Theses and Dissertations
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Item Open Access Associations between white matter micro- and macrostructural integrity, neurophysiology, and motor function in people with multiple sclerosis(Colorado State University. Libraries, 2025) Patrick, Christopher Michael, author; Fling, Brett W., advisor; Clapp, Tod R., committee member; LaRocca, Thomas J., committee member; Tracy, Brian L., committee memberMovement is one of the most fundamental expressions of brain function. From "simple" movements like reaching and walking to the most complex aerial gymnastic stunts, voluntary movement emerges from the seamless integration of sensory input, motor planning, and execution. Such integration relies on a symphony of widespread, dynamic communication across cortical, subcortical, brainstem, and spinal regions orchestrated to produce smooth, purposeful movement. In this way, the brain does not merely support movement, it is shaped by and for it. However, when the integrity of these neural systems is disrupted, as in neurodegenerative conditions like multiple sclerosis (MS), the consequences can be life altering, leading to impaired mobility, loss of independence, and diminished quality of life. MS is a chronic disease of the central nervous system (CNS) that results in neural injury, impairing communication within neural networks. Damage to neurons and their connections gives rise to a range of heterogeneous symptoms, among which challenges with balance and mobility are among the most common and impactful. Understanding how MS-related damage to the CNS contributes to functional impairment requires tools that can capture different aspects of neural integrity and motor performance. This dissertation integrates biomechanical, neurophysiological, and neuroimaging approaches to characterize the state of the CNS in people with MS and to link these metrics to real-world movement abilities. Using biomechanical techniques, the first study found that individuals with MS control their bodyweight differently during a sit-to-stand transfer movement, producing less force and power than neurotypical controls, with power helping to distinguish fallers from non-fallers. Building on this, the second study examined corticospinal integrity using neurophysiological measures, finding that altered excitability and prolonged conduction were associated with reduced force during both isolated muscle contractions and a sit-to-stand transfer movement, linking corticospinal function to movement performance. The third study used advanced neuroimaging techniques, including diffusion tensor imaging, diffusion kurtosis imaging, and fixel-based analysis, to assess corticospinal tract integrity in people with MS, revealing white matter alterations throughout the corticospinal tract. Among these methods, fixel-based metrics demonstrated the strongest associations with clinical measures of balance, disability, and neurophysiological outcomes. Finally, recognizing that the corticospinal tract is not the sole motor pathway, the fourth study examined the corticoreticulospinal tract and found that fiber density in this pathway correlates with balance and walking performance in people with MS. Together, these studies illustrate the complex ways in which neural damage in MS disrupts the intricate networks essential for effective movement. By employing a multimodal approach, this work enhances understanding of how structural and functional changes across multiple motor pathways contribute to motor function. These insights may help inform future efforts to assess and manage mobility impairments in people with MS.Item Embargo The time course of the therapeutic influence of a single exercise bout on cancer-related fatigue(Colorado State University. Libraries, 2025) Gomes, Emma, author; Leach, Heather, advisor; Marker, Ryan, committee member; Bell, Christopher, committee member; Aichele, Stephen, committee memberIntroduction: Cancer-related fatigue (CRF) is a critical outcome for cancer survivors due to its high prevalence, impact on activities of daily living (ADLs), and quality of life (QOL). Non-pharmacological interventions, such as chronic exercise interventions, are a promising intervention target to improve CRF. However, the effect of these interventions is often only studied at the baseline and post-intervention period; therefore, it does not capture the dynamic nature of how CRF may change daily and even weekly within those intervention periods. Studying these within-day and weekly changes may have important implications on exercise motivation, especially when cancer survivors are experiencing severe CRF. Exploring these effects may lead to improved long-term exercise adherence in cancer survivors. To fill in the gap of how exercise affects CRF daily during a 12-week exercise program, additional research must be conducted to explore the acute effects of exercise on CRF and how factors such as exercise intensity may have a role in the impact of change. Therefore, the purpose of this dissertation is to (1) examine changes in CRF from immediately before to immediately after exercise sessions during an exercise program for cancer survivors, (2) changes in CRF up to 7-hours following a single-bout of exercise on an exercise and non-exercise day, and (3) how self-selected exercise intensity impacts CRF immediately following, and after up to 7-hours after an exercise session. Methods: An observational, longitudinal cohort study of (n=25) cancer survivors was conducted to study within-day trends of CRF. Participants (for all studies) completed a 12-week exercise program in an outpatient cancer rehabilitation program. Exercise classes were held twice per week, and participants were assigned to a set day and time. CRF was assessed using a visual analog scale (0=no fatigue–10=worst fatigue), before, and immediately after exercise; and 1-, 4-, & 7- hours following one exercise class per week and at the same times the following day on one non-exercise day per week via a phone application, ExpiWell. Finally, heart rate and rate of perceived exertion were collected once a week to capture participants' self-selected exercise intensity for each given session. Demographics were calculated using mean ± standard deviation or frequencies (%). Mixed effects models with random and fixed effects were used to evaluate CRF immediately after exercise and over the course of the day. Statistical significance for all studies was set at p<.05. Results: This work examined changes in CRF from immediately before to immediately after exercise sessions. Overall, it did not demonstrate acute effects of exercise on CRF, and there was no difference in the magnitude of CRF change from week to week. When assessing CRF at hour 1-, 4 and 7-hours post exercise, findings revealed that on exercise days, CRF demonstrated a positive significant slope for CRF from immediately post-exercise through 1, -4, and -7 hours, with CRF levels remaining stable at 1- and 4-hours compared to post exercise before rising significantly by the 7-hour timepoint compared to post-exercise. On non-exercise days, CRF demonstrated a positive significant slope for CRF from the 1-hour timepoint through 4, and -7 hours; however, CRF levels at each timepoint (4 and 7 hours) were not significantly different than the 1-hour timepoint. Notably, comparisons between exercise and