clk-1;daf-2

Cold temperature, dietary restriction, reduced insulin/insulin-like growth factor signaling, and mutations in mitochondrial genes have all been shown to extend the lifespan of Caenorhabditis elegans (Kenyon et al., Nature 366:461-464, 1993; Klass, Mech Ageing Dev 6:413-429, 1977; Lakowski and Hekimi, Science 272:1010-1013, 1996). Additionally, all of them extend the lifespan of mice (Bluher et al., Science 299:572-574, 2003; Conti et al., Science 314:825-828, 2006; Holzenberger et al., Nature 421:182-187, 2003; Liu et al., Genes Dev 19:2424-2434, 2005; Weindruch and Walford, Science 215:1415-1418, 1982). The mechanism by which these treatments extend lifespan is currently unknown, but our study uses an epistatic approach to show that these four manipulations are mainly additive in terms of lifespan. Classical interpretation of this data suggests that these manipulations are independent of each other. However, using a Gompertz mortality rate analysis, the maximum mortality rate doubling time can be achieved through the use of only dietary restriction and cold temperature, suggesting that the mechanisms by which cold temperature and caloric restriction extend lifespan are the only independent mechanisms.

Cold temperature, dietary restriction, reduced insulin/insulin-like growth factor signaling, and mutations in mitochondrial genes have all been shown to extend the lifespan of Caenorhabditis elegans (Kenyon et al., Nature 366:461-464, 1993; Klass, Mech Ageing Dev 6:413-429, 1977; Lakowski and Hekimi, Science 272:1010-1013, 1996). Additionally, all of them extend the lifespan of mice (Bluher et al., Science 299:572-574, 2003; Conti et al., Science 314:825-828, 2006; Holzenberger et al., Nature 421:182-187, 2003; Liu et al., Genes Dev 19:2424-2434, 2005; Weindruch and Walford, Science 215:1415-1418, 1982). The mechanism by which these treatments extend lifespan is currently unknown, but our study uses an epistatic approach to show that these four manipulations are mainly additive in terms of lifespan. Classical interpretation of this data suggests that these manipulations are independent of each other. However, using a Gompertz mortality rate analysis, the maximum mortality rate doubling time can be achieved through the use of only dietary restriction and cold temperature, suggesting that the mechanisms by which cold temperature and caloric restriction extend lifespan are the only independent mechanisms.

The nematode worm Caenorhabditis elegans is a model system for the study of the genetic basis of aging. Maternal-effect mutations in four genes--clk-1, clk-2, clk-3, and gro-1--interact genetically to determine both the duration of development and life-span. Analysis of the phenotypes of these mutants suggests the existence of a general physiological clock in the worm. Mutations in certain genes involved in dauer formation (an alternative larval stage induced by adverse conditions in which development is arrested) can also extend life-span, but the life extension of Clock mutants appears to be independent of these genes. The daf-2(e1370) clk-1(e2519) worms, which carry life-span-extending mutations from two different pathways, live nearly five times as long as wild-type worms.

The nematode worm Caenorhabditis elegans is a model system for the study of the genetic basis of aging. Maternal-effect mutations in four genes--clk-1, clk-2, clk-3, and gro-1--interact genetically to determine both the duration of development and life-span. Analysis of the phenotypes of these mutants suggests the existence of a general physiological clock in the worm. Mutations in certain genes involved in dauer formation (an alternative larval stage induced by adverse conditions in which development is arrested) can also extend life-span, but the life extension of Clock mutants appears to be independent of these genes. The daf-2(e1370) clk-1(e2519) worms, which carry life-span-extending mutations from two different pathways, live nearly five times as long as wild-type worms.