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Browsing Theses and Dissertations by Subject "aging"
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Item Open Access Novel modulators of blood pressure with age: a physiological and bioinformatics-based approach(Colorado State University. Libraries, 2021) Bachman, Nate P., author; Braun, Barry, advisor; LaRocca, Thomas J., advisor; Chicco, Adam J., committee member; Gentile, Christopher L., committee memberSystolic blood pressure (SBP) increases with age and is a significant risk factor cardio- and cerebrovascular diseases. While the causes of high blood pressure (hypertension) have been extensively studied, the causes of the age-related rise in blood pressure independent of chronic disease remain unclear. Thus, the identification of novel mechanisms underlying age-related high blood pressure may lead to new strategies to reduce chronic disease risk in older adults. Therefore, the goal of this dissertation was to use both physiological and bioinformatics-based approaches to better elucidate contributors to elevated blood pressure in healthy older adults. The main findings are that 1) inhibition of Rho-kinase (an enzyme that participates in numerous cellular/regulatory pathways) lowers systemic blood pressure in healthy older adults concomitant with reduced vascular resistance but not improved endothelial function, 2) genes expression patterns in peripheral white blood cells differ in healthy older adults with elevated SBP compared to those with normal SBP and transcriptomic (RNA) changes relate to vascular and immune function, and 3) circulating chemokines and whole blood immune-related transcripts track with elevated SBP in healthy older adults. Taken together, this work shows that Rho-kinase, circulating RNA transcripts, and circulating chemokines may be novel therapeutic targets and/or biomarkers of elevated blood pressure in healthy older adults with untreated hypertension.Item Open Access Novel transcriptomic mechanisms of brain aging(Colorado State University. Libraries, 2023) Cavalier, Alyssa Nicole, author; LaRocca, Thomas, advisor; Lark, Daniel, committee member; Hamilton, Karyn, committee member; Weir, Tiffany, committee memberAs the world ages, the incidence of age-related diseases like dementia is expected to increase. Brain aging is characterized by declines in cognitive function that may develop into mild cognitive impairment, which increases the risk for dementia. In fact, age is the primary risk factor for late-onset Alzheimer's disease, which is the most common age-related dementia. The adverse cellular and molecular processes that underlie cognitive decline with aging in the brain are known collectively as the "hallmarks of brain aging." Advances in next-generation sequencing (e.g., transcriptomics/RNA-seq) have made it possible to investigate age- and disease-related changes in the brain at the broad gene expression level, and to identify potential therapeutic targets. With the support of my committee and mentoring team, I completed three studies using transcriptomics that characterize novel mechanisms that underlie brain aging. My findings include: (1) doxorubicin chemotherapy accelerates brain aging at the gene expression level, (2) apigenin nutraceutical supplementation targets age-related inflammation in the brain and rescues cognitive impairment in old mice, and (3) epigenetic dysregulation of transposable elements (remnants of viral infection in the genome) with aging contributes to age-related inflammation in Alzheimer's disease. Together, my work provides insight into transcripts and cellular/molecular pathways that are modifiable and may be therapeutic targets to delay or prevent consequences of brain aging.Item Open Access Oxidative and energetic stress: regulation of Nrf2 and mitochondrial biogenesis for slowed aging interventions(Colorado State University. Libraries, 2013) Bruns, Danielle Reuland, author; Hamilton, Karyn L., advisor; Miller, Benjamin F., advisor; Wilusz, Carol J., committee member; Pagliassotti, Michael J., committee memberThe following dissertation describes a series of experiments with the overall aim to understand the cellular energetic and oxidative stresses associated with aging, and to investigate treatments which may attenuate these stresses and promote healthspan. The specific aims of the four sets of experiments were 1) to determine if treatment with the phytochemicals in Protandim activates Nrf2 and 2) the mechanisms by which this activation occurs; 3) to assess sexually dimorphic Nrf2 signaling across three rodent models of longevity; and 4) to determine if mitochondrial related proteins are preferentially translated under energetic stress. In Experiments #1 and #2, we found that phytochemicals activate Nrf2 and protect cells against oxidant stress. None of the mechanisms we investigated appear to be responsible for phytochemical-induced Nrf2 activation, and continued investigations must be undertaken to identify how Protandim robustly induces Nrf2 nuclear accumulation. In Experiment #3, we found that Nrf2 signaling was not consistently upregulated in tissues from long-lived models compared to controls, but we did elucidate important sex differences, with female mice generally displaying greater Nrf2 signaling than male mice. We believe this finding, in the context of sexual dimorphism in aging, warrants future investigations into Nrf2, stress resistance, and longevity between males and females. In Experiment #4, we found that