In many regions worldwide, older adults now form the fastest growing portion of the population. As such, aging research has seen tremendous growth in recent years, with a focus on identifying early biomarkers of age-related disease. However, crucial to understanding age-related disease is to identify what constitutes normal brain aging, and the life-course factors associated with positive outcomes in later life. In support of this goal, the current dissertation is comprised of three manuscripts that aim to investigate the functional and structural correlates of normal aging in a sample of community-dwelling younger and older adults, from both a multimodal and multi-analysis perspective. Study 1: The first study examined how cumulative cardiovascular risk and self-reported levels of physical, social, and cognitive activity are associated with differences in hippocampal volumes in early and later adulthood. Results indicated that greater cumulative cardiovascular risk was associated with smaller hippocampal volumes across age cohorts. Moreover, a negative association found between frequency of social activities and bilateral hippocampal volumes in older adults, suggesting that social activities with a low cognitive load may not be beneficial to structural brain outcomes in older age. Study 2: This study employed novel advances in functional magnetic resonance imaging (fMRI) to study fluctuations in the blood-oxygen-level dependent (BOLD) signal in relation to age and markers of brain health. Specifically, the study examined the relationship between resting-state BOLD variability and markers of both vascular health and lifestyle activity levels. Results indicated that resting-state BOLD variability is increased in older relative to younger adults. The findings also suggest that the association between BOLD variability and lifestyle activity levels may differ depending on age. Study 3: The final study aimed to further investigate the origins of the BOLD variability signal by examining the feasibility of combining functional near infrared spectroscopy (fNIRS) with fMRI brain signal fluctuation data. In addition to providing proof of concept of combining fNIRS hemoglobin metrics with fMRI BOLD variability maps, the results of this study also indicate that the patterns of regional association between resting hemoglobin concentrations and BOLD fluctuations may vary according to age cohort. Together, the three studies comprising this dissertation illustrate the value of adopting a multimodal, life-course perspective in the study of normal aging. These findings also support increasing evidence of a relationship between the BOLD variability signal and age. Given the limitations of cross-sectional designs for demonstrating change over time, longitudinal investigations with larger sample sizes across multiple age groups are needed to further the development of public health measures aimed at promoting successful aging from early adulthood. / Graduate / 2022-12-08

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Studying older adults who are aging ‘successfully’ (i.e., avoiding disease/disability; maintaining high cognitive and physical functioning; engaging in meaningful interpersonal/social engagement) may offer insight into variables that contribute to cognitive change throughout the lifespan. Successful aging is related to levels of engagement, which may be promoted by the problem solving and reevaluation encouraged by the creative process (Fisher & Specht, 1999). Creative thinking requires the consideration of diverse concepts and strategies (e.g., generating many solutions), as well as the regulated filtering of these possibilities (e.g., neither too permissive nor too narrow when eliminating ideas; Baas, De Dreu, & Nijstad, 2011). Cognitive inhibition is necessary for goal-directed behavior, and may also promote creativity by influencing abilities such as plasticity and innovation. Performance on executive control tasks, especially those that draw on inhibition, are impacted by age. Performance on inhibitory (but not excitatory) tasks may be sensitive to arousal levels that fluctuate with circadian rhythm (synchrony effect). The current study examined performance on a variety of neuropsychological and creativity measures at two times of the day in a sample of successfully aging adults aged 70-79. Assessments of executive function, inhibition, and creativity (i.e., verbal and non-verbal divergent thinking) were administered to older adults twice, once at a time when inhibitory performance was expected to be ideal (synchronous) and another at a time when inhibitory performance was expected to be reduced (non-synchronous). We hypothesized that morning testing (synchronous) trials of inhibitory tasks would exhibit lower latency and error rates than evening testing (non-synchronous) trials; morning testing (synchronous) trials of creative potential tasks would exhibit lower fluency, flexibility, and originality scores than evening testing (non-synchronous) trials; and that Need For Cognition (NFC) scores and Information-Orientation ISI subscale scores would be positively correlated with overall (AM + PM) creativity scores (fluency, flexibility, originality). Participants were expected to demonstrate time of day effects on Stroop and TMT performance. Synchrony effects were not observed in this study. There was a significant relation between creative potential and Need for Cognition scores but not between creative potential and scores on the Information-Orientation subscale of the ISI. The current sample may have compensated with cognitive challenges such as those induced by testing time effects. These findings may suggest that a successfully-aging cohort is not impacted by synchrony effects. No previous research has used synchrony to compare aging trajectories (pathological, usual, successful) on cognitive performance. It is feasible that a successfully aging population would have significant cognitive reserve, brain reserve, or scaffolding strategies to compensate for the additional cognitive challenge of non-optimal testing time (Düzel, Schütze, Yonelinas, & Heinze, 2011; Reuter-Lorenz & Park, 2014). Indeed, a marker of successful aging is to compensate well with age-related changes and demonstrate minimal- to no- deficits in performance (Rowe & Kahn, 1997). Synchrony changes in cognitive performance may not be evident in a successfully aging population. The current study provides evidence that motivates intriguing questions about successful aging, inhibition, creativity, and time of day.

