In Caenorhabditis elegans and Drosophila melanogaster, removal of the germline stem cells slows down aging of the organism. Nevertheless, the mechanism by which somatic tissues respond to loss of the germline and how this promotes longevity is not well understood. In this study, we identified an innate immunity-associated C-type lectin protein encoded by the upr-1 gene as a novel determinant of this longevity pathway.upr-1 is required for loss of the germ cells to increase C. elegans' lifespan, but is not required for lifespan extension by other longevity pathways. Accordingly, in the absence of upr-1, the activation of the germ cell-regulated transcription factors DAF-16/FOXO and NHR/DAF-12 is compromised. Furthermore, when the germline is removed, upr-1's transcription in the intestine increases. This induction may be functionally significant as upr-1 overexpression or a gain-of function mutation in upr-1 in normal, fertile animals bypasses the requirement for germ-cell loss and extends lifespan. Strikingly, this lifespan extension relies on the same set of genes required for extending lifespan in the reproductive longevity pathway. In addition, similarly to the longevity conferred upon germ cell removal, upr-1-mediated longevity also requires an intact somatic gonad.In agreement with the presumed role of CTLD proteins in the innate immune response, upr-1 promotes longevity by modulating the nematode's innate immune response. Accordingly, upr-1 activation is sufficient to stimulate the PMK-1/ATF-7 innate immune response pathway and the stimulation of this innate immune response pathway is essential for the lifespan-extending phenotype of upr-1 gof mutants. Furthermore, upr-1 activation extends the lifespan of animals fed with live bacteria, but does not further extend the lifespan of animals fed with dead bacteria. This indicates that in animals with an intact germline, upr-1 promotes longevity primarily by improving their ability to deal with pathogens. In summary, our findings indicate that upr-1 plays a key role in transducing longevity-promoting signals from the reproductive system to the somatic tissues in germlineless animals and that it can practically activate the germ cell-associated longevity program as well as an innate immunity program independently of pathogen exposure or germ cell removal. These findings shed light on the important crosstalk between the reproductive system, innate immunity system and longevity.

Affiliation:
- The Mina and Everard Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel