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All The Rage: Assessing The Age/Rage Signaling Pathway’S Effects On Healthspan And The Physiological Processes Of Aging, Brandon Ashmore

Honors Theses

Advanced glycation end products (AGEs) are protein, lipid, or nucleotide molecules that have been combined with sugars through nonenzymatic, irreversible glycation and oxidation reactions. Their accumulation in the body has been associated with the natural aging process and a wide range of pathologies, including chronic inflammation, sustained oxidative stress, diabetes, neurodegenerative diseases, atherosclerosis, and cancer. Their interaction with the receptor for advanced glycation end products (RAGE) has been linked to several proinflammatory signaling pathways associated with neurotoxicity and vascular lesions. While some research has been done on the possible health benefits of RAGE inhibition to extend lifespan, our study hopes …

Nicotinamide Riboside And Beta-Hydroxybutyrate Activate Parallel Pathways For C. Elegans Lifespan Extension, Mckenzie Peters

Undergraduate Honors Theses

Supplementation with nicotinamide riboside (NR), a form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide (NAD⁺) extends lifespan in the nematode C. elegans and delays aging-related pathologies in mammals. During aging, levels of NAD⁺ decline causing metabolic dysfunction and oxidative damage. Studies in C. elegans found that when NR was administered during larval development it induced the mitochondrial unfolded protein response (UPR^mt), which is frequently associated with lifespan extension. Both calorie restriction (CR) and ketogenic diets (KD) have been shown to extend lifespan, in part through increasing NAD⁺ and through increasing levels …

Specialized Metabolism In Retina, Retinal Pigmented Epithelium, And Testis, Siyan Zhu

Graduate Theses, Dissertations, and Problem Reports

The retina and its neighboring retinal pigmented epithelium (RPE) are high energy-demanding and metabolically active tissues with specialized and complementary metabolism. They are metabolically interdependent and impact each other’s viability. Interestingly, many of the metabolic features in the retina and RPE are shared with the testis. For example, testis is also energy costly due to continuous sperm differentiation and it has similar metabolic inter-dependence between different testis cells. Both the retina and testis are vulnerable to mitochondrial metabolic impairments.

We conducted three research projects to understand 1) the nutrient utilization and communication in retina and RPE; 2) The profiling of …

Regulation Of The Heat Shock Response Via Lysine Acetyltransferase Cbp-1 And In Neurodegenerative Disease In Caenorhabditis Elegans, Lindsey N. Barrett

USF Tampa Graduate Theses and Dissertations

The decline of proteostasis is a hallmark of aging that is, in part, affected by the dysregulation of the heat shock response (HSR), a highly conserved cellular response to proteotoxic stress in the cell. The heat shock transcription factor HSF-1 is well-studied as a key regulator of proteostasis, but mechanisms that could be used to modulate HSF-1 function to enhance proteostasis during aging are largely unknown. In this study, we examined lysine acetyltransferase regulation of the HSR and HSF-1 in C. elegans. We performed an RNA interference screen of lysine acetyltransferases and examined mRNA expression of the heat-shock inducible gene …

The Effects Of Aging On Wound Healing And Limb Regeneration In The Axolotl, Hande Sahin

Graduate Masters Theses

The Mexican axolotl is capable of regenerating various parts of its body and maintains this capacity throughout its entire life. Although this ability is sustained through adulthood, multiple regenerative processes appear to be negatively affected by aging. Here, we focus on evaluating the effect of aging on the rate of wound healing and limb regeneration. We have developed new in vivo, and ex vivo assays to characterize wound healing and identify differences between young and aged animals during this process. We have also characterized morphological features of mature skin from both groups of animals and although there are no obvious …

Essential Amino Acid (Eaa) Regulation Of Skeletal Muscle Protein Turnover With Age, Mary Komp

Graduate Theses and Dissertations

Skeletal muscle (SM) is vital for both long term health and quality of life. Recent research suggests an increase in catabolic signals with age triggers pathologic conditions, such as sarcopenia. Although results from in vitro studies model how EAA can regulate muscle protein synthesis (MPS), the relevance of these models to muscle protein breakdown (MPB) and the presence of physiological EAA concentrations remains to be established. Therefore, the objective of this study was to determine the effects of a low, normal, and supra physiological dose of EAA (0.2, 1.0, and 3.0 x EAA) in a young (passages 2-10) and aging …

An Investigation Into The Mechanism Of Proteasome Dysfunction In Neurodegenerative Disease And The Biological Impact Of Proteasome Hyperactivation In C. Elegans, Raymond T. Anderson

Graduate Theses, Dissertations, and Problem Reports

Aging is an inevitable process that occurs as humans grow older. It is characterized by the chronological accumulation of cellular damage over time leading to functional decline as an organism grows older. Several processes are thought to contribute to the aging phenomenon, but one of the most prolific of these is the disruption of protein homeostasis (proteostasis). The collapse of proteostasis can lead to accelerated aging and the development of age-related diseases including devastating neurodegenerative diseases (NDs) like Alzheimer and Parkinson disease. Virtually all NDs are characterized by the buildup of proteins in and around neurons resulting in neuronal death …

Characterization Of Biomarkers For Alzheimer’S Disease And Hiv-1 Associated Neurocognitive Disorders, Armando Garces Iii

Theses and Dissertations

Alzheimer’s disease is a neurodegenerative disorder that is characterized by progressive cognitive decline and the accumulation of amyloid beta and neurofibrillary tangles in regions of the brain. These protein deposits are known to generate multiple effects on the brain that lead to neurodegeneration. It has been established that (Human Immunodeficiency Virus) HIV-1 accelerates the aging process of people living with HIV-1. Moreover, there is significant clinical evidence indicating a potential link between the neurodegeneration developed by those with an HIV-1 infection and AD. HIV-1 viral infection causes cognitive impairment known as …

The Role Of Enampt-Mediated Systemic Nad+ Biosynthesis In Aging And Lifespan, Mitsukuni Yoshida

Arts & Sciences Electronic Theses and Dissertations

Aging is a systemic decline in tissue functions that occurs during the course of our life leading to the development of age-associated health deteriorations and ultimately to the expiration of life. Over the past few decades, population aging has become increasingly evident in many parts of the world, leading to increased prevalence of age-related disabilities and diseases. Because age is a major risk factor for many chronic diseases, extensive research effort has been spent to identify common age-associated molecular changes contributing to the pathogenesis and progression of these health issues. One such molecule identified to play a central role in …

Elevated Cochlear Adenosine Causes Hearing Loss Via Adora2b Signaling, Jeanne Manalo

Dissertations & Theses (Open Access)

Over 538 million people in the world have been diagnosed with hearing loss (HL). Current treatments for the most common type of HL, sensorineural HL, are limited to hearing aids and cochlear implants with no FDA-drugs available. The hearing process demands an abundance of ATP and HL is often attributed to a disruption in this metabolic energy currency. Patients who lack adenosine deaminase (ADA), the enzyme that irreversibly metabolizes adenosine, have high levels of adenosine that yield severe health problems, including HL; however, the pathogenic mechanisms behind HL and adenosine remain elusive. Our lab has found a HL phenotype in …

Tools To Evaluate Nanodiamond-Mediated Delivery Of Tiopronin For Cataract Prevention, Justin Beltz

Doctoral Dissertations

”There is a growing demand for non-surgical means of cataract treatment. This dissertation presents three bodies of work that reflect the early-stage development of eye drop formulations aimed at delaying cataract progression. These formulations consist of the antioxidant 2-mercaptopropionylglycine (MPG) loaded onto nanodiamond particles.

Cataractogenesis is linked to oxidative damage to lens proteins. To investigate the potential of MPG for protection against oxidative damage, A549 cells were incubated in 0.6 mM tert-butylhydroperoxide (tBHP). Cells exposed to tBHP without MPG exhibited elevated levels of reactive oxygen species, which led to the depletion of the vital antioxidant glutathione and, ultimately, apoptosis. Co-administration …

Amelioration Of Alzheimer's Disease Pathology In 12-Month-Old Happ(Sweind) Transgenic Mice After Treatment With A Cysteine Rich Whey Supplement, Immunocal®, Srivalli Puttagunta

Electronic Theses and Dissertations

Deficits in Reelin expression and signaling play a pathogenic role in Alzheimer’s disease (AD). Thus, strategies aimed at correcting Reelin deficits may provide a novel therapeutic approach to treating AD. The cysteine-rich, whey protein supplement, Immunocal®, has recently been shown to rescue Reelin expression in a mouse model of Schizophrenia. Given that Reelin-expressing neurons of the entorhinal cortex region are a highly vulnerable population of cells that are lost early in AD, we examined the effects of Immunocal® in the hippocampal-entorhinal cortex formation in a mouse model of AD. Glutathione levels and Reelin expression in the hippocampal-entorhinal cortex formation (entorhinal …

Qualitative And Quantitative Fitness Consequences Of Advanced Maternal Age, Claudia Jean Hallagan

Electronic Theses and Dissertations

Parental age can affect offspring fitness across taxa and through various mechanisms. However, the effect(s) of advanced maternal age on offspring, particularly in insects, has not been comprehensively reviewed making it difficult to draw conclusions about the effects of advanced maternal age on offspring in insects. In my first chapter, I reviewed maternal age literature and found overall negative effects of advanced maternal age on offspring fitness. However, results vary depending on which fitness measures were used, the life stages at which offspring were measured, and the experimental design of the study. In my second chapter, I conducted an experiment …

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

USF Tampa 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 by a …

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

Graduate 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 …

Optimizing Pharmacological Lifespan Extension: Testing Chemical Compounds For Additive Effects On Longevity, Elizabeth Chao

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

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 …

Efficient In Vitro Development Of Photoreceptors From Human Pluripotent Stem Cells, Joseph C. Reynolds

Dissertations, Masters Theses, Capstones, and Culminating Projects

Degeneration of the rod and cone photoreceptors in the human retina is among the most common causes of blindness. Replacing these damaged photoreceptors may help to restore vision. Repairing the damaged retina relies on the insertion of new, healthy cells. Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are two possible sources of photoreceptors to restore vision. Previous data shows that human ES cells and iPS cells can be differentiated into photoreceptors and transplanted into the eye to restore some vision. However, this process is inefficient, and costly. Here, we show a new method for inducing photoreceptor production …

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

USF Tampa 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 paraquat-induced …

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

USF Tampa 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 …

Effect Of Long Term Rapamycin Treatment On Mtor Signalling Network In Colon And Liver Of C57bl/6 Mice, John Sorge

Wayne State University Theses

Many studies have investigated the effects of rapamycin on aging and cancer. However, the effects of long-term rapamycin supplementation on a cancer model have not been performed. This is the first study that investigates the effects of long-term supplementation of rapamycin in a cancer model. ACF analysis of colon tissues in mice showed no significant difference between controls and those supplemented with rapamycin. Factors such as energy balance, cellular environment, PI3K/Akt/mTOR pathway, and more have been assessed in this study. The duration of rapamycin supplementation seems to play an important role in the protection against cancer. Ultimately, this study suggests …

Mechanisms Of Age-Related Inflammation And Cancer : The Synergistic Effect Of Oxidants And Calcium, Donald A. Mccarthy

Legacy Theses & Dissertations (2009 - 2024)

The accumulation of senescent cells during the process of aging has been implicated as causal in numerous age-related pathologies. Senescent cells adopt a secretory phenotype consisting of many factors including matrix remodeling enzymes, growth factors, cytokines, and chemokines. Their secretory nature is the primary reason that they are associated with disease, but it remains unclear why they become so inflammatory. Using primary human fibroblasts cultured to senescence, we mechanistically determined why senescent cells are such potent inducers of inflammation. Our findings indicate that the early production of the cytokine Interleukin 1-α (IL-1α) is central to this transition. We found that …

Ascorbic Acid, Lipid Peroxidation, And Aging, Brian Evan Leibovitz

Dissertations and Theses

The role of ascorbic acid with regard to lipid peroxidation and aging has been examined. A thorough literature analysis indicates that free radical-induced lipid peroxidation is a plausible biochemical explanation for aging. Lipid peroxidation causes cellular damage due to altered enzyme activities, error-prone nucleic acid metabolism, and membrane dysfunction, as well as the accumulation of aging pigments in the lysomes. Ascorbic acid, a water soluble free radical quencher, was examined with regard to carbon tetra-chloride-induced lipid peroxidation and in vivo aging. Carbon tetrachloride, a well-known free radical inducer, caused marked increases in the ration of oxidized/reduced vitamin C only …