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This research study intends to address a problem parents face as the assumptive primary faith influencers in their children's discipleship and spiritual development. The goal is to discover the support parents receive as World Changers Church International members while growing in the Christian faith as a family. The problem manifests when youth pastors and workers struggle to help student ministries make real-life connections through discipleship and mission. Due to the COVID-19 pandemic, the physical church closure is considered in exploring the study and further augment parents' struggles. In the discovery process, the study will assess how guidance through the Christian Education Department potentially affects children’s and youth's discipleship across their lifespan. Exploring this problem will provide insight regarding how parents access church tools that undergird them as faith leaders of their family. The methodology used in this faith development study project is qualitative, comparing sample responses and analyzing perception data collected from a faith development survey. There is also a small focus group component, chiseling into survey responses and interviews with willing sample participants discussing practical next steps derived from small group sessions. The research will seek to bring a theological and theoretical perspective to the practice of ministry stakeholders’ roles, such as pastors, youth workers, group leaders, and mentors in the lives of children and youth. The conclusion of the project provides questions derived from the study results. The questions offer the church direction in assisting parents as the primary faith influencers in their children’s lives.

Few studies have examined whether the benefits of education for health differ across sociodemographic subgroups. We investigated whether educational attainment is associated with cardiovascular health, as measured by the Life’s Simple 7 (LS7) score, and whether the association differs by demographic characteristics. Data were obtained from the REasons for Geographic and Racial Differences in Stroke study (N=8,759 participants; mean age=63.8). We used linear regression analyses with interactions by sex, race, childhood socioeconomic status (SES), and geography. Socially vulnerable groups (i.e., men from low childhood SES backgrounds, White people from low childhood SES backgrounds, Black people from low childhood SES backgrounds) benefitted less from each additional year of education than socially advantaged groups in predicting LS7 scores. However, we did not find evidence that differential returns extended to every group. Findings suggest that the inequalities present in the education system may further exacerbate the gap between advantaged and disadvantaged.

Signaling pathways that are involved in stress resistance have often been implicated in the regulation of the rate of aging in normal physiological conditions. The evolutionarily conserved transcription factor heat shock factor 1 (HSF-1) provides protection to animals from a multitude of environmental stresses. In addition, overexpression of HSF 1 promotes longevity in the nematode worm Caenorhabditis elegans also in non stressed conditions. Previous studies have shown that a negative regulator of HSF 1, termed as heat shock factor binding protein 1 (HSB-1), physically binds to HSF 1 and limits its transactivation potential. Genetic ablation of hsb-1 induces a robust hsf-1-dependent life span extension in worms via mechanisms that are less understood. In this study, we show that ablation of hsb-1 results in an altered transactivation status of the HSF-1 protein. In hsb-1 null animals, HSF-1 shows increased binding to its genomic target sequences. However, the transcriptome of hsb-1 null animals is largely distinct from that of HSF-1 overexpressing worms. While HSF-1 overexpression induces large-scale transcriptional upregulation in C. elegans, HSB-1 inhibition alters the expression of a much smaller number of genes, but still produces a similar life span extension as in HSF-1 overexpressing worms. Roughly half of the differentially regulated transcriptome in hsb-1 null animals overlaps with that of worms overexpressing HSF-1, and these genes show a strongly correlated expression pattern in the two long-lived strains. Genes that are upregulated via both HSB-1 inhibition and HSF-1 overexpression include many longevity-promoting transcriptional targets of the C. elegans FOXO homolog DAF-16. Overall, this suggests that HSB-1 acts as a selective regulator of HSF-1 transactivation potential and hence, inhibition of HSB-1 results in change in expression of a subset of HSF-1 target genes that are potentially involved in longevity determination in animals. In addition to the characterization of transcriptional changes associated with HSB-1 inhibition in worms, we also performed an unbiased RNAi-based screen to identify genetic suppressors of HSB-1 associated longevity. We found that knockdown of several histone H4-coding genes can completely suppress the life span extension phenotype in hsb-1 null animals. Worms lacking HSB-1 have elevated H4 protein levels in somatic tissues during development, while H4 overexpression in wild-type worms is sufficient to extend their life span. In hsb-1 null animals, elevated H4 levels induce reduced MNase-accessibility of both nuclear chromatin and mitochondrial DNA (mtDNA). This results in an H4-dependent reduction in expression of mtDNA-encoded genes and lower respiratory capacity in hsb-1 null worms, which leads to a mitochondrial unfolded protein response (UPRmt)-dependent life span extension. We further show that extranuclear histone H4 is present in mitochondria of intestinal tissue in C. elegans. This suggests a novel and unexpected role of histone H4 in regulating mitochondrial gene expression via directly modulating the accessibility of mtDNA. Moreover, our findings show interplay between three distinct cellular processes – stress resistance, chromatin dynamics and mitochondrial function – that were previously known to promote longevity in animals via seemingly independent mechanisms. In summary, this study has identified several novel HSF-1-mediated signaling interactions in C. elegans that have significantly broadened our understanding of how HSB-1/HSF-1 pathway regulates organismal life span in normal physiological conditions. Our findings will potentially guide the design of targeted therapies to selectively modulate the function of HSF-1 in order to delay the progression of aging and age-related diseases in metazoans.

