An investigation of the relationship between levels of apoptosis during aging and longetivity
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In multicellular organisms, apoptosis plays an important role in maintaining cellular homeostasis and removing damaged cells that present a threat to the integrity of the organism. Several lines of evidence suggest that apoptosis might also play a role in the normal aging process. In Drosophila, inhibition of apoptosis in muscle tissues results in lifespan extension. The magnitude of lifespan extension depends on the nature of the UAS-DIAP1 transgene. These results led to the working hypothesis that there might be an optimal level of apoptosis needed to maximally extend lifespan, and was tested with two experimental approaches. First, in order to determine the correlation between longevity and the level of apoptosis in four different genotypes that overexpress DIAP1 using the DJ694-GAL4 driver, DIAP1 expression and caspase activity were examined by way of western blots and caspase assays, respectively. Second, the hypothesis was also tested through the manipulation of DIAP1 expression levels. The number of the UAS-DIAP1 transgene was doubled in the genome, which resulted in an increase in DIAP1 expression levels. The DJ694 driver is able to drive the expression of the UAS-DIAP1 transgene, which resulted in DIAP1 overexpression during adult life as confirmed by western blots. The elevated DIAP1 protein levels resulted in lower caspase activity in animals with one copy of the UAS-DIAP1 transgene and a DJ694 driver. Lifespan extension was observed in these animals overexpressing DIAP1. In animals possessing two copies of the UAS-DIAP1 transgene and a DJ694-GAL4 driver, there was a two-fold increase at transcriptional level. Elevated levels of the DIAP1 protein and a reduction in caspase activity were observed in these animals, but these animals did not exhibit a greater extension in lifespan as compared to the animals driving the expression of only one UAS-DIAP1 transgene. Based on the results obtained, three models for the relationship between longevity and inhibition of apoptosis were proposed. The first model predicts that lifespan is expected to increase with apoptosis inhibition. According to the second model, a specific level of apoptosis inhibition is needed to achieve an optimal extension in lifespan. Inhibition of apoptosis outside of this specific level results in a shortened lifespan. The third model hypothesizes that there is a maximum lifespan that can be achieved by the presence of apoptosis inhibition, however further inhibition beyond this point will not result in an additional increase in longevity.