abstract: Reproductive hormones are recognized for their diverse functions beyond reproduction itself, including a vital role in brain organization, structure, and function throughout the lifespan. From puberty to reproductive senescence, the female is characterized by inherent responsiveness to hormonal cyclicity. For most women, a natural transition to menopause occurs in midlife, wherein the endogenous hormonal milieu undergoes significant changes and marks the end of the reproductive life stage. Although most women experience natural menopause, many women will undergo gynecological surgery during their lifetime, which can lead to an abrupt surgical menopause. It is of critical importance to better understand how endogenous and exogenous reproductive hormone exposures across the lifespan influence cognitive and brain aging, as women are at a greater risk for developing a variety of diseases after menopause, including dementia. Using rodent models, this dissertation explores how the etiology of reproductive senescence, that is, whether it is transitional or surgical, influences the female phenotype to result in divergent cognitive outcomes dependent upon a variety of factors, with an emphasis on age at the time of intervention playing a key role in brain outcomes. Furthermore, the impact of exogenous hormone therapy on cognition is evaluated in the context of surgical menopause. A novel rat model of hysterectomy is also presented, with results demonstrating for the first time that the nonpregnant uterus, which is typically considered to be a quiescent organ, may play a unique, direct role in modulating cognitive outcomes. Neurobiological mechanisms associated with reproductive hormones and aging are assessed to better recognize neural correlates underlying the observed behavior changes. The overarching goal of this dissertation was to elucidate novel factors contributing to cognitive aging outcomes in females. Collectively, the data presented herein indicate that the age at the onset of reproductive senescence has significant implications for learning and memory outcomes, and that variations in gynecological surgery can have unique, long-lasting effects on the brain and cognition. Translationally, this series of experiments moves the field forward toward the goal of improving the health and quality of life for women throughout the lifespan. / Dissertation/Thesis / Doctoral Dissertation Psychology 2019

