Assessing Lomecel-B Infusion in Individuals with Aging Frailty: Study Design and Rationale
Authors: Ramdas Kevin , Hitchinson Ben , McClain-Moss Lisa , Yousefi Keyvan , Diaz Liliana , Ruiz Jorge , Hare Joshua , Oliva Anthony 
Published: December 2021

Abstract
Frailty is a common and important geriatric syndrome characterized by age-associated declines in physiology and function across multiple organ systems, which lead to increased vulnerability to adverse health outcomes. A biological mechanism that underlies the decline in physical function associated with aging frailty is chronic inflammation. The MSCs in Lomecel-B have immuno-modulatory capacity and control inflammation and the cytokine production of lymphocytes. An individual’s endogenous stem cell production decreases with age, this decrease likely contributes to reduced ability to regenerate and repair organs and tissues. Aging Frailty represents an exciting potential indication for cellular based therapies like Lomecel-B. This study is intended to evaluate the effects of Lomecel-B infusion compared to placebo on mobility and exercise tolerance, patient-reported physical function assessments and biomarkers for inflammation in individuals with Aging Frailty. This is a randomized, double-blind placebo-controlled, parallel multi-arm multicenter study enrolling adults aged 70-85 years identified as mildly or moderately frail per the CSHA Clinical Frailty Scale (CFS), with reduced six minute walk test (6MWT) and elevated Tumor Necrosis Factor-α (TNF-α), at screening. 150 subjects (30 per group) were randomized to receive a single peripheral intravenous infusion of 25, 50, 100, or 200 million doses, or placebo. Safety and efficacy assessments were conducted at 30, 90, 180, and 270 days after infusion. A follow up telephone call to subjects was placed at 365 days. We describe the design and rationale in detail of this 2b study assessing the effects of Lomecel-B on older adults with Aging Frailty.
Exercise-Induced Transcriptional Changes in Aged Skeletal Muscle
Authors: Endo Yori , Zhang Yuteng , Olumi Shayan , Karvar Mehran , Sinha Indranil 
Published: December 2021

Abstract
Exercise is beneficial for physical functions across all ages. However, the response to exercise shifts from anabolism, resulting in limited gain of muscle strength and endurance. These changes likely reflect age-related alterations in transcriptional response underlying the muscular adaptation to exercise. The exact changes in gene expression accompanying exercise, however, are largely unknown, and elucidating them is of a great clinical interest for optimizing the exercise-based therapies for sarcopenia. In order to characterize the exercise-induced transcriptomic changes in aged muscle, a paired-end RNA sequencing was performed on the rRNA-depleted total RNA extracted from the gastrocnemius muscles of 24 months-old mice after 8 weeks of regimented exercise (exercise group) or sedentary activities (sedentary group). Differential gene expression analysis revealed upregulations in the group of genes involved in neurotransmission. In particular, genes encoding the transporters and receptor components of glutaminergic transmission were significantly upregulated in exercised muscles, as exemplified by Gria 1, Gria 2 and Grin2c encoding glutamate receptor 1, 2 and 2C respectively, Grin1 and Grin2b encoding N-methyl-D-aspartate receptors (NMDARs), Nptx1 responsible for glutaminergic receptor clustering, and Slc1a2 and Slc17a7 regulating synaptic uptake of glutamate. These changes were accompanied by an increase in post-synaptic NMDARs and acetylcholine receptors (AChRs), as well as their innervation at neuromuscular junctions (NMJs). These results suggest that neural responses predominate aged skeletal muscle following exercise, and indicate a possibility that glutaminergic transmission at NMJs may be responsible for synaptic protection and neural remodeling accompanying the exercise-induced functional enhancement in aged skeletal muscle.
Immature Pear Extract Constituents Exert Multifaceted Anti-aging Effects
Authors: Ogita Akira , Murata Wakae , Yamauchi Ken , Sakai Akiko , Yamaguchi Yoshihiro , Tanaka Toshio , Fujita Ken-ichi 
Published: December 2021

