The gene
ndg-4 encodes a transmembrane protein with largely unknown function.
ndg-4 belongs to a small group of genes causing nose contraction resistance to the anti-depressive drug fluoxetine (Nrf phenotype). Some Nrf mutants, including
ndg-4, lay pale eggs, presumably due to yolk and lipid deficiency [1]. We have isolated
ndg-4 in a whole genome RNAi screen for resistance to stalled replication forks induced by treatment with hydroxy urea (HU). Interestingly, we find that two different alleles of
ndg-4 both confer large increases in lifespan (more than 50 percent) and stress resistance in C. elegans. Both the stress resistance and the longevity of
ndg-4 mutants are, at least in part, independent of the insulin signaling pathway as mutation of
ndg-4 can increase both stress resistance and lifespan of
daf-16 null mutants. Furthermore, we observe a large synergistic effect on lifespan when
ndg-4 mutants are treated with
daf-2 RNAi which doubles the already long lifespan.
ndg-4 appears to function in the same stress resistance and longevity pathway as the checkpoint protein
chk-1 [2], since inactivation of
chk-1 does not further increase stress resistance and lifespan of
ndg-4 mutants. Nrf mutants with the pale egg phenotype are resistant to sterility caused by the dietary lipid DGLA, suggesting a failure to distributing lipophilic substances in these mutants [3]. We find that two other Nrf mutants that display the pale egg phenotype,
nrf-5 encoding a putative lipid binding protein and
nrf-6 encoding an
ndg-4 homolog, are also long-lived and stress resistant. In contrast, other Nrf mutants not conferring the pale egg phenotype have normal lifespan. Therefore, it is tempting to speculate that the increase in stress resistance and longevity in
ndg-4,
nrf-5 and
nrf-6 mutants may be connected to lipid signaling. 1.Choy, R.K., J.M. Kemner, and J.H. Thomas. Genetics, 2006. 172(2): p. 885-92. 2.Olsen, A., M.C. Vantipalli, and G.J. Lithgow. Science, 2006. 312(5778): p. 1381-5. 3.Watts, J.L. and J. Browse. Dev Biol, 2006. 292(2): p. 381-92.