Regulation of Aging in Nematodes, Flies, and Yeast

Nematodes

Many mutants are known that increase the life span of Caenorhabditis elegans. Several of these act to reduce signaling in a pathway that is stimulated by insulin-like molecules (Fig. WN20.6A). The normal function of this pathway is to stimulate reproduction and suppress the formation of hardy dauer larvae. C. elegans has only one receptor for insulin-like molecules, which is coded by the gene daf-2. Mutations in this gene can greatly increase life span (Fig. WN20.6A). A defective sense of smell increases life span and also reduces signaling by the insulin-related pathway. All this suggests that food availability is detected by the chemosensory system, which then acts to suppress the insulin-related pathway