(A) Mutations in the histone-modifying enzyme WDR-5 (which forms part of the TrxG complex) causes increased longevity in C. elegans. When wdr-5 mutants are crossed with wild-type worms and their heterozygous F1 progeny selfed to produce wild-type (+/+) offspring, the F3 and F4 progeny are also long-lived and exhibit gene expression changes similar to the wdr-5 mutant, despite lacking the mutation themselves. This inherited change is not perpetuated in the F5 offspring, however, suggesting that the epigenetic changes are removed after three generations. (B) Starvation also induces upregulation of small RNAs in C. elegans, which is heritably maintained in F3 offspring despite being returned to normal nutrition for three generations. F3 offspring of starved animals have also been reported to exhibit an increase in lifespan and resistance to heat shock, which may be mediated by these changes in small RNA expression. Red circles represent altered gene expression, and blue circles represent wild-type levels of gene expression. See 15,16,26 for details.