Progress on Understanding How Germline Cell Loss Extends Life in Nematode Worms
Researchers have known for a long time that removal of germline cells extends life in nematode worms. Since this discovery, research groups have been digging into the biochemistry of this species in order to try to understand why germline loss can trigger greater longevity. Here, researchers identify some of the important signaling involved, finding that it originates in the stem cell niche that normally hosts the germline cells. Targeting this signaling with various forms of therapy might form the basis for interventions that slow aging.
Reproduction and ageing tightly interact with each other. It has been shown in various organisms that the absence of germline significantly extends lifespan. Studies in the nematode Caenorhabditis elegans indicate that the somatic gonad generates an unknown signal to trigger a complex signalling network in other tissues to promote longevity when the germline is removed. Downstream of the somatic gonad-derived signal lies a complex genetic network. For example, daf-16/FOXO controls gonadal longevity. The biosynthesis of dafachronic acids (DAs) and the subsequent activation of the nuclear hormone receptor DAF-12/FXR is another critical pathway driving gonadal longevity. Intriguingly, the gonadal longevity signalling shares components with developmental timing machinery. In particular, the DA synthesis and DAF-12 activation are initiated at the end of germline development, implying that gonadal longevity could be from a checkpoint for germline integrity.
Despite the extensive understanding of the molecules controlling ageing upon germline ablation, the longevity signal from the somatic gonad remains poorly understood. Within the germline, the somatic gonad constitutes the niche of germ cells and regulates their development. It is the germline stem cells (GSCs) but not the oocytes or sperms that influence ageing. Therefore, we hypothesize that the gonadal longevity signal originates from the somatic gonadal cells neighbouring GSCs because these cells have intensive interactions with GSCs as their niche and should be the first to sense their absence.
In this study, we found that removing worm germline disrupts the cell adhesions between GSC and its niche, the distal tip cell (DTC), causing a significant transcriptomic change in DTC through the translocation of two GATA transcription factors, elt-3 and pqm-1, and the translocation of hmp-2/β-catenin. This, in turn, extends the lifespan of worms. Moreover, we further identified the TGF-β ligand, tig-2, as the cytokine from DTC upon germline ablation, which evokes the downstream longevity pathways throughout the body. Our findings thus reveal the origin of the longevity signalling in response to germline ablation, underscoring the interaction of stem cells and their niche in metazoan ageing.