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...

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.

Mutations in the Caenorhabditis elegans gene clk-1 affect biological timing and extend longevity. The gene clk-1 was identified, and the cloned gene complemented the clk-1 phenotypes and restored normal longevity. The CLK-1 protein was found to be conserved among eukaryotes, including humans, and structurally similar to the yeast metabolic regulator Cat5p (also called Coq7p). These proteins contain a tandem duplication of a core 82-residue domain. clk-1 complemented the phenotype of cat5/coq7 null mutants, demonstrating that clk-1 and CAT5/COQ7 share biochemical function and that clk-1 acts at the level of cellular physiology.

Presenilins are part of a protease complex that is responsible for the intramembraneous cleavage of the amyloid precursor protein involved in Alzheimer's disease and of Notch receptors. In Caenorhabditis elegans, mutations in the presenilin sel-12 result in a highly penetrant egg-laying defect. spr-5 was identi®ed as an extragenic suppressor of the sel-12 mutant phenotype. The SPR-5 protein has similarity to the human polyamine oxidase-like protein encoded by KIAA0601 that is part of the HDAC±CoREST corepressor complex. Suppression of sel-12 by spr-5 requires the activity of HOP-1, the second somatic presenilin in C.elegans. spr-5 mutants derepress hop-1 expression 20-to 30-fold in the early larval stages when hop-1 normally is almost undetectable. SPR-1, a C.elegans homologue of CoREST, physically interacts with SPR-5. Moreover, down-regulation of SPR-1 by mutation or RNA interference also bypasses the need for sel-12. These data strongly suggest that SPR-5 and SPR-1 are part of a CoREST-like co-repressor complex in C.elegans. This complex might be recruited to the hop-1 locus controlling its expression during development. Keywords: Alzheimer's disease/C.elegans/Notch/ presenilins/suppressor genetics IntroductionMutations in the presenilins PS1 and PS2 account for the majority of early-onset familial Alzheimer's disease (Selkoe, 2001). These mutations lead to the aberrant processing of the amyloid precursor protein (APP) and the generation of increasing amounts of the highly amyloidogenic form of Ab, the amyloid b-peptide. Ab is the predominant component of the plaques found in the brains of Alzheimer's patients. Presenilins are polytopic transmembrane proteins that are part of the proteolytic gsecretase complex that liberates Ab. Apart from their role in APP processing, presenilins are also required for proteolytic processing of the Notch receptors in their transmembrane domain. Ligand-induced cleavage and release of the intracellular domain of the Notch receptor (NICD) are crucial for nuclear Notch signalling (Struhl and Adachi, 1998). In agreement with these results, in all organisms tested so far, the loss of presenilin activity leads to phenotypes that resemble that of Notch loss-of-function mutants (Fortini, 2001).Similarly to humans, Caenorhabditis elegans has two somatically expressed presenilin genes, hop-1 and sel-12 (Levitan and Greenwald, 1995;Li and Greenwald, 1997). hop-1 and sel-12, like PS1 and PS2, show redundant activities since only double mutants display phenotypes associated with a complete loss of Notch signalling in C.elegans (Li and Greenwald, 1997;Westlund et al., 1999). A sel-12 null mutant can be rescued by transgenic expression of hop-1 (as well as either of the human PS1 or PS2). sel-12 is expressed rather uniformly at all developmental stages, while hop-1 expression is very weak and could not be detected by reporter gene fusions (Westlund et al., 1999). Probably as a consequence of these different levels of expression, hop-1 mutants are viable with no obvious phenotype, whereas sel...

The mammalian CoREST ([co]repressor for element-1-silencing transcription factor) complex was first identified associated with the repressor for element-1 silencing transcription factor (REST)/neuronal restrictive silencing factor. The CoREST complex is a chromatin-modifying corepressor complex that acts with REST to regulate neuronal gene expression and neuronal stem cell fate. Components of a CoREST-like complex have been identified recently in Xenopus laevis, Caenorhabditis elegans, and Drosophila melanogaster. Like the mammalian complex, the Drosophila complex is required to regulate neuronal gene expression, whereas the C. elegans homologs regulate the expression of the hop-1 presenilin gene, suggesting an ancient conserved function of CoREST complexes in regulating neuronal gene expression.