The genetics of caloric restriction in Caenorhabditis elegans

Abstract

Low caloric intake (caloric restriction) can lengthen the life span of a wide range of animals and possibly even of humans. To understand better how caloric restriction lengthens life span, we used genetic methods and criteria to investigate its mechanism of action in the nematode Caenorhabditis elegans. Mutations in many genes (eat genes) result in partial starvation of the worm by disrupting the function of the pharynx, the feeding organ. We found that most eat mutations significantly lengthen life span (by up to 50%). In C. elegans, mutations in a number of other genes that can extend life span have been found. Two genetically distinct mechanisms of life span extension are known: a mechanism involving genes that regulate dauer formation (age-1, daf-2, daf-16, and daf-28) and a mechanism involving genes that affect the rate of development and behavior (clk-1, clk-2, clk-3, and gro-1). We find that the long life of eat-2 mutants does not require the activity of DAF-16 and that eat-2; daf-2 double mutants live even longer than extremely long-lived daf-2 mutants. These findings demonstrate that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants. In contrast, we find that food restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clk-1 and caloric restriction affect similar processes.It was shown more than 50 years ago that reducing the caloric intake (caloric restriction) of rodents can significantly lengthen their mean and maximal life span (1). It subsequently has been shown that caloric restriction (CR) can lengthen the life span of a wide variety of animals (2). Trials have even begun with higher primates; based on preliminary evidence, calorically restricted rhesus monkeys show similar signs of delayed aging to those seen in the calorically restricted rodents (3-7). CR has been best studied in rodents, and it is known that rodents undergoing CR display many physiological changes, including reduced body weight, temperature, blood glucose, and insulin levels (reviewed in refs. 8 and 9). However, it is unclear which of these changes are required for an extended life span (8, 9). Several studies indicate that reducing caloric intake reduces the amount of damage attributable to free radicals (reviewed in refs. 8 and 9). One simple hypothesis to explain how CR extends life span is that CR may reduce basal metabolic rates. Rodents and primates undergoing CR have lowered body temperatures (10-12), an indication of lower metabolic rates. However, studies on the effect of CR on the metabolic rates of various mammals have given equivocal results, with some studies showing no change in oxygen consumption per unit of lean body mass (13,14) and other studies showing a decrease of consumption under CR (15, 16). In spite of uncertainty about how CR affects life span, it remains the only experimental treatment that has been shown repeatedly to significantly prolong the life of vertebrates (8,9,17).On the other hand, it is in Cae...

Chemical activation of a food deprivation signal extends lifespan

“…As NP1 did not appear to decrease feeding rate in vivo and did not cause worms to appear starved or poorly fed, we thought it unlikely that the NP1 pumping rate defect could cause such a profound increase in lifespan. Genetic mutations that result in DR from mechanical impairments of feeding are well known in C. elegans (Lakowski & Hekimi, 1998). EAT‐2 is an acetylcholine receptor subunit responsible for promoting the rapid pumping of pharyngeal muscle (Raizen et al ., 1995; McKay et al ., 2004).…”

Genes regulated by caloric restriction have unique roles within transcriptional networks

“…Dauer-formation is not considered a model for the mammalian CR response, and mechanisms regulating dauer formation appear to be independent of those regulating response to standard C. elegans CR treatments (applied during the adult stage) (Lakowski and Hekimi 1998). However, since dauer formation represents a metabolic response to resource limitation that is accompanied by increased longevity, it was suspected that dauerregulated genes could share some network properties with CR-regulated genes.…”

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

“…To determine if there is a single pathway by which senescence is retarded, we have examined four separate manipulations that have been shown to increase lifespan in C. elegans: dietary restriction (DR), cold-/hypothermic-induced longevity (CHIL), decreased insulin signaling, and mutations influencing mitochondrial respiration (Ball et al 1947;Conti et alDietary restriction has been shown to extend lifespan by up to 50% in mammals (Davis et al 1983;Yu et al 1985;Weindruch and Walford 1982). In several different worm models of dietary restriction, evidence has revealed that DAF-16, a forkhead box O (FOXO) transcription factor that is required for lifeextension via the insulin pathway, is not required for the life-extending effects of dietary restriction (Houthoofd et al 2003;Lakowski and Hekimi 1998). This observation suggests, contrary to the overwhelmingly compelling hypothesis, that the insulin-like pathway does not mediate the effects of dietary restriction.…”

“…The mechanism by which clk-1 extends lifespan is controversial. Studies have both shown that clk-1 does and does not extend lifespan when the worms undergo dietary restriction (Braeckman et al 2000;Lakowski and Hekimi 1998). This difference may be explained by the difference in application of caloric restriction.…”

“…In the field of aging research, epistatic analysis using survival curves and average lifespan has become a standard method of determining the independence of genes and pathways (Bartke et al 2001;Bonkowski et al 2006;Braeckman et al 2000;Clancy et al 2002;Kenyon et al 1993;Lakowski and Hekimi 1998;Tissenbaum and Ruvkun 1998). As such, this study uses a similar epistatic design.…”