Genetic pathways that regulate ageing in model organisms

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Abstract

Searches for genes involved in the ageing process have been made in genetically tractable model organisms such as yeast, the nematode Caenorhabditis elegans , Drosophila melanogaster fruitflies and mice. These genetic studies have established that ageing is indeed regulated by specific genes, and have allowed an analysis of the pathways involved, linking physiology, signal transduction and gene regulation. Intriguing similarities in the phenotypes of many of these mutants indicate that the mutations may also perturb regulatory systems that control ageing in higher organisms.

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Figure 1: Ageing in budding yeast.
Figure 2: Caloric restriction in yeast.
Figure 3: Regulation of C. elegans ageing by an elaborate endocrine system.

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Note added in proof. Recently, Wolkow et al.97 have shown that expression of the C. elegans daf-2 receptor or age-1 PI(3)K only in neurons can confer normal life span, and that expression of daf-2 only in endoderm has a significant, but lesser, effect. These findings are in accord with previous mosaic analysis65. An important caveat is that the levels of DAF-2 and AGE-1 produced in these transgenic animals may differ from endogenous levels, possibly altering the level of downstream signal. Wolkow et al. also demonstrate that expressing daf-2 or age-1 only in neurons can be sufficient for normal fat metabolism in the intestine. This is consistent with earlier findings that daf-2 activity in the ectoderm can be necessary and sufficient for normal intestinal pigmentation65, although it should be noted that genetic mosaic animals with a nervous system that is almost completely wild type but internal tissues that are daf-2 often have a Daf-2 intestinal phenotype. Finally, the new study reported that the altered intestinal metabolism of insulin/IGF-1 pathway mutants is not required for longevity, as had been shown previously by analysing intestinal pigmentation and life span in genetic mosaics65 (see text).

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