mitochondrial proteins were preferentially translated upon pharmaceutical energetic stress, and that this selective translation occurred in the vicinity of the mitochondria. Our results indicate activation of Nrf2 protects cells against oxidant stress, and may be a therapeutic target for cardiovascular diseases and other age-related diseases. Further, we assess selective translation of mitochondrial proteins during energetic stress as a means of understanding how energetic stress mimetics selectively facilitate the translation of key mitochondrial proteins. Taken together, these studies provide the basis for future work aimed at attenuating diseases with oxidant stress and mitochondrial dysfunction components.Item Open Access Protein synthesis in slowed aging: insights into shared characteristics of long-lived mouse models(Colorado State University. Libraries, 2014) Drake, Joshua Chadwick, author; Miller, Benjamin F., advisor; Hamilton, Karyn L., advisor; Wilusz, Carol J., committee member; Hickey, Matthew S., committee memberThe following dissertation describes a series of experiments with the overall aim to understand the role that changes in protein synthesis have in slowed aging. The specific aims of the three sets of experiments were 1) to determine if chronic administration of the mTORC1 inhibitor rapamycin to mice increases proteostatic mechanisms in skeletal muscle, heart, and liver; 2) to determine if an underdeveloped anterior pituitary, caused by deletion of the Pit-1 gene in mice, increases proteostatic mechanisms in skeletal muscle, heart, and liver of long-lived Snell dwarf mice; 3) and to determine if transient nutrient restriction during the suckling period in mice (i.e. crowded litter), increases proteostatic mechanisms in skeletal muscle, heart, and liver later in life. In Experiment #1 we found that mitochondrial proteins were preferentially synthesized in skeletal muscle and that global protein synthesis in the heart was maintained despite reduced cellular proliferation and mTORC1 activity in mice fed rapamycin compared to normal diet controls. Originally we determined that these data were indicative of an improved somatic maintenance of skeletal muscle mitochondria and the heart proteome. Since we could not account for changes to other energetic processes (e.g. metabolism), we reasoned that our data was more consistent with proteostasis, a component of somatic maintenance. In Experiment #2 we developed a novel method for assessing proteostasis and determined that Snell dwarf mice had an increase in proteostatic mechanisms across sub-cellular fractions within skeletal muscle and heart compared control mice, despite differential rates of protein synthesis in the face of decreased mTORC1. Together with our previous investigations into rapamycin fed and caloric restriction models of long-life we concluded that increased proteostatic mechanisms may be a shared characteristic of models of slowed aging. In Experiment #3 we demonstrate that the crowded litter mouse transitions from growth to maintenance as it ages. Furthermore, in the crowded litter mouse, we demonstrate that proteostasis is not dependent upon decreased mTORC1. Our results indicate that decreased mTORC1 does not necessarily correlate to decreases in protein synthesis across all sub-cellular fractions. Discerning which proteins and the mechanism(s) of how specific proteins can be preferentially synthesized despite decreases in protein synthesis in other fractions and decreased mTORC1, may give further insight into characteristics of slowed aging. Further, we demonstrate that increases in proteostasic mechanisms are a shared characteristic of multiple unique models of slowed aging and therefore, provides a basis for future work aimed at slowing the aging process.Item Open Access Protein synthesis rates in response to exercise and β-adrenergic signaling in human skeletal muscle(Colorado State University. Libraries, 2011) Robinson, Matthew McHutcheson, author; Miller, Benjamin F., advisor; Pagliassotti, Michael J., committee member; Hamilton, Karyn L., committee member; Chicco, Adam J., committee member; Hickey, Matthew S., committee memberSkeletal muscle protein turnover is determined by the synthesis and degradation of skeletal muscle proteins and is the mechanism that determines skeletal muscle protein content. A loss of skeletal muscle mass and function occurs during aging (sarcopenia) due to a net imbalance between synthesis and degradation pathways. Mitochondrial protein turnover, a component of skeletal muscle protein turnover, is decreased with aging. A decline in mitochondrial protein turnover and subsequent decline in mitochondrial function is associated with the progression of chronic diseases associated with aging. Aging populations are commonly prescribed medications to combat age-related chronic diseases. Among commonly prescribed medications are β-adrenergic receptor blockers as anti-hypertensive therapy. Decreased β-adrenergic signaling may impair skeletal muscle adaptations to exercise, particular the mitochondrial fraction, and potentially diminish the benefits of exercise training on skeletal muscle protein synthesis. The regulation of post-exercise mitochondrial protein synthesis by β-adrenergic receptor signaling is not well known in humans. Protein consumption following exercise induces net synthesis of skeletal muscle proteins in younger populations, however the effect appears to be blunted with aging and likely lead to sarcopenia. The net positive