There is evidence that cholesterol presents an important risk factor for Alzheimer’s disease (AD), but the direction of this relationship is modified by age. High cholesterol during midlife and low cholesterol during late life are both associated with an increased risk for AD. This dissertation research engaged a life span approach to study the relationship between cholesterol, AD and cognitive functioning among older adults. The purpose of this research was to determine if trajectories of cholesterol from midlife through late life differ according to AD status and if these trajectories are associated with cognitive functioning during old age. This research employed a secondary analysis of cognitive, phenotypic and genetic data collected from subjects of the Framingham Heart Study (FHS) Original and Offspring Cohorts. Aim One involved creating three summary scores of the FHS neuropsychological battery. ROC analysis was used to determine which score best differentiated between cognitively normal, impaired and dementia subjects. Aim Two used generalized additive mixed models to examine trajectories of total, HDL and total/HDL cholesterol ratio according to AD status in the Original Cohort. Aim Three used mixed-effects models to examine the relationship between subject-specific trajectories of total cholesterol and cognition during old age. Aim One determined that a summary score that provided equal weight to each assessment in the FHS neuropsychological battery best differentiates between subjects classified as cognitively normal, cognitively impaired and dementia. The findings from Aim Two indicated that there are subtle differences in the longitudinal trajectories of total, HDL and total/HDL ratio according to AD status. The findings from Aim Three provide limited evidence for a relationship between subject-specific trajectories of total cholesterol and cognitive functioning later in life. Older adults in the highest quartile for cognitive functioning had lower total cholesterol at approximately 55 years of age, but there were no differences in the mean trajectories of total cholesterol according to cognitive functioning later in life. The findings from this research suggest that older adults with high cognitive functioning have lower total cholesterol during midlife, but life span cholesterol trajectories do not appear to be associated with AD status or cognitive function.

Polycomb group (PcG) proteins are most well known for their role in the transcriptional regulation of homeotic genes, mediated in part by specific epigenetic modifications to chromatin. Trimethylation of histone H3 lysine 27 (H3K27me3) is a highly conserved modification required for Polycomb silencing and is specifically mediated by the histone methyl transferase E(Z), found in Polycomb Repressive Complex 2 (PRC2). Recently, PcG proteins have been shown to bind thousands of target genes and are now implicated in a growing number of biological processes, some of which are associated with modulating longevity.This study demonstrates that mutations in PRC2 subunits including E(Z), and the histone H3 binding protein ESC, increase life span and resistance to oxidative stress and starvation in Drosophila. Their increased longevity and stress resistance correlates with a decrease in bulk H3K27me3 levels in adults. Mutations in trithorax (trx) partially suppress the increased longevity and stress resistance phenotypes of E(z) mutants, while concomitantly increasing their reduced H3K27me3 toward a normal level. Heterozygous E(z) mutants also partially derepress known and putative direct targets of Polycomb silencing, which are restored toward normal expression levels in E(z) trx double mutant heterozygotes. Together, this strongly suggests that perturbations to Polycomb silencing mediate the increased longevity and stress resistance phenotypes of PRC2 mutant heterozygotes by derepressing one or more direct or indirect Polycomb target genes.Initial genome-wide microarray expression analysis of long-lived E(z) and esc mutants were conducted to identify the differentially expressed candidate genes that may be responsible for mediating their longevity and stress resistance phenotyptes. 65 transcripts are differentially expressed in both PRC2 mutants and those transcripts are highly enriched for genes associated with lipid biosynthesis. Consistent with this, E(z) and esc mutant adults display a significant increase in total triglycerides, suggesting the long-lived mutants may have some altered energy utilization. Transcripts shown to modulate the JNK and IIS signaling pathway components, which have previously been implicated in modulating Drosophila longevity, are also increased in PRC2 mutants. These findings identify several metabolic and stress response pathways that may modulate the increased longevity and stress resistance phenotypes of PRC2 mutant heterozygotes.

This thesis has been an attempt to observe the role antibodies play in extending the life span of tumor infected Akr mice.