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Epigenetic marks encoded by DNA methylation, drifts with age, this results in gain of methylation in CpG islands and loss of methylation in repeat regions. This drift correlates with lifespan and is conserved across species mice, rhesus monkeys, and humans. However, the biology of how this drift occurs is still unexplained. Our hypothesis is that epigenetic drift occurs in aging stem cells. i.e. young stem cells have a stable, uniform DNA methylation pattern. However, as stem cells age, due to cell division and environmental effects, old stem cells have an unstable mosaic methylation pattern which leads to stem cell depletion and exhaustion, focal proliferation, etc., causing cancer and various age-related diseases. To evaluate this hypothesis, we analyzed DNA methylation pattern in mouse colon intestinal stem cells (Lgr5-gfp+) mice from four different age groups (4,12,18, and 24-months) against nonstem cells (Lgr5-GFP-). We found that there are not many methylation changes between stem cells and nonstem cells of the same age (0% change in 4 month and +- 0.2% in 24-month-old samples). This demonstrates that DNA methylation changes primarily occur in stem cells. Permutation analysis of all four aging time points (stem and nonstem) revealed 8102 CpG sites that changed methylation with age, with hypermethylated CpG sites in the promoter-nonCpG islands having the highest odds of gaining methylation with age. CpG sites that changed in DNA methylation levels between tissues (colon and small intestine) were also analyzed through permutation testing. CpG sites that changed between tissues did not overlap with age, showing that CpG sites that change with age and differentiation are different. Gene expression changes with aging was also analyzed, however, compared to DNA methylation not many genes changed in expression with age. We compared the correlation between levels of DNA methylation and gene expression. Low levels of methylation (0-10%) had higher levels of gene expression and increase in DNA methylation led to a decrease in RNA expression. We compared gene expression with CpG sites that change significantly with age in the promoter region from the permutation analysis and found that gene expression is correlated with DNA methylation in CpG sites in promoter-CpG island (r= -0.18). We used principles of entropy and information theory to better analyze the pattern of methylation drift with age in the intestine and found that entropy, measured through Jensen-Shannon Distance (JSD), increased with age but not with differentiation from stem to nonstem cells and the entropy increased 2.5-3 folds in the old when compared to the young. We extended this analysis to other organs with different rates of cell division and found that entropy does not change with age in organs with low rate of cell division such as the heart and kidney. Thus, the rate of cell division and change in entropy with age are highly correlated (r=0.89, p =<0.001). This demonstrates that we can use DNA methylation entropy to measure stem cell replication and aging. We also did not find many loci that changed with age overlapping across tissues, showing that change in methylation entropy is tissue specific. Thus, our data suggests that tissue specific clocks that measure entropy may provide a more accurate measurement of methylation age when compared to clocks based solely on percent methylation. Finally, we looked at DNA methylation changes in intestinal organoids and compared them to primary stem and nonstem cells and found a very weak correlation between them (r=0.23, p=<0.001) and no correlation as the organoids are passaged. We assessed DNA methylation changes caused by long-term passaging (28 weeks). DNA methylation changes with passage, in 4-month and 24-month upper small intestine (USI) organoids, was compared to aging in USI primary cells and we found a weak correlation with 4-month organoids (r=0.28, p=<0.001) and no correlation in 24-month organoids passaged long-term. This demonstrates there are changes in DNA methylation when transitioning from in vivo to in vitro and could result in gene expression and function of the organoid. More studies need to be done to assess the impact of these changes. / Biomedical Sciences

Cerebrovascular burden (CVB) is a significant factor among the aging population. Age-related cognitive decline is an important social and economic issue, and understanding the mechanisms has clinical implications, both in selecting potential therapies and in choosing specific modifiers for their evaluation. In summary, past work suggests that high CVB is one source of variance in neurovascular functioning among older adults. High CVB and associated brain-changes have been identified as causes of age-related changes and it may be that high CVB is a correlate of age-related changes in sleep quality. The primary hypothesis to be tested is that cerebrovascular burden measured using an index variable reflecting blood pressure, resting heart rate, and blood oxygen saturation, will predict subjective sleep quality in a sample of adults over age 70. Sleep quality was measured using the Pittsburgh Sleep Quality Index. A sample of 8 dementia-free, community dwelling participants over the age of 70 completed the study. Though individual cerebrovascular risk factors (blood pressure, resting heart rate) had moderate but non-significant correlations with sleep quality, only the CVB index variable significantly related (1-tailed) to sleep quality. Findings support the hypothesized relationship. Future research should seek to replicate these findings with a larger sample, and to identify mechanisms by which this relationship may function.

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