protein synthesis following exercise with protein feeding occurs for several hours and may be effective therapy for age-related declines in skeletal muscle mass, yet it is not known whether these short increases will persist over longer periods. The overall objective of our three projects was to investigate the regulation of skeletal muscle protein synthesis in response to exercise, protein consumption, and β-adrenergic signaling in humans. We tested the hypothesis that β-adrenergic signals can regulate mitochondrial biogenesis by examining non-selective β-adrenergic stimulation during resting conditions (Experiment #1) and non-selective β-adrenergic blockade during aerobic exercise (Experiment #2). Furthermore, we tested the hypothesis that protein consumption following exercise can promote skeletal muscle protein synthesis over several weeks of aerobic training (Experiment #3). We used stable isotopic methods to determine rates of skeletal muscle protein synthesis including analysis of the mitochondrial fraction as a measure of mitochondrial biogenesis. Additional measures of mitochondrial biogenesis included mitochondrial DNA content and mRNA content of signaling pathways for mitochondrial adaptations. Deuterium labeling over several weeks was used to measure the synthetic rates of skeletal muscle proteins and DNA during aerobic training. Experiment #1 involved examining the short-term response of skeletal muscle protein synthesis and mitochondrial biogenesis following infusion of a non-selective β-adrenergic agonist. We found that non-selective β-adrenergic activation did not increase skeletal muscle synthesis, whole body protein turnover, or measures of mitochondrial biogenesis. Experiment #2 included investigation of the short-term response of skeletal muscle protein synthesis following infusion of a non-selective β-adrenergic antagonist during a one-hour bout of cycling. Mitochondrial protein fractional synthesis rates were decreased following cycling with non-selective β-adrenergic blockade, yet signals for mitochondrial biogenesis were not different compared to a saline control infusion. Experiment #3 included evaluating the ability for post-exercise protein consumption during aerobic training to stimulate long-term measures of multiple skeletal muscle synthetic processes. We determined that consuming protein compared to carbohydrates after exercise did not lead to differences in protein synthesis or mitochondrial DNA content over several weeks. Interestingly, we measured the amount of newly synthesized DNA in skeletal muscle to be ~5%. Skeletal muscle does not undergo regular cell division, therefore the DNA synthesis was higher than expected. It is likely that the DNA synthesis is due to satellite cell activation. We conclude that β-adrenergic signaling during exercise is a signal for mitochondrial protein synthesis in skeletal muscle. Additionally, the ability for protein consumption following exercise to increase protein synthesis over several hours does not lead to long-term increases in protein synthesis. Collectively, these results provide insight into the regulation of skeletal muscle protein turnover with exercise and β-adrenergic signaling. Understanding potential negative drug and exercise interactions can help improve future therapeutic recommendations for healthy aging.Item Open Access Targeting skeletal muscle mitochondrial function with a Nrf2 activator in a novel model of musculoskeletal decline(Colorado State University. Libraries, 2020) Musci, Robert Vincent, author; Hamilton, Karyn L., advisor; Hickey, Matthew S., committee member; Lark, Daniel S., committee member; Santangelo, Kelly S., committee memberThis dissertation describes a series of three experiments with an overall objective to understand how targeting mitochondrial function with a phytochemical Nrf2 activator can prevent the onset of or mitigate the progression of mitochondrial dysfunction and sarcopenia in a novel model of musculoskeletal aging. The specific aims of the three experiments were to 1) characterize the age-related changes in skeletal muscle in Dunkin-Hartley guinea pigs; 2) assess the effect of Nrf2 activator treatment on skeletal muscle energetics by measuring mitochondrial function; and 3) determine how Nrf2 activator treatment influences components of skeletal muscle proteostasis. Dunkin-Hartley guinea pigs exhibit several characteristics reflective of human musculoskeletal aging including a decline in the proportion of type II muscle fibers, a shift towards a smaller myofiber size distribution, and a decline in muscle density in the gastrocnemius, as well as a decline in protein synthesis in both the soleus and gastrocnemius. In the second experiment, Nrf2 activator treatment improved mitochondrial respiration in both 5- and 15-month-old male and female guinea pigs. Moreover, Nrf2 activator treatment attenuated the age-related decline in mitochondrial respiration. In the third experiment, Nrf2 activator treatment attenuated the age-related decline in protein synthesis in Dunkin-Hartley guinea pigs. Altogether, these data demonstrate 1) Dunkin-Hartley guinea pigs experience age-related changes in skeletal muscle consistent with the aged musculoskeletal phenotype in humans 2) this phytochemical Nrf2 activator can improve mitochondrial function and 3) targeting mitochondrial dysfunction is an efficacious intervention to mitigate age-related declines in components of proteostasis in skeletal muscle and improve overall musculoskeletal function.