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Articles 1 - 19 of 19

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto Nov 2017

Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto

UMass Metabolic Network Publications

In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target ...


Age-Associated Microrna Expression In Human Peripheral Blood Is Associated With All-Cause Mortality And Age-Related Traits, Tianxiao Huan, George Chen, Chunyu Liu, Anindya Bhattacharya, Jian Rong, Brian H. Chen, Sudha Seshadri, Kahraman Tanriverdi, Jane E. Freedman, Martin G. Larson, Joanne M. Murabito, Daniel Levy Oct 2017

Age-Associated Microrna Expression In Human Peripheral Blood Is Associated With All-Cause Mortality And Age-Related Traits, Tianxiao Huan, George Chen, Chunyu Liu, Anindya Bhattacharya, Jian Rong, Brian H. Chen, Sudha Seshadri, Kahraman Tanriverdi, Jane E. Freedman, Martin G. Larson, Joanne M. Murabito, Daniel Levy

UMass Metabolic Network Publications

Recent studies provide evidence of correlations of DNA methylation and expression of protein-coding genes with human aging. The relations of microRNA expression with age and age-related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 x 10(-4) (Bonferroni-corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age-associated mRNA expression possibly driven by age-associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict 'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Deltaage) and found that Deltaage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 x 10(-5) adjusted for sex and chronological age). Additionally, Deltaage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age-related diseases. Wiley and Sons Ltd.


Cross-Sectional Relations Of Whole-Blood Mirna Expression Levels And Hand Grip Strength In A Community Sample, Joanne M. Murabito, Jian Rong, Kathryn L. Lunetta, Tianxiao Huan, Honghuang Lin, Qiang Zhao, Jane E. Freedman, Kahraman Tanriverdi, Daniel Levy, Martin G. Larson Aug 2017

Cross-Sectional Relations Of Whole-Blood Mirna Expression Levels And Hand Grip Strength In A Community Sample, Joanne M. Murabito, Jian Rong, Kathryn L. Lunetta, Tianxiao Huan, Honghuang Lin, Qiang Zhao, Jane E. Freedman, Kahraman Tanriverdi, Daniel Levy, Martin G. Larson

UMass Metabolic Network Publications

MicroRNAs (miRNAs) regulate gene expression with emerging data suggesting miRNAs play a role in skeletal muscle biology. We sought to examine the association of miRNAs with grip strength in a community-based sample. Framingham Heart Study Offspring and Generation 3 participants (n = 5668 54% women, mean age 55 years, range 24, 90 years) underwent grip strength measurement and miRNA profiling using whole blood from fasting morning samples. Linear mixed-effects regression modeling of grip strength (kg) versus continuous miRNA 'Cq' values and versus binary miRNA expression was performed. We conducted an integrative miRNA-mRNA coexpression analysis and examined the enrichment of biologic pathways ...


Mass-Spectrometry Based Proteomics Of Age-Related Changes In Murine Microglia, Antwoine Flowers Mar 2017

Mass-Spectrometry Based Proteomics Of Age-Related Changes In Murine Microglia, Antwoine Flowers

Graduate Theses and Dissertations

The last century has seen a steady increase in the extension of the average lifespan. This has concomitantly produced higher incidences of age-related chronic degenerative diseases like Alzheimer’s and Parkinson’s diseases. Age is the single greatest risk factor for the development of not just these degenerative conditions but cancer as well. The aged niche undergoes a number of maladaptive changes that allow underlying conditions to present and progress. Exactly which changes, contribute to the progression of which disease is currently an area of intense study. However, these answers often present therapeutic targets for disease prevention. Age is characterized ...


Extracellular Matrix Remodeling And The Inflammatory Response During Skeletal Muscle Regeneration In Sarcopenic Obese Mice, Lemuel Arthur Brown Dec 2016

Extracellular Matrix Remodeling And The Inflammatory Response During Skeletal Muscle Regeneration In Sarcopenic Obese Mice, Lemuel Arthur Brown

Theses and Dissertations

AIM: Sarocpenic obesity is a national concern within the United States because this metabolic syndrome is tied with reduced mobility and quality of life. Both obesity and aging are associated with insulin-resistance, chronic low-grade inflammation and muscle weakness. Skeletal muscle regeneration is a process that involves the coordinated effort of myogenic regulatory factors (MRFs), inflammatory signaling, and extracellular matrix (ECM) remodeling for optimal regeneration. It has been demonstrated that obesity and aging have a reduction in muscle regeneration. It has not been examined if sarcopenic obesity will further reduce muscle mass and the regenerative process. The purpose of this study ...


Investigating The Role Of Dna Polymerase Beta In The Aging Phenotype Of Down Syndrome, Aqila Ahmed Ahmed Jan 2016

Investigating The Role Of Dna Polymerase Beta In The Aging Phenotype Of Down Syndrome, Aqila Ahmed Ahmed

Wayne State University Dissertations

Down syndrome (DS) is a chromosomal condition characterized by accelerated aging that has yet to be directly linked to a DNA repair defect. Reduced PolB and unrepaired damage from oxidative stress observed in DS, point toward defective base excision repair (BER). In this study, we report that low PolB transcript correlates with increased markers of senescence. The gene dosage effect of Trisomy 21 is likely the source for PolB downregulation. We show that the HSA21-localized miR-155 overexpression correlates with a decrease in Creb1 and PolB, thus establishing a putative regulatory pathway. Data from the DS mouse model, Ts65Dn, reveal low ...


It Is All About (U)Biquitin: Role Of Altered Ubiquitin-Proteasome System And Uchl1 In Alzheimer Disease, Antonella Tramutola, Fabio Di Domenico, Eugenio Barone, Marzia Perluigi, D. Allan Butterfield Jan 2016

It Is All About (U)Biquitin: Role Of Altered Ubiquitin-Proteasome System And Uchl1 In Alzheimer Disease, Antonella Tramutola, Fabio Di Domenico, Eugenio Barone, Marzia Perluigi, D. Allan Butterfield

Chemistry Faculty Publications

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased ...


High-Throughput Screening Of Age-Related Changes In Caenorhabditis Elegans, Neil Copes Jan 2015

High-Throughput Screening Of Age-Related Changes In Caenorhabditis Elegans, Neil Copes

Graduate Theses and Dissertations

This project was developed to identify novel methods for high-throughput culturing and screening of C. elegans to investigate age-related metabolic changes and to survey the proteomic and metabolomic factors associated with age-related changes. To accomplish these goals we developed a novel way to grow C. elegans in liquid culture in 96-well microplates for several weeks without suffering significant fluid loss due to evaporation and without needing to shake or unseal the plates for aeration. We also developed methods for assaying the total volume of live C. elegans in microplate cultures using a fluorescence microplate reader and for performing RNAi experiments ...


Iron-Induced Complement Dysregulation In The Retinal Pigment Epithelium: Implications For Age-Related Macular Degeneration, Yafeng Li Jan 2015

Iron-Induced Complement Dysregulation In The Retinal Pigment Epithelium: Implications For Age-Related Macular Degeneration, Yafeng Li

Publicly Accessible Penn Dissertations

Age-related macular degeneration (AMD), typically manifesting as a loss of central vision in elderly persons, is a leading cause of blindness in highly developed nations. AMD is a multifactorial disease associated with aging, oxidative stress, complement dysregulation, dsRNA toxicity, among many other possible factors. The formation of extracellular deposits, termed drusen, below the retinal pigment epithelial (RPE) cell layer in the outer retina is a pathognomonic hallmark of AMD. The composition of drusen is complex, but identified elements include iron, complement components, and amyloid protein derivatives. This suggests that iron may be involved in the pathophysiology of AMD. Further support ...


The Effects Of Supplemented Metabolites On Lifespan And Stress Response Pathways In Caenorhabditis Elegans, Clare B. Edwards Jan 2015

The Effects Of Supplemented Metabolites On Lifespan And Stress Response Pathways In Caenorhabditis Elegans, Clare B. Edwards

Graduate Theses and Dissertations

Understanding how metabolites contribute to anaplerosis, antioxidant effects, and hormetic pathways during aging is fundamental to creating supplements and dietary habits that may decrease age-associated disease and decline, thus improving the quality of life in old age. In order to uncover metabolic pathways that delay aging, the effects of large sets of metabolites associated with mitochondrial function on lifespan were investigated.

Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in C. elegans. Addition of fumarate and succinate also extended lifespan and all three metabolites activated nuclear translocation of the cytoprotective DAF-16/FOXO transcription factor and protected from ...


Transcriptional Regulation Of Caenorhabditis Elegans Foxo/Daf-16 Modulates Lifespan, Ankita Bansal, Eun-Soo Kwon, Darryl Conte Jr., Haibo Liu, Michael J. Gilchrist, Lesley T. Macneil, Heidi A. Tissenbaum Apr 2014

Transcriptional Regulation Of Caenorhabditis Elegans Foxo/Daf-16 Modulates Lifespan, Ankita Bansal, Eun-Soo Kwon, Darryl Conte Jr., Haibo Liu, Michael J. Gilchrist, Lesley T. Macneil, Heidi A. Tissenbaum

Program in Gene Function and Expression Publications and Presentations

BACKGROUND: Insulin/IGF-1 signaling plays a central role in longevity across phylogeny. In C. elegans, the forkhead box O (FOXO) transcription factor, DAF-16, is the primary target of insulin/IGF-1 signaling, and multiple isoforms of DAF-16 (a, b, and d/f) modulate lifespan, metabolism, dauer formation, and stress resistance. Thus far, across phylogeny modulation of mammalian FOXOs and DAF-16 have focused on post-translational regulation with little focus on transcriptional regulation. In C. elegans, we have previously shown that DAF-16d/f cooperates with DAF-16a to promote longevity. In this study, we generated transgenic strains expressing near-endogenous levels of either daf-16a or ...


Examining Post-Transcriptional Regulation Of Skeletal Muscle Satellite Cell Homeostasis, Activation And Fate Determination, Crystal Dawn Pulliam Jan 2014

Examining Post-Transcriptional Regulation Of Skeletal Muscle Satellite Cell Homeostasis, Activation And Fate Determination, Crystal Dawn Pulliam

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Skeletal muscle is essential for respiration, mobility, reproduction and metabolism. Deficits in muscle function due to disease, injury or age reduce both quality of life and lifespan. Muscles are long-lived tissues that require maintenance to retain functional integrity throughout the life of an organism. Satellite cells are the adult stem cells responsible for muscle repair and maintenance. Upon myotrauma, satellite cells re-enter the cell cycle, proliferate, and terminally differentiate to repair the muscle. In uninjured tissue, satellite cells are quiescent and infrequently proceed through myogenesis for muscle maintenance. The molecular mechanisms that regulate satellite cell quiescence and activation are poorly ...


Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe Jan 2013

Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe

Publicly Accessible Penn Dissertations

microRNAs (miRNAs) are 20~24nt small RNAs that are critical for many biological aspects, from development to age-associated processes. Starting from the identification of the first miRNA, lin-4, hundreds of miRNAs have been discovered across species. To reveal the role of miRNAs in aging, studies have profiled changes in miRNA levels with age. However, increasing evidence suggests that miRNAs show heterogeneity in length and sequence in different biological contexts. Despite the observation of such heterogeneity, it is largely unknown how such heterogeneity is generated, and whether it is biologically regulated or important. Here we report the characterization of a novel ...


The Combination Of Aging And Inflammation Interact To Produce Specific Changes In Bdnf Protein Isoform Expression, Bdnf-Dependent Signaling And Hippocampal Synaptic Plasticity, Giuseppe Paolo Cortese Jan 2013

The Combination Of Aging And Inflammation Interact To Produce Specific Changes In Bdnf Protein Isoform Expression, Bdnf-Dependent Signaling And Hippocampal Synaptic Plasticity, Giuseppe Paolo Cortese

Psychology and Neuroscience Graduate Theses & Dissertations

The goals of this research were to investigate the combined effects of aging and inflammation on brain-derived neurotrophin (BDNF) protein biology and BDNF-dependent synaptic plasticity in the hippocampus. For the past two decades neurotrophin research has generated a large body of evidence supporting the role for neurotrophins in facilitating multiple forms of synaptic plasticity and memory in the hippocampus. However, little is known about the effects that both aging and neuroinflammation may impose on these neurotrophin-related pathways.

To carry out the experiments in this study we utilized multiple models: (1) A rodent model of aging and inflammation using young (3-month-old ...


Dysregulated Fgf And P38 Mapk Signaling Underlies Loss Of Stem Cell Self-Renewal In Aging Skeletal Muscle, Jennifer Delaney Bernet Jan 2013

Dysregulated Fgf And P38 Mapk Signaling Underlies Loss Of Stem Cell Self-Renewal In Aging Skeletal Muscle, Jennifer Delaney Bernet

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Sarcopenia is a geriatric syndrome characterized by loss of skeletal muscle mass, skeletal muscle function and decreased regenerative capacity. A number of skeletal muscle-specific physiological decrements may contribute to sarcopenia; among these is an age-related impairment of satellite cells, the skeletal muscle stem cells required for muscle regeneration. I find that cell-autonomous deficits underlie a loss of self-renewal in aging satellite cells. The decline in self-renewal implicates altered p38αβ mitogen-activated protein kinase (MAPK) activity, which is activated by fibroblast growth factor (FGF) signaling and involved in satellite cell activation, differentiation and self-renewal in young satellite cells. Asymmetric activation of active ...


Regulation And Dynamic Behavior Of The Heat Shock Transcription Factor Hsf-1 In C. Elegans, Elizabeth A. Morton Jan 2013

Regulation And Dynamic Behavior Of The Heat Shock Transcription Factor Hsf-1 In C. Elegans, Elizabeth A. Morton

Publicly Accessible Penn Dissertations

Eukaryotic cells respond to heat stress by activating the transcription factor HSF1. In addition to its role in stress response, HSF1 also functions in protein homeostasis, aging, innate immunity, and cancer. Despite prominent HSF1 involvement in processes pertinent to human health and disease, there are still gaps in our understanding of HSF1. For example, controversy exists regarding the localization of HSF1, the identity of HSF1 regulators, and the function and conservation of heat-induced HSF1 stress granules. Many of the physiological roles for HSF1 have been defined using the model organism Caenorhabditis elegans, yet little is known about how the molecular ...


Molecular Mechanisms Of Sleep/Wake Regulation And Memory Formation In Young And Aged Mice, Mathieu E. Wimmer Jan 2012

Molecular Mechanisms Of Sleep/Wake Regulation And Memory Formation In Young And Aged Mice, Mathieu E. Wimmer

Publicly Accessible Penn Dissertations

Advancements in healthcare and medicine have greatly increased lifespan. Normal aging is accompanied by deterioration of key physiological processes, including sleep and cognition. Understanding the mechanisms by which these functions go awry with age is a critical step in identifying novel therapeutic strategies to improve quality of life for the elderly. One of the most prevalent complaints in the elderly is the deterioration of sleep/wake patterns, difficulties staying awake and reduced vigilance. Little is known about the molecular mechanisms controlling these states in the brain. Mouse models are ideally suited to address this question because they share many similarities ...


Dopaminergic Innervation Of The Subventricular Zone In The Murine Brain, Linda Beth Drozdowicz May 2010

Dopaminergic Innervation Of The Subventricular Zone In The Murine Brain, Linda Beth Drozdowicz

Honors Scholar Theses

The subventricular zone (SVZ) is one of two areas in the brain that, in a healthy mouse, continually generate neurons throughout adulthood. While it was previously thought that only the A9 neurons of the substantia nigra sent dopaminergic afferents to the SVZ, recent studies suggest that the A10 neurons of the ventral tegmental area may innervate this area. This project has aimed to discover which, if either, model is correct.

Examination of the Aphakia (AK) mouse was used to determine the role of distinct midbrain regions in SVZ regulation. Additionally, intraperitoneal injections of the chemical MPTP were used to deduce ...


Evaluation Of Mitochondrial Dysfunction And Α-Synuclein Aggregation In Yeast Models Of Parkinson’S Disease, Michael Zorniak Apr 2008

Evaluation Of Mitochondrial Dysfunction And Α-Synuclein Aggregation In Yeast Models Of Parkinson’S Disease, Michael Zorniak

Eukaryon

Parkinson's disease (PD) is characterized by the progressive death of dopaminergic neurons in the human brain. The misfolding and aggregation of alpha-synuclein, as well as the presence of reactive oxygen species (ROS), are throught to contribute to the cytoxicity. The mechanism of interaction between these two pathways is unknown. Mitochondrial dysfunction, specifically, incomplete respiratory metabolism and loss of antioxidants, has long been implicated as the culprit of ROS accumulation. Our lab has previously developed budding and fission yeast models to study genetic regulation of alpha-synuclein misfolding and toxicity. My thesis is composed of two studies. For my first goal ...