Mutations in the genes
clk-1,
clk-2,
clk-3 and
gro-1 are all maternally rescued and lead to a very similar phenotype: a pleiotropic alteration of developmental and behavioral timing (Hekimi et al. 1995, Wong et al. 1995). Mutations in the best characterized of these genes,
clk-1, lengthen early embryonic cell cycles, embryonic and post-embryonic development, the periods rhythmic behaviors, such as defecation, and ultimately total lifespan (Wong et al. 1995). We have determined that mutations in all four of these genes increase both mean and maximum lifespan. To examine how these genes interact genetically, we made seven double mutant strains containing combinations of Clock mutations. Although there is a range of severity, all double mutants take longer to develop than mutants in the individual constituent genes. Most double mutants also have much longer mean and maximum lifespans than the individual Clock mutants. The strongest double mutant combination,
clk-3(
qm38);
clk-1(
qm30), takes four times as long to develop and lives three times as long as N2. Life span extension in clk mutants and
gro-1 is not dependent on the activity of
daf-16, which is essential for the life extension seen in
age-1,
daf-2 and
daf-23 mutants, suggesting that the Clock genes and the dauer genes act in different pathways. To examine the effect of carrying a life extending mutation from two different pathways, we made a
daf-2(
e1370)
clk-1(
e2519) double mutant.
daf-2 clk-1 double mutants live longer than either
daf-2 or
clk-1 and can live up to five times as long as N2. This is the greatest increase in lifespan recorded for any organism by any means. By other criterion, lifespan extension in the Clock mutants also appears to be mechanistically distinct from that of the dauer mutants. For example, when dauer mutants are raised at the permissive temperature, adult lifespan is lengthened without any increase in the length of development. However, in Clock mutants, increased adult lifespan is accompanied by changes in developmental and behavioral timing. In particular, mean adult lifespan and the length of post-embryonic development are strongly correlated among all clk single and double mutants. These observations lead us to suggest that Clock mutants have a slower "rate of living" than the wild type, which may lead to longer lifespan, possibly by slowing the production of reactive byproducts of metabolism. Hekimi et al. Genetics 141, 1351 (1995). Wong et al. Genetics 139, 1247 (1995).