non-exercise days revealed no significant differences in CRF slopes, suggesting that CRF tends to follow a similar trend during the day, independent of exercising. Conclusion: CRF did not significantly decrease following a single session of exercise, nor did categorizing exercise sessions by intensity level reveal differences in CRF outcomes. Across the course of the exercise day, CRF gradually increased, peaking at hour 7. Interestingly, this pattern was also observed on non-exercise days. However, the reported CRF remained below a moderate threshold, suggesting that while exercise did not alleviate CRF, it also did not lead to a statistically significant increase in CRF during or after the sessions. The findings presented in this dissertation offer a vital perspective on the acute effects of a single bout of exercise on CRF. Future research should conduct randomized controlled trials that will aim to establish a causal relationship between exercise and immediate reductions in CRF, while allowing for consideration of several key CRF moderators. In addition, future studies should include the collection of biomarkers that examine the underlying physiologic mechanisms of the change in CRF immediately following a bout of exercise and over the course of a day.Item Open Access Mechanisms of transposable element transcript dysregulation in brain aging and Alzheimers disease(Colorado State University. Libraries, 2025) McEntee, Cali Madison, author; LaRocca, Thomas J., advisor; Lark, Daniel S., committee member; Moreno, Julei A., committee member; Tjalkens, Ronald B,, committee memberTransposable element (TE) transcript accumulation may significantly contribute to neuroinflammation in brain aging and Alzheimer's disease; however, the mechanisms underlying TE dysregulation in this context have not been well characterized. The studies in this dissertation investigate two possible causes of TE dysregulation: 1) reduced expression and/or activity of the adenosine deaminase acting on RNA 1 (ADAR1) enzyme; and 2) increased chromatin accessibility in repressed regions of the genome. Guided by my mentoring team, I investigated these hypotheses in various experimental models and datasets throughout four studies. First, I examined changes in inflammatory signaling and TE transcript expression with ADAR1 suppression in primary human astrocytes. Second, I attempted to upregulate ADAR1 in the brains of older mice to prevent age-related cognitive decline and neuroinflammation. Third, I identified TE transcripts that form double-stranded RNA in the absence of ADAR1, and those that are most likely to stimulate inflammation, through cell culture experiments and RNA immunoprecipitation analyses. Finally, I analyzed cell-type-specific changes in TE transcript expression and chromatin accessibility in Alzheimer's disease using prefrontal cortex single-nucleus RNA-seq data. These studies also addressed the potential pro-inflammatory signaling pathways activated by TE transcripts, potentially driving neuroinflammation with brain aging and Alzheimer's disease. In summary, this work may serve as a foundation for future studies examining mechanisms of TE transcript dysregulation, and it suggests potential therapeutic targets to modulate their expression.Item Open Access Locomotor adaptation in people with multiple sclerosis: mechanisms and neuromodulation(Colorado State University. Libraries, 2025) Hagen, Andrew Carter, author; Fling, Brett W., advisor; Mañago, Mark M., committee member; Reiser, Raoul F., committee member; Schmid, Arlene A., committee member; Stephens, Jaclyn A., committee memberLocomotor adaptation on a split-belt treadmill is a popular motor learning technique where two independent treadmill belts move at different speeds, generating adaptation of stepping over time. Much is understood about the dynamics and neural control of this adaptation, but large questions remain about its long-term retention and applicability beyond controlled laboratory settings. In this dissertation, locomotor adaptability was assessed in people with multiple sclerosis (PwMS), a population with pronounced sensory impairments. This investigation was among the first to show that despite disrupted neural communication, PwMS maintained the ability to adapt their stepping in space and in time in response to the split-belt treadmill. Following, a biomechanical assessment found that for PwMS, increased propulsive force was the largest kinetic contributor to adaptation and was strongly linked to decreased dorsiflexion, indicating that ankle joint dynamics drive much of the observed stepping changes. To address sensory impairments in PwMS, the next study evaluated the use of transcutaneous electrical nerve stimulation (TENS), a neuromodulation method that increases afferent excitability and has been used to improve motor coordination. However, TENS has yet to be investigated in the context of motor learning. This work demonstrated that TENS improved the retention of locomotor adaptation in PwMS after four weeks and decreased cortical activation in both PwMS and healthy controls. These findings suggest that TENS facilitates the recall of motor memories and promotes the automaticity of motor learning, giving it potential as an additional tool to enhance rehabilitation effectiveness in PwMS.Item Open Access Skeletal muscle derived CD81+ extracellular vesicles as a potential therapeutic for insulin resistance in adipocytes(Colorado State University. Libraries, 2025) Easterday, Darby, author; Lark, Dan, advisor; LaRocca, Tom, committee member; Gentile, Chris, committee memberObesity and its related metabolic disorders, including insulin resistance (IR), represent a growing public health crisis, with 50% of the U.S. population projected to have obesity by 2030 and an estimated $173 billion cost to the U.S. healthcare system currently. While skeletal muscle and adipose tissue are central to insulin-stimulated glucose disposal, current therapeutic strategies for IR like exercise, pharmacological agents, and bariatric surgery are limited by adherence, accessibility, and a lack of targeted mechanisms. One emerging area of interest in novel therapeutics is the role of extracellular vesicles (EVs), lipid-bound particles released by all cell types that carry bioactive cargo and influence recipient cell behavior. CD81, a tetraspanin protein highly enriched in EVs, plays a structural role in membrane signaling domains and is increasingly implicated as a mediator of insulin sensitivity and adipose tissue homeostasis. Many studies have shown that CD81-expressing EVs are released from skeletal muscle (SkM) and may be capable of modulating metabolic signaling in distal tissues, like adipose tissue. The purpose of the present study was to investigate the functional impact of skeletal muscle-derived CD81+ EVs on adipocyte insulin signaling (Figure 1). Specifically, these studies aimed to determine whether CD81 physically interacts with insulin signaling machinery, whether loss of CD81 impairs insulin sensitivity, and whether delivery of CD81 via SkM-derived EVs could restore insulin action in adipocytes. Using 3T3L1 preadipocytes, we demonstrate that CD81 co-immunoprecipitates with phosphorylated Akt (pAkt), suggesting a physical interaction between CD81 and insulin signaling machinery. While silencing CD81 did not significantly impair insulin signaling, a modest trend toward reduced pAkt suggests a potential role. Notably, treatment with SkM-derived CD81+ EVs successfully restored CD81 content in CD81-silenced cells, confirming that CD81 can be delivered to adipocytes via EVs, but failed to significantly enhance insulin-stimulated pAkt signaling. Taken together, these data provide the first evidence that CD81 physically associates with pAkt in preadipocytes and suggest that CD81+ EVs, isolated by magnetically labelled immunocapture, may modulate membrane protein content without strongly altering downstream signaling under the tested conditions. This work contributes to establishing a framework for exploring skeletal muscle-derived CD81+ EVs as a potential tissue-specific therapy for insulin resistance and metabolic dysfunction.Item Open Access Examining cancer-related fatigue through FITT principles of exercise: a cross-sectional analysis of cancer wellness program baseline data(Colorado State University. Libraries, 2025) Dawson, Jacob, author; Leach, Heather, advisor; Marker, Ryan, committee member; Eilertson, Kirsten, committee memberBackground: Cancer-related fatigue (CRF) is a distressing and prevalent symptom with limited treatment options. While exercise is the most effective treatment for CRF, more evidence is needed to recommend individualized prescription to meet the complex needs of those experiencing fatigue. Moreover, literature on CRF's subdomains is sparse, and no framework exists to target physical or cognitive dimensions. Therefore, the purpose of this study was to examine how exercise frequency, intensity, time, and type (FITT) are related to general, physical, and cognitive CRF. Methods: Retrospective, secondary analysis of baseline data from individuals with a cancer diagnosis enrolled in a clinical exercise program. Exercise was self-reported using the Godin-Leisure-Time Exercise Questionnaire. CRF was self-reported using the FACIT-F for general fatigue, and QLQ-FA12 for fatigue subdomains. Univariate associations between exercise volume, frequency, and time were assessed using Pearson correlations. Group mean differences were compared using two sample t-tests and supplemented with effect sizes. Post-hoc regression analyses were performed to control for exercise volume. Results: Higher reported exercise volume, time, and frequency were all significantly associated with lower general fatigue (p <0.05). Only exercise volume had a significant association with physical fatigue (p <.05); no significant associations were observed for cognitive fatigue. Those who reported moderate-to-vigorous intensity exercise reported lower fatigue across all measures when compared to those who reported light intensity only, but differences were not statistically significant. Those who reported combined aerobic and resistance training on average reported lower fatigue across all measures, but only differences in physical fatigue were significant. After controlling for volume, no significant differences in general fatigue or subdomains were found by exercise intensity or type. Conclusion: Individuals looking to reduce general and physical cancer-related fatigue may benefit from exercising according to preference, prioritizing a combination of FITT principles that promote greater volumes of exercise, as fatigue-specific benefits do not appear to differ across intensity and type. Prospective studies are needed to investigate the impact of specific FITT prescriptions on cognitive fatigue before exercise can be recommended as a viable treatment.Item Open Access Evaluation of cytosolic DNA synthesis rates as a potential driver of musculoskeletal aging in the Hartley guinea pig(Colorado State University. Libraries, 2025) Barragan, Martin Alexander, author; Hamilton, Karyn L., advisor; LaRocca, Thomas J., committee member; Santangelo, Kelly S., committee memberAdvancing age is the greatest risk factor for many chronic diseases and, by 2035, the number of U.S. citizens over the age of 65 will exceed the number under the age of 18 for the first time in history. Inflammaging, systemic aging associated low grade chronic inflammation, is a contributing factor to age-related chronic disease in multiple tissue types and organ systems, including the musculoskeletal system. Age-related musculoskeletal decline is characterized by diseases such as sarcopenia and osteoarthritis and has a strong correlation with an increase in all-cause mortality. While markers of inflammation are present in circulation, key drivers of inflammation that propagate age-related musculoskeletal decline are not well established. However, DNA that resides misplaced in the cytosol (cytoDNA) is a potent activator of the cGAS-STING pathway, an innate immune response that drives inflammation and disrupts cell function. While cytoDNA and the cGAS-STING pathway have been linked to increased inflammation in a host of tissues and disease states, very little evidence supports its role in skeletal muscle aging. Hartley guinea pigs (HGPs) are a translational, non-transgenic model of spontaneous musculoskeletal decline known to develop systemic inflammation and progressive age-related comorbidities characteristic of human aging. To begin establishing if cytoDNA contributes to age-related musculoskeletal decline, we assessed age-related differences in rates of newly synthesized cytoDNA in the tibialis anterior (TA), a locomotor muscle susceptible to age-related decline, from male and female 5- and 15-month-old (mo) HGPs. To assess this, we used stable isotope labeling with deuterium oxide, a sensitive approach for measuring rates of DNA synthesis in vivo. Although our primary findings showed that overall rates of cytoDNA synthesis did not increase with age or differ between sexes, we did identify a species of cytoDNA for which synthesis decreased with age, suggesting that the relationship between cytoDNA synthesis and aging is more complex than initially anticipated.Item Open Access Countermeasures to the cardiometabolic impairments associated with sleep and circadian disruption(Colorado State University. Libraries, 2024) Seward, Sophie Lynn, author; Broussard, Josiane L., advisor; Blankenship, Jennifer M., committee member; Foster, Michelle T., committee member; Moreau, Kerrie L., committee memberSleep and circadian disruption are widespread and have both been recognized as independent risk factors for cardiometabolic diseases, including cardiovascular disease and type 2 diabetes. Circadian misalignment, defined as a mismatch between the endogenous circadian system and external behavioral/environmental factors such as sleep, energy intake, activity and light, is one mechanism suggested to increase the risk of cardiometabolic disease risk during combined sleep and circadian disruption. In some populations, such as night shift workers, sleep and circadian disruption are often unavoidable and lead to an increased risk for cardiovascular disease and type 2 diabetes. Therefore, strategies are needed to mitigate the negative impact of sleep and circadian disruption on cardiometabolic disease risk. The following dissertation is comprised of a series of experiments with the overall aims to (1) examine the acute cardiometabolic impairments associated with sleep and circadian disruption; and (2) investigate a potential countermeasure to mitigate cardiometabolic impairments when sleep and circadian disruption are unavoidable. Several study designs were employed to address the aims of this dissertation. In the first investigation, a quasi-randomized crossover study was conducted in a free-living setting to compare blood pressure in adults during a 24h period during both a day shift versus a night shift. Because elevated blood pressure is an important CVD risk factor, throughout this study blood pressure was measured every 30 minutes to assess 24h, waking, and sleeping levels. In the second study, a 2-week consecutive design experiment was conducted in healthy adults to examine the impact of altered meal timing on cardiometabolic health. During Week 1, participants consumed energy over a 13h period with meals individually anchored to habitual wake time. In week 2, participants matched their food intake from week 1 but restricted intake to an 8h period. At the end of each week, participants were admitted to the laboratory for an in-patient overnight stay where hourly blood samples were collected and assayed for circulating factors including glucose, insulin, and lipid species. This alteration in meal timing was then employed in another study where participants underwent a simulated nightshift work protocol. In this study, participants underwent a 6d randomized crossover inpatient study with at least 1 month between conditions. In one condition, participants ate during the biological night as typically done during night shift work (circadian misalignment). In the other condition, participants consolidated meals to the biological daytime (circadian misalignment + time restricted eating), while still providing the same sleep opportunity and diet. Consolidating food intake to the biological daytime, particularly in night shift work, was hypothesized to reduce the risk of cardiometabolic disease by reducing the mismatch between the endogenous circadian system and external behaviors. Major themes emerging from these studies are that as little as one night of shift work in a free-living setting is sufficient to induce multiple CVD risk factors including increased BP and reduced sleep duration in healthy adults. Furthermore, data presented throughout this dissertation suggest daytime eating during sleep and circadian disruption, within a highly controlled laboratory setting, improves important markers of cardiometabolic health including blood pressure. Data presented here indicates that meal timing interventions may be a potential countermeasure to improve cardiometabolic health in conditions of circadian disruption. However, more research is needed in a free-living shift work population. Additionally, future research should explore how other countermeasures may improve cardiometabolic health when sleep and circadian disruption are unavoidable. Overall, work presented throughout this dissertation underscores the urgent need for effective strategies to mitigate cardiometabolic risks associated with sleep and circadian disruption, especially in vulnerable populations such as night shift workers.Item Embargo Countermeasures to metabolic impairment during circadian misalignment(Colorado State University. Libraries, 2024) Lowry, Catherine, author; Broussard, Josiane, advisor; Fling, Brett, advisor; DuBose, Lyndsey, committee member; Johnson, Sarah, committee memberPeople who work evening, night or rotating shifts (i.e. "nonstandard" work hours) represent one in five U.S. employees and are at a 44% increased risk for developing Type 2 diabetes (T2D) compared to people who work standard day shifts. Shift workers experience acute, repeated bouts of misalignment between their endogenous circadian system and external behavior/environmental factors such as sleep, energy intake, activity, and light. Circadian misalignment is one mechanism suggested to increases the risk of T2D in shift-working populations. To date, there have been limited attempts at identifying strategies or countermeasures to prevent the impact of such circadian misalignment on T2D risk in a sizeable proportion of the population. The following thesis aims to test a nutritional countermeasure known as time-restricted eating (TRE). TRE has previously shown metabolic benefits in people with obesity. The overall aims of the two studies compiled within this thesis are to determine the impact of TRE on (1) circulating and muscle lipid accumulation and (2) insulin sensitivity and glycemic homeostasis. Both studies follow a randomized crossover design with a rigorous inpatient diet-, activity and light-controlled protocol in 32 healthy men and women. In these studies, participants underwent a 6d randomized crossover inpatient study with at least 1 month between conditions. In one condition, participants ate during the biological night as typically done during night shift work (circadian misalignment). In the other condition, participants consumed meals only in the biological daytime (circadian misalignment + time restricted eating), while keeping sleep times and diet consistent. Consolidating food intake to the biological daytime, particularly in night shift work, was hypothesized to reduce the risk of T2D by reducing the mismatch between the endogenous circadian system and external behaviors. Findings from this study represent a critical advancement in the fields of translational circadian and metabolic physiology by identifying and testing a countermeasure to circadian misalignment. Achievement of our proposed aims could lead to the development of new intervention strategies for chronic disease prevention and management. The knowledge to be gained offers the potential to support cost-effective programs that may inform our healthcare approach to metabolic disease prevention in populations at risk for these diseases such as shift workers, individuals with sleep disorders and anyone who eats outside of daytime hours.Item Open Access Development and evaluation of physical and mental readiness training programs for Army Reserve officer training cadets(Colorado State University. Libraries, 2024) Newman, Alissa A., author; Nelson, Tracy, advisor; Braun, Barry, advisor; Graham, Daniel, committee member; Cooper, K. Bradford, committee memberMilitary personnel face myriad stressors in both the combat and training environments, including the singular and combined effects of physical exertion, cognitive overload, sleep restriction, energy insufficiency, ambiguous operational environments, as well as emotional and psychological stress. Though the demands of modern military operations continue to shift with technological advances, humans remain the central element and to be successful in the volatile and uncertain modern operating environments, high levels of both physical and psychological readiness and resilience are required. As failure to meet these demands can have catastrophic consequences, the military has placed a high emphasis on the development of physical and mental fitness, with each branch developing their own programs and initiatives. In 2019, the Army introduced its Holistic Health and Fitness (H2F) system, with the aim of improving individual warfighter health and wellbeing as well as overall operational readiness. While H2F is a step in the right direction for the Army as a whole, non-Active-Duty components may have difficulty implementing the system. Reserve Officer Training Corps (ROTC) programs often have limited access to the space, time, equipment, and expertise needed to optimally promote physical and mental readiness. ROTC cadets will commission as officers upon their graduation, will serve in leadership roles, and will be expected to perform at a high level both physically and mentally. Importantly, ROTC programs produce approximately 70% of the officers entering the Army each year and their preparedness, or lack thereof, has substantial impact on those they lead. The feasibility of delivering physical and mental readiness training programs in real-time within the Army ROTC environment and under the time and resource constraints is unclear. One possible mechanism for implementing readiness training in ROTC programs is through collaboration with university partners. By developing cross-campus collaborations, ROTC programs can access necessary resources, especially fitness programing, supervision, and support, to bolster readiness and prepare cadets for success as future Officers. The purpose of this dissertation is to explore the development and implementation of physical and mental readiness training programs in an Army ROTC program, specifically through a collaborative effort between Colorado State University's Health and Exercise Science Department and Army ROTC programs. Study 1 evaluated two training programs designed to improve ACFT performance. The first was an adaptation of programs from Army Training Publication 7-22: Holistic Health and Fitness (ATP 7-22) and the other was designed by HES staff. HES staff, including a Certified Strength and Conditioning Coach and undergraduate practicum students, supervised all physical training sessions alongside Army ROTC cadre. While we saw no significant differences between groups, we found a statistically significant improvement in ACFT scores in our collective study cohort. We faced several challenges over the course of the study period, including a global pandemic and severe weather that impacted and cancelled training sessions. Despite this, we showed that it is feasible to provide effective, multidimensional physical training with limited time and equipment, even in the face of unforeseen challenges. In Study 2, we delivered an 8-week mental skills training (MST) program to first- and second-year Army ROTC cadets. Our qualitative findings suggest that the intervention was impactful and that the participants were able to learn and apply the skills taught during the intervention in physical training and academic settings, as well as during their ROTC training. While we did not find any statistically significant performance outcomes, the results of this study demonstrate a positive impact of MST in this population and provide support for the integration of increased MST into the ROTC curriculum. Collectively, these studies show the impact of both physical and mental readiness training interventions in ROTC cadets. Perhaps more importantly, these studies demonstrate the feasibility of conducting such programs in real time, even with limited time and resources, as well as the capacity for a partnership between ROTC and other university academic departments. We believe that this collaboration is a successful model for the integration of H2F into ROTC programs and could be an effective solution to the challenges faced in delivering comprehensive readiness programming to ROTC cadets.Item Open Access Reasons for joining and adhering to a community-based fitness program among middle-aged and older adults(Colorado State University. Libraries, 2024) Kirksey, Zoe, author; Leach, Heather, advisor; Burke, Kimberly, committee member; Brothers, Allyson, committee memberPurpose: Community-based fitness (CBF) programs address common barriers to physical activity (PA) participation for middle-aged and older adults and can help to increase regular PA. However, engagement in CBF programs among middle-aged and older adults is suboptimal, and those who do join tend to not adhere long-term. This study examined reasons for joining and adhering to a CBF program and explore common characteristics among long-term members. Methods: Observational, cross-sectional cohort study. Participants were monthly paying members of Adult Fitness, a CBF program at Colorado State University. Participants completed a 24-question quantitative survey, and monthly membership length was determined from participant records. To determine reasons for joining and adhering to Adult Fitness, two 5-point Likert scale questions, on a scale from 1(not motivated at all) to 5 (extremely motivated) were used. The response options were the same and consisted of unique aspects of Adult Fitness and replicated responses from a previous study. Frequency statistics were run on both questions and "motivated a great deal" and "extremely motivated" percentages were summed to determine most prevalent reasons for joining and most prevalent reasons for adhering. Long-term adhering members were defined as having a membership length of ≥5 years, and common characteristics were determined by a response that had more than a 50% response rate. Frequency statistics were run on survey questions to determine common characteristics. Results: The survey was distributed to N=151 members, and N=95 returned, for a response rate of 62%. There were n=8 duplicate and incomplete surveys, leaving a total of N=88 surveys included in analyses. Respondents were 70.5% older adults, 65+, 26.1% middle-aged adults, 35-64, and 3.4% young adults 18-34. Respondents were 50% female, and 50% male and average membership length was 132 months, 11 years (SD=142.8 months; range=563 months). For aim 1, the most frequently reported reasons for joining the Adult Fitness program were facilities available which 79.3% selected "motivated a great deal" or "extremely motivated", followed by self-initiated search for an activity program, 74.7%, and low cost, 60%. Most frequently reported reasons for adhering, were self-initiated desire to promote fitness and/or overall health, 95.4%, facilities available, 80.4%, and low cost, 60%. For aim 2, long-term adhering members (N=58) were motivated to join due to facilities available or self-initiated search for an activity program, motivated to adhere due to self-initiated desire to promote fitness and/or overall health, facilities available, and low cost, reported their current physical as either "good" or "very good", selected either "improvement of health" or "help me stay active" as their most perceived benefit of participating in Adult Fitness, attended the program on average of 3-days a week, and participated in 21-60 min of physical activity (PA) outside of Adult Fitness per day. Conclusion and Clinical Implications: The current study offers valuable insight to CBF program staff and organizational leaders. Understanding motivators of joining and adhering to CBF programs can contribute to tailoring these programs to increase membership and promote long-term participation/membership. These strategies may include offering competitive pricing, adding to existing facilities to cater to interest or needs of members and providing educational resources and progress tracking tools to keep members informed of their health status and/or improvement. Future studies are needed to better understand reasons for discontinuing CBF program.Item Open Access Characterization of the Dunkin Hartley guinea pig as a non-transgenic and multimorbid model of brain aging(Colorado State