Germline and steroid regulation of Drosophila Aging

In many organisms, from fruit flies to humans, reproduction shortens lifespan, but the underlying mechanisms remain unknown. Recent progress on this problem has been made in C. elegans. Ablation of germline precursor cells in this nematode worm extends lifespan by signaling through DAF-12, a nuclear receptor activated by steroids called dafachronic acids (DA). While germline ablation cannot extend lifespan in DA-deficient mutants, longevity is restored by application of DA. DA also increases activity of DAF-16, a transcription factor downstream of insulin/IGF-1 like signaling (IIS) which is required for germline loss to extend lifespan. Gonadal signals might thus regulate aging by modulating steroid hormone signaling and IIS. However, the details of this systemic regulation are not well understood, and it is unclear whether the observations in C. elegans also apply to other organisms. We have recently found that germline ablation can also extend lifespan and activate DAF-16 (dFOXO) in Drosophila melanogaster, suggesting that the gonadal regulation of aging might be evolutionarily conserved. Here we propose to investigate whether reproductive signals affect Drosophila lifespan by modulating steroid hormone signaling, as is the case in the worm. Interestingly, a steroid hormone (20-hydroxy-ecdysone, 20E) is known to affect lifespan in fruit flies by signaling through a nuclear receptor (ecdysone receptor, EcR) similar to DAF-12, but the exact mechanisms by which 20E/EcR regulate fly longevity have not yet been explored. We hypothesize that the DA/DAF-12 signaling pathway of C. elegans corresponds to the 20E/EcR pathway in Drosophila and that these endocrine systems have homologous effects on aging. Several facts lend support to our model: (1) the ligand binding domain of EcR shares 34% sequence identity with that of DAF-12; (2) the enzyme encoded by DAF-36 is required for DA production, whereas its Drosophila homolog neverland is required for 20E production; and (3) both DA and 20E affect DAF-16/dFOXO activity. Our research project will address this model in two specific aims, using the powerful tools of Drosophila genetics and endocrine physiology. Our first aim is to test whether and how the effects of germline ablation on lifespan depend on 20E/EcR signaling using epistasis analysis. Our second aim is to investigate whether and how 20E/EcR affects aging by modulating, or interacting with, the transcription factor DAF-16/dFOXO downstream of IIS. Research in this proposal will generate novel insights into the germline regulation of aging and help to unravel the mechanisms whereby steroid hormones affect lifespan.

In many organisms reproduction shortens lifespan, but the underlying physiological reasons for this phenomenon remain largely unclear. In our experiments with fruit flies we have previously found that sterile flies without an active germline live longer, presumably due to a reduction in insulin metabolism. Similar observations have previously been made in nematode worms; in addition, in the worm it has been found that steroid hormones also play a major role in mediating the negative effects of reproduction upon longevity. In our project we essentially aimed to find out whether the same is true in the fruit fly. Our preliminary observations indicate that steroid hormone metabolism indeed plays a major role in affecting the lifespan of the fly; however, the magnitude of this effect seems to depend upon the reproductive status of the fly. We speculate that similar effects might exist in mammals, including humans.