Abstract
Cellular senescence causes a gradual loss of physiological functions and induces chronic diseases, which negatively affect the quality of human life. Intervention in the cellular senescence process may reduce the incidence of these diseases while delaying the progression of age-related diseases, thereby prolonging human lifespan. In our previous study, we found that extending the chronological lifespan of budding yeast cells, a suitable cellular model for research on mammalian cells, could be achieved by adding immature pear extract (iPE). Moreover, at the 2020 GSA meeting, using a colony-counting method, we reported that both hydrophilic (WiPE) and hydrophobic (OiPE) iPE components exhibited a chronological lifespan prolongation on yeast cells. In this study, the expression of sirtuin-related genes, which regulate cellular senescence, was verified by quantitative real-time reverse-transcription polymerase chain reaction. Interestingly, sirtuin-related gene expression was significantly increased in the WiPE-treated cells only, and OiPE could extend the chronological lifespan of yeast cells through the mechanisms not involved in sirtuin-related gene expression. In general, hydrophobic and hydrophilic components exhibit different degradation and metabolism in cells. Since each component has a different strategy of absorption and excretion in the body, we hypothesize that iPE with multiple active components will have multifaceted effects on anti-aging. Our research on elucidating the mechanism of lifespan extension by OiPE and its application to mammalian cells is ongoing.
Kynurenine Metabolism Lifespan Extension Mediated by Oxidative Stress Response and Hypoxic Response in C. elegans
Authors: Castro-Portuguez Raul , Meyers Jeremy , Freitas Sam , Dang Hope , Turner Emily , DeNicola Destiny , Espejo Luis , Sutphin George 
Published: December 2021

Abstract
Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Metabolic changes throughout the aging process disrupt the balance and homeostasis of the cell. The kynurenine metabolic pathway is the sole de novo biosynthetic pathway for producing NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases, and kynurenine-based interventions can extend lifespan in Caenorhabditis elegans. Our laboratory recently demonstrated knockdown of the kynurenine pathway enzymes kynureninase (KYNU) or 3-hydroxyanthranilic acid dioxygenase (HAAO) increases lifespan by 20-30% in C elegans. However, the mechanism of how these interventions may modulate response against different stressors during the aging process has yet to be explored. Fluorescent reporter strains show the stress-responsive transcription factors skn-1 (ortholog of NRF2/NFE2L2; oxidative stress response) and hif-1 (ortholog of HIF1A; hypoxic stress response) to be highly upregulated when the kynurenine pathway is inhibited. We also demonstrated the increase expression of gst-4 and gcs-1 (transcriptional targets skn-1), which are involved in production of the antioxidant glutathione (GSH), as well as upregulation of cysl-2 (transcriptional target of hif-1), a regulator of cysteine biosynthesis from serine. We hypothesize that lifespan extension resulting from kynurenine pathway inhibition is mediated, at least in part, by upregulation of these transcription factors, providing elevated defense against oxidative stress and hypoxic stress.
Targeting kynurenine metabolism to reduce inflammation and enhance stress response during aging
Authors: Sutphin George , Dang Hope , Espejo Luis , Castro-Portuguez Raul , Hull Bradford , Meyers Jeremy , Turner Emily , DeNicola Destiny 
Published: December 2021

Abstract
Aberrant kynurenine pathway metabolism is increasingly linked to aging and age-associated disease. Kynurenine metabolic activity increases with age and becomes dysregulated during various forms of age-associated pathology in humans. By manipulating one or more kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. In particular, elevating physiological levels of the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends C. elegans lifespan by ~30%. 3HAA delivered chronically in chow similarly extends lifespan in aged C57BL/6 mice. In ongoing work, we are investigating the mechanisms underlying the benefits of multiple kynurenine pathway interventions using tools in C. elegans, mice, and human cell culture. We have preliminary evidence for activation of broad-spectrum cellular stress response, enhanced immune function, and reduced inflammation. Among other roles, the kynurenine pathway is the sole metabolic route for de novo synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan in Eukaryotic cells. We are examining the regulatory interaction between kynurenine metabolism and the two NAD+ recycling pathways, Salvage and Preiss-Handler, both as potential mechanistic mediators and as possible parallel targets for combined interventions with synergistic benefits in aging. We are further evaluating the impact of these interventions in several models of specific age-associated diseases, including sepsis, chronic inflammation, stroke, Alzheimer’s disease, and cancer. Finally, we are developing pharmaceutical strategies to replicate key genetic and metabolic interventions within the kynurenine pathway that can be readily translated into clinical applications.
Infusing Representativeness and Cultivating Harmonization in Alzheimer’s Trials: World Wide FINGERS
Authors: Raman Rema , Aggarwal Neelum 
Published: December 2021

