Mutations in four genes,
clk-1,
clk-2,
clk-3 and
gro-1 display similar effects on the control of timing. Mutations in the best characterized of these genes,
clk-1, increase the length of the cell cycle, embryonic and post-embryonic development, mean and maximal life span as well as the period of rhythmic adult behaviours such as pumping, swimming and defecation (Wong et al. 1995). To investigate the interaction of these four genes we have constructed five double mutant combinations. All double mutants have a more severe phenotype than their constituent single mutations, and develop, defecate and move extremely slowly. We have conducted a systematic analysis of longevity in single and double mutant strains at various temperatures. N2 and
age-1(
hx546) were included as controls. All single mutants display a measurable increase in life span, and every double mutant combination, except one, has a much more profound effect. In fact, two double mutant strains display at least a two fold increase in mean and maximal life span versus N2, comparable to the largest increase in life span previously described. In addition, one of these strains,
clk-1 clk-2, displays a significant delay in the onset of first death. The longevity of double mutants is not due to a simple addition of phenotypes but rather to specific genetic interactions between these genes. For example, even though two
clk-1 alleles,
e2519 and
qm30, have similar aging profiles,
clk-1 clk-3 doubles containing
qm30 live much longer than those with
e2519. Also,
clk-3 gro-1 double mutants have a mean life span indistinguishable from wild type even though
clk-3 and
gro-1 each live longer than N2. The mean life span of strains containing
clk-1,
clk-2 or
clk-3 show a profound temperature sensitivity and display a greater increase in life span versus N2 at low temperatures. This is in contrast to
gro-1 and
age-1 which show very little temperature sensitivity, and suggests that
clk-1,
clk-2 and
clk-3 extend life span by a different mechanism than
age-1 or
gro-1. We are currently investigating the interaction of the clk genes with other genes which affect longevity.