University. Libraries, 2024) Glennie, Kristen Skye, author; Hamilton, Karyn L., advisor; Moreno, Julie A., advisor; LaRocca, Thomas J., committee member; Santangelo, Kelly S., committee memberAlzheimer's Disease and Alzheimer's Disease Related Dementia (AD/ADRD) affect an estimated 55 million people worldwide; a staggering figure that is expected to grow in the coming years. With this projection looming, we have yet to identify any effective cures, treatments, or preventative strategies. Historically, AD/ADRD research is conducted using genetically engineered pre-clinical models, that express a specific brain aging pathology. Recent discoveries, however, have identified a dynamic whole-body "inflammaging" phenotype that exists with, and likely contributes to, AD/ADRD onset and progression. Currently, we do not have an accessible and tractable preclinical model that naturally mimics the age-related, systemic and progressive neurodegenerative phenotype present in humans. Recent findings, however, suggest the Dunkin Hartley guinea pig (HGP) may address this need. HGPs are known to develop systemic inflammation and progressive age-related comorbidities characteristic of human aging. The presence of this whole-body aging phenotype prompted investigation into the brain. Genetic and transcriptomic analyses found aged HGPs exhibit strong sequence homology, and similar protein expression patterns to human brain aging and AD. Further, immunohistochemical assessment found aged HGPs express markers of neuroinflammation and misfolded proteins in the hippocampus. To further interrogate these novel findings, we examined the histopathology of 4 brain regions often implicated in neurodegenerative decline for evidence of progressive neuropathology. Our results identify the presence of an age related neuroinflammatory and phosphorylated tau phenotype. Findings from this study contribute to the overarching hypothesis that AD/ADRD is a whole-body disease, and ultimately support the goal of closing the existing translational gap between preclinical and clinical neurodegenerative research.Item Open Access Association between youth involvement in home/community gardening and health behaviors(Colorado State University. Libraries, 2024) Perrault, Ashley, author; Li, Kaigang, advisor; Butki, Brian, committee member; Braungart-Rieker, Julia, committee memberAmerican youth are developing risk factors for historically "adult diseases" at increasingly high rates. These risk factors, such as obesity, elevated blood lipid, blood pressure and insulin resistance, put children at a high risk for developing chronic disease early in life, including before reaching adulthood. School gardening programs are effective at improving dietary intake, physical activity levels and BMI of youth. Despite the success of such programs, there is a need for interventions that effectively target child behaviors while at home. Family-based home and/or community gardens may promote child health behaviors similar to those that occur in school-based gardening programs. A home and/or community garden has the added benefit of parental involvement, which has been shown to be essential for effective child health interventions. The current study examined the relationship between youth involvement in a home and/or community garden and various health behaviors. A convenience sample of 124 adults participated in a cross-sectional survey from June – October 2023. Participants answered questions about family and child involvement in a home/community garden, child health behaviors and parent health behaviors. Health behaviors assessed were physical activity minutes, sedentary behavior, frequency of fruit and vegetable intake and mental health symptoms. Independent sample t-tests indicated that gardening youth had lower sedentary time (t(112) = -1.95, p = 0.03), as well as higher frequency of fruit (t(110) = 2.14, p = 0.02) and vegetable intake (t(109) = 2.67, p = 0.004). Parent fruit intake had a positive linear association with child fruit intake (β = 0.51, p = <0.001), as did parent gardening belief (β = 4.04, p = 0.01). Mediation analysis indicated a positive association between path a (gardening status and parent fruit intake: β=3.06, 95% CI: 0.08, 6.03, p = 0.04) and path b (parent fruit intake and child fruit intake: β = 0.48, 95% CI: 0.30, 0.65, p = <0.001). Gardening status was no longer associated with child fruit intake after the inclusion of parent intake (c': β = 1.64, 95% CI: -1.06, 4.35, p = 0.23), suggesting that parental fruit intake fully mediated the relationship between gardening status and child fruit intake. Gardening status had a positive linear association with child vegetable intake (β = 3.4, p = 0.02), as did parent vegetable intake (β = 0.21, p = 0.004). These findings indicate that youth involvement in a family-based home and/or community garden may be associated with positive health outcomes, especially regarding dietary intake. Parental influence was also associated with positive youth health outcomes. Our findings suggest that home and/or community gardens may provide an effective technique for child health interventions.Item Embargo Targeting proteostatic maintenance and mitochondrial function with phytochemical compounds in models of brain and skeletal muscle aging(Colorado State University. Libraries, 2024) Walsh, Maureen Ann, author; Hamilton, Karyn L., advisor; Fling, Brett W., committee member; Moreno, Julie A., committee member; LaRocca, Thomas J., committee member; Santangelo, Kelly S., committee memberThere is a growing population of older adults (>65+ years) worldwide that is projected to increase in coming decades, presenting both a challenge and an opportunity. Specifically, age is the number one risk factor for chronic diseases like sarcopenia, the loss of muscle mass and function, and neurodegenerative diseases such as Alzheimer's Disease. The twelve hallmarks of aging are a collection of cellular changes that drive the aging process. Two highly interconnected hallmarks of aging that drive the development and progression of sarcopenia and neurodegeneration are loss of proteostasis (protein homeostasis) and mitochondrial dysfunction. While progress has been made in understanding the etiology of chronic diseases, treatments for age-related chronic diseases affecting skeletal muscle and the brain are lacking. One reason for the lack of effective treatments in humans is the absence of preclinical animal models that recapitulate human aging. However, our group previously identified the Hartley guinea pig as a novel model of brain and skeletal muscle aging. We then treated these guinea pigs with a phytochemical compound to delay the onset and/or slow the progression of brain and skeletal muscle aging. Through the experiments in this dissertation, I observed that: 1.) phytochemical compounds, branded as Protandim, can improve mechanisms of proteostasis independent of changes in mitochondrial respiration in muscle precursor cells; 2.) the phytochemical compound, branded as PB125, can improve mechanisms of skeletal muscle proteostasis in the Hartley guinea pig; 3.) PB125 can also decrease neuroinflammation in the Hartley guinea pig; and 4.) despite the lack of declines in hippocampal mitochondrial respiration with age, Hartley guinea pigs exhibit decreased mitochondrial efficiency. Collectively, this dissertation builds on prior work suggesting