Abstract
World Wide Fingers is a network involving over 30 countries organized to conduct randomized controlled clinical trials to slow the progression of cognitive decline and reduce dementia risks. Trials are designed to parallel the successful Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial of a multidomain lifestyle intervention featuring increased physical activity, improved diet, cognitive training, and metabolic risk factor monitoring. While FINGER found that its intervention significantly benefited cognitive function, it is not clear whether this approach might be successfully tailored to other cultures and environments to yield similar results. This is the goal of World Wide FINGERS. It infuses representativeness by enrolling cohorts that reflect the communities in which it is conducted. For findings across the many trials to be integrated, it is necessary for protocols to be harmonized as much as possible. The COVID-19 pandemic presents special challenges towards harmonization as its disruptions of trial protocols and conduct vary among countries and over time. This symposium is organized to provide the scientific background and framework for the World Wide FINGERS. Novel grassroots efforts towards enrolling representative cohorts in the US will be described. Plans for harmonization and federated data analyses spanning international boundaries and regulations will be outlined. Integrated approaches to challenges of COVID-19 pandemic across trials will be presented. The conclusion of this session will be a discussion of how World Wide FINGERS may serve as a model for collaborative approaches to identify effective, translatable approaches to reduce risks for Alzheimer’s disease.
Treadmill Training Improves Aerobic Capacity in Aged Male Mice Compared to Voluntary Wheel Running
Authors: Schmitt Emily , Graves Hunter , Bruns Danielle 
Published: December 2021

Abstract
Preclinical exercise studies typically use two forms of exercise training protocols: 1) voluntary wheel running and 2) forced treadmill running. Previous work from our group clearly demonstrates that older (18-month-old) male mice do not voluntarily engage in wheel running, especially compared to younger males or female mice. Therefore, we implemented a forced exercise treadmill training protocol to determine if treadmill training was superior to wheel running in improving aerobic capacity in older male mice. PURPOSE: To determine if a 3-week treadmill training protocol improved time to exhaustion (TTE) in older male mice. METHODS: 18-month-old male mice (n=5) were provided a running wheel in their individual cage for 2 weeks or underwent daily treadmill training (n=6) for 3 weeks with increasing speed/incline. At the end of the training period we assessed TTE. RESULTS: Older male mice that trained on the treadmill demonstrated higher TTE compared to wheel (1382 □ 32 seconds versus 500 □ 99 seconds, respectively). In addition, older male mice that trained on the treadmill improved on average ~8% in their TTE test. CONCLUSION: A 3-week treadmill training protocol improves aerobic capacity in older male mice to a greater extent than voluntary wheel running. Ongoing experiments will utilize this training protocol to understand age-related declines in cardiorespiratory fitness, circadian rhythm, and to test exercise as an intervention in the aging population.
Depletion of the miR-34a “sponge” MALAT1 in aging skeletal muscle: Implications for age-related muscle loss
Authors: Ruan Ling , Mendhe Bharati , Isales Carlos , Hill William , McGee-Lawrence Meghan , Fulzele Sadanand , Hamrick Mark 
Published: December 2021

Abstract
We have recently shown that increased levels of reactive oxygen species (ROS) in aging skeletal muscle are associated with increased expression of the senescence-associated microRNA miR-34a-5p (miR-34a). The histone deacetylase Sirt1 is a validated target of miR-34a, and miR-34a expression is induced by the tumor suppressor p53 which is itself stimulated by ROS. Long noncoding RNAs (lncRNAs) are known to function as “sponges” for microRNAs, but the role of such competing endogenous RNAs (ceRNA) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4-6 mos) and aged (22-24) male and female mice the expression of several lncRNAs that are predicted to bind miR-34a-5p in silico and whose predicted binding has been validated experimentally. Results indicate a significant decrease in lncRNA MALAT1 expression with aging. MALAT1 is known to be highly expressed during the later stages of myoblast differentiation and myotube maturation. We therefore treated C2C12 cells at 48 hrs with hydrogen peroxide (10 uM) and examined changes in MALAT1 expression. MALAT1 was significantly decreased with H2O2 treatment, whereas miR-34a is increased in C2C12 cells after hydrogen peroxide exposure. Age-related muscle atrophy mediated by ROS may therefore result in part from related mechanisms involving miR-34a activity: an increase in miR-34a targeting Sirt1 resulting from p53 activation and an increase in miR-34a bioavailability resulting from a decline in miR-34a “sponging” due to ceRNA MALAT1 depletion. These findings suggest that therapeutic interventions increasing MALAT1 expression in muscle may potentially enhance the preservation of muscle mass with aging.
Effects of glycine and n-acetylcysteine on glutathione levels and mitochondrial energy metabolism in healthy aging
Authors: Gut Philipp , Lizzo Giulia , Migliavacca Eugenia , Karagounis Leonidas , Heise Tim , Eynatten Maximilian 
Published: December 2021

Abstract
Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks (1.2g/1.2, 2.4g/2.4g, 3.6g/.3.6g of each amino acid). Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC.