DOR/TP53INP Regulates Organismal Aging Through Ovarian Senescence in Drosophila melanogaster

Aging of the reproductive system in women occurs much earlier in life than the other organ systems. The onset of ovarian aging occurs around 51 years of age, and the average life expectancy for women is 80 years. Ovary aging ultimately leads to menopause, characterized by the cessation of menses. Menopause is associated with increased risk for systemic diseases such as cardiovascular disease, obesity, diabetes, and osteoporosis. Research shows an association between early natural menopause and increased mortality, but the mechanism behind this is not clear. Our lab has identified the protein TP53INP (DOR) in Drosophila melanogaster as having a locus associated with late-life mortality. Inhibition of DOR in the whole body of the fly resulted in decreased lifespan, decreased healthspan(definition), and increased markers of ovarian senescence(definition). This study aimed to elucidate the mechanism behind DOR’s systemic effects by inhibiting its expression in specific tissues of the ovary. We inhibited the expression of DOR in the germline stem cell and the follicle stem cell of the fly ovary by using the GAL4-UAS system to introduce RNAi targeting of this gene. Assays included lifespan, starvation, gut permeability, climbing, fecundity, and senescence marker staining. Contrary to studies in which whole-body DOR expression was inhibited, we found that DOR inhibition in the germline stem cells did not lead to a decrease in lifespan or healthspan markers. However, DOR inhibition in the follicle and escort cells was associated with a significant reduction in lifespan as well as an increase in senescence markers in the ovaries. These findings demonstrate the significance of the intersection between reproductive and organismal health and aging.