Sunday, November 24, 2024
11/24/2024
ABSTRACT Aging causes cellular damage that leads to functional decline, chronic diseases, and ultimately mortality. Stem cell functional impairment or loss is a significant effect of aging. To counter the effects of aging, intervention strategies are being developed to refocus efforts on extending/enhancing the healthspan, i.e., the period of life prior to the onset of chronic disease and disabilities of aging by maintaining good health. Endurance exercise has long been held as an important lifestyle intervention to boost healthspan. However, the ability of chronic exercise adaptations to affect signaling pathways that impinge on stem cell functions is unclear. Two key stem cell populations—somatic intestinal stem cells (ISCs) and germline testis stem cells (GSCs)—serve as ideal model cell types in Drosophila to determine the impact of exercise adaptations on the aging stem cell. Despite their key similarities and differences in functional dynamics, both stem cell populations respond strongly to JAK-STAT signaling, which, with aging, produces paradoxical effects on each population. In the ISCs, aging increases JAK-STAT signaling and leads to a hyperproliferative phenotype resulting in gut dysplasia and decreased healthspan. In the GSCs, however, aging leads to JAK-STAT hypoactivation and results in reduced stem cell number and functional decline. Hence, aging perturbs the functional equilibrium for stem cell JAK- STAT signaling. Using a Drosophila model of endurance exercise training, this project investigates the capacity of exercise adaptations to ameliorate or even significantly prevent the deterioration of JAK-STAT signaling dynamics in ISCs and GSCs, thus, furthering the healthspan of aging animals. Genetic approaches are combined with morphometric imaging to determine the impact of exercise on aging ISCs and GSCs. Furthermore, cell biological approaches complement unbiased, whole genome approaches—ChIP-Seq and single cell transcriptomic profiling—to determine whether exercise adaptations can reset the gene expression profiles and prolong normal functions in the aging stem cell. Together, these approaches are likely to uncover results that are expected to enhance the understanding of fundamental molecular and cellular mechanisms driving the impact of exercise on stem cell aging. These findings will have important implications for translational approaches directed at investigating lifestyle intervention strategies to prevent aging-induced stem cell malfunction.
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