Germ cells can maintain themselves indefinitely over many generations, effectively free of proliferative damage. Pathways that promote germ cell immortality could be relevant to forms of stress that accumulate to cause aging as human somatic cells proliferate. Deficiency for the C. elegans Piwi orthologue
prg-1 has been previously reported to result in sterility at high temperature (1, 2, 3). We found that outcrossed
prg-1 strains display germ cell mortality, in which lineages display normal fertility for many generations but ultimately become completely sterile. Although PRG-1 can repress the Tc3 transposon, our data suggest that transposition is unlikely to cause sterility. Instead, several lines of evidence suggest that
prg-1 mutants may become sterile as a consequence of a heritable form of stress. For example, the transgenerational lifespan of
prg-1 mutants (number of generations to sterility) was doubled by brief periods of starvation at high temperature, a condition that promotes formation of stress-resistant dauer larvae. In addition, reduced levels of
daf-2-mediated insulin/IGF1 signaling, which promotes dauer formation and somatic longevity, rescued the progressive sterility phenotype of
prg-1 mutants, and even restored fertility to sterile
prg-1 mutants. Desilencing of repetitive segments of the genome occurred in late-generation
prg-1 mutants but not in late-generation
prg-1;
daf-2 mutants. Further, reduced insulin/IGF1 signaling restored levels of 22G siRNAs that target repetitive loci in
prg-1 mutants. Thus, desilencing of repetitive loci could be relevant to germ cell mortality of
prg-1 mutants. We propose that the Piwi/PRG-1 small RNA silencing pathway represses a heritable epigenetic stress that can be transmitted via gametes, that can be ameliorated by insulin/IGF1 signaling, and that could be relevant to proliferative aging of somatic cells. 1. Batista, P.J. et al. (2008). 2. Das, P.P. et al. (2008). 3. Wang, G. & Reinke, V. (2008).