that the Hartley guinea pig is a valuable model to test preclinical interventions.Item Open Access Neuromuscular electrical stimulation: getting amped up to prevent exercise resistance(Colorado State University. Libraries, 2024) Bomar, Matthew Charles, author; Bell, Christopher, advisor; Perry, Richard, committee member; Stephens, Jaclyn, committee memberPurpose: Exercise resistance (ER) is characterized by the absence of exercise induced improvements in fat metabolism following a meal. The prolonged sedentary behavior between successive workouts is what contributes to this lack of health improvements typically associated with exercise. The suggested energy expenditure (EE) threshold for avoiding ER is the equivalent of walking ~8,500 steps/day. Population data indicate that the typical adult walks 5,000 steps/day. Neuromuscular Electrical Stimulation (NMES) evokes skeletal muscle contractions and increases EE. This study aims to determine the feasibility of using NMES to increase total daily EE by the equivalent of 3,500 steps, thereby meeting the theoretical threshold sufficient to prevent ER. Methods: Fourteen recreationally active males and females (7/7) underwent measures of resting EE, with and without NMES, and EE while walking 8,500 steps on a treadmill. The duration of NMES sufficient to increase EE to match 3,500 steps was calculated, and then verified with measures of EE while walking 5,000 steps after a bout of NMES. Results: Bland–Altman statistics of agreement were used to assess concordance between the EE associated with walking 8,500 steps (286 ± 64 kcal; mean ± SD), and the EE associated with walking 5,000 steps after NMES (293 ± 65 kcal). The mean difference between the EE values was 7 kcal, and the 95% limits of agreement were -39 to 53 kcal. Implications: These preliminary data suggest NMES can be used to increase total daily EE by the equivalent of 3,500 steps, thereby meeting the theoretical threshold to prevent ER.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 Effect of a videoconference-delivered physical activity intervention on quality of life in colorectal cancer survivors(Colorado State University. Libraries, 2023) Prien, Lydia, author; Leach, Heather, advisor; Schmid, Arlene A., committee member; Zimmaro, Lauren A., committee memberINTRODUCTION: Colorectal cancer is the fourth most common cancer diagnosed in both men and women in the United States. For every 100 people diagnosed with colon cancer, 64 are expected to live five or more years after diagnosis. With this growing number of colorectal cancer survivors, quality of life (QOL) becomes an important patient reported outcome within this population. QOL is multidimensional and includes various dimensions of wellbeing (e.g., physical, emotional, social) that can be improved with physical activity. Previous research has established that face-to-face supervised physical activity (PA) interventions can improve QOL among colorectal cancer survivors (CRC) (Mishra et al., 2012). However, these interventions require a lot of resources, and may be difficult to access. Thus, researchers have turned to distance-based physical activity (PA) interventions (digital health tools, text messaging, prerecorded home-based workouts etc.) to increase access and scalability of PA interventions for CRC survivors. Previous studies that have examined the effect of distance-based PA interventions for improving QOL in CRC survivors did not find improvements in QOL. For example, Kim et al. (2019) found no significant improvements in QOL following an unsupervised, homebased, DVD exercise program, and Chan et al. (2022) found no significant changes in QOL, following a text messaging intervention. These finding suggest that distance-based PA interventions may not be as effective as face-to-face for improving QOL in CRC survivors and may be due to a lack of contact with other survivors and/or diminished PA adherence/compliance due to lack of supervision and instruction from an exercise professional. Since the COVID-19 pandemic, videoconference PA interventions have grown in popularity, and may be able to overcome some of the limitations of both face-to-face and distance-based PA interventions for improving QOL in CRC survivors. However, to date there are no previous studies that have examined the effect of a videoconference intervention on QOL in CRC survivors. This study will examine changes in QOL in colorectal cancer survivors following a 12-week, videoconference, PA intervention. This study will be a secondary data analysis of participants enrolled in Testing Group Activity CorrelaTes In Colorectal Cancer Survivors (TACTICS), a pilot randomized controlled trial with the primary aims of determining feasibility, and preliminary effects on physical activity. METHODS: TACTICS is a 12-week pilot randomized controlled trial where the intervention group received group-based exercise sessions 2x/week, and five behavior change discussion sessions delivered via Zoom. The control group received standard physical activity recommendations. QOL was measured at baseline and 12-weeks using the Functional Assessment of Cancer Therapy–Colorectal (FACT-C). Mean change, standard deviation, and effect size were reported to measure improvements in QOL. Established minimal clinically important differences (MCID) are a Δ5 points for total and a Δ2 points for QOL subscales. The proportion achieving MCID's in intervention vs. control were compared using Fisher's Exact tests, and independent t-tests or chi square tests explored differences in participant characteristics between those did vs. did not achieve MCID. RESULTS: Participants (n= 13 intervention, n=12 control) were mostly 56% female and M=61.2±11.7 years old. Among intervention participants, proportion who achieved MCID was 23.1% total, 15.4% physical, 38.5% functional, 23.1% social, and 15.4 % emotional, compared to 41.7% total, 33.3% physical, 25.0% functional, 41.7% social wellbeing, and 16.7% emotional among control. None of these proportions differed between groups (p>.05). For the physical QOL subscale, BMI was higher [t(11)=2.92, p=.014] and baseline scores were lower [t(7)=-2.34, p=.052] among those who achieved MCID. CONCLUSION: We observed small improvements in QOL within CRC survivors. There were no statistically significant differences in achieving clinically relevant improvements in QOL between intervention and control group participants. Larger randomized studies are needed to definitively determine if a videoconference exercise intervention can elicit clinically relevant improvements in QOL compared to a control group.Item Open Access Exploring cancer survivors' preferences for a physical activity maintenance program(Colorado State University. Libraries, 2023) Anderson, Hadalyn, author; Leach, Heather, advisor; Fruhauf, Christine, committee member; Faro, Jamie, committee memberPurpose: Physical activity (PA) offers long-term health benefits for cancer survivors (CS), if sustained. Community-based exercise programs have shown short-term effectiveness in increasing PA among cancer survivors, but evidence of their effect on long-term PA engagement (i.e., PA maintenance) is lacking. This study (1) quantitatively explored cancer survivors' preferences for a PA maintenance program and whether preferences were impacted by PA levels, and (2) qualitatively explored participants' preferences of a PA maintenance program and PA-related barriers. Methods: CS who completed one of three original cancer-specific community-based exercise programs participated in a pilot PA maintenance program (i.e., two exercise and discussion sessions). (1) Participants completed questionnaires via REDCap database to assess interest in a PA maintenance program (i.e., likelihood of attending, perceived helpfulness and enjoyment, and preferences of frequency, duration, and time until maintenance program commencement) and PA levels. Participants reported current PA levels compared to when they finished the original program (greater or same vs. lower PA levels) and completed the Godin Leisure-Time Exercise Questionnaire to determine whether they were currently meeting PA guidelines (≥150 mins/week of moderate aerobic PA + 2 days of strength training). (2) Participants also completed semi-structured focus groups via Zoom that aimed to answer the following questions regarding participants': (i) maintenance program experience, (ii) suggestions for future maintenance program implementation, (iii) perceived elements of the original program that were helpful in maintaining PA, and (iv) barriers experienced following the original program. Frequencies from (1) were calculated, and Fisher's exact tests were used to compare proportions between maintenance program preferences and participants' PA levels. Qualitative data from (2) were transcribed verbatim, coded inductively, and analyzed using thematic analysis. Themes and frequencies of references (%) were calculated. Results: (1) Participants (N=20) were M=60±13 years old, non-Hispanic White (95%), female (95%), and diagnosed with breast (50%), ovarian (20%), or other (30%) cancer. Average time since program completion was M=26.2 ± 35.7 (1-110) months. Most participants (65%) reported exercising more or the same amount since original program completion, and 35% met PA guidelines. The majority were likely to attend maintenance exercise (90%) and discussion (80%) sessions. All (100%) participants thought maintenance exercise sessions would be helpful and most (85%) for discussion sessions. There were no differences in responses based on PA levels (all p>.05). (2) Themes identified for (i) were Accountability (36%), Shared Cancer Survivor Experience (26%), Individualized Exercise Prescription (30%), and Discussion Session Content (8%); (ii) were Accountability (8.929%), Discussion Session Content (26.79%), and Discussion (19.64%) and Exercise (44.64%) Session Delivery; (iii) were Accountability (39.39%), Individualized Exercise Prescription (30.3%), and Discussion Session Content (30.3%); and (iv) were Psychological (41.38%), Physical (27.59%), and Environmental (31.03%). Conclusion: Participants had positive perceptions of the maintenance program. Future studies should measure effectiveness of a maintenance program to support PA maintenance and encompass program leader perspectives to work towards achieving pragmatic solutions to maintain PA maintenance programs within community-based settings.Item Open Access How are driving licensure status, delay in driving licensure, and driving exposure associated with alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults?(Colorado State University. Libraries, 2023) Gao, Xiang, author; Li, Kaigang, advisor; Vaca, Federico E., committee member; Sharp, Julia, committee member; DeYoung, Wendy, committee memberIndependence and mobility facilitated by driving privileges could have a major impact on alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults. Driving privileges may provide emerging adults with the ability to move more freely, and that mobility may affect their access to drugs and alcohol. It may also mean that emerging adults with driving privileges were more likely to be in environments where alcohol and drugs were available. Parents of emerging adults with driving privileges may be more involved in monitoring their child's driving activities, resulting in higher levels of parental monitoring knowledge. Emerging adults with driving privileges were more likely to report a higher level of peer alcohol and drug use because having access to a car allowed them to spend more time with their peers and engage in alcohol and drug use. On the other hand, driving privileges may have positive impacts on the health, education, and employment of emerging adults. Having the ability to travel to places of employment and educational institutions may open more opportunities and allow for greater access to resources. This could lead to improved academic and professional outcomes. Overall, driving privileges may have both positive and negative impacts on alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults. It was important to consider these trade-off impacts when considering how to best support emerging adults in their development. My dissertation explored how were driving licensure status, delay in driving licensure, and driving exposure associated with alcohol and drug use, parental monitoring knowledge, peer alcohol and drug use, and health, education, and employment of emerging adults. Data was collected from a nationally representative sample of U.S. emerging adults starting at grade 10th for a seven-year longitudinal assessment. Having driving licensure in high school, no delay in driving licensure, and higher driving exposure were associated with higher levels of alcohol and drug use, higher levels of parental monitoring knowledge, higher levels of peer alcohol and drug use, better health, higher levels of education attainment, and more working hours in emerging adulthood. My dissertation could inform policymakers and practitioners on the importance of driving privileges in promoting the well-being of emerging adults.Item Open Access Identifying novel molecular mechanisms of healthspan using multi-omics(Colorado State University. Libraries, 2023) Smith, Meghan Elizabeth, author; LaRocca, Tom, advisor; Hamilton, Karyn, committee member; Broussard, Josiane, committee member; Ehrhart, Nicole, committee memberAn important goal in research on aging is to extend healthspan, the period of life spent healthy and disease-free. Next-generation sequencing and other emerging bioinformatics technologies (e.g., RNA-seq/transcriptomics, epigenetic profiling, and proteomics) have made it possible to broadly profile potential molecular mediators of aging, and perhaps identify therapeutic targets. The studies in this dissertation focus on using transcriptomics and complementary "multi-omics" strategies to characterize novel cellular mechanisms of aging, and to determine their relevance to systemic/functional health in humans. With the guidance of my mentoring team, I completed three studies in which I identified novel mediators of healthspan-related exercise training responsiveness, age-related inflammation, and cognitive/motor function decline in middle-aged and older adults. One particularly novel focus among these studies was the role of non-coding repetitive RNAs (derived from transposable elements) in healthspan. Transposable elements have been linked to known mechanisms of aging, and this topic is reviewed at the start of this dissertation to provide perspective on their role in the context of research on aging biology. Collectively, my findings represent new ideas for targetable genes and proteins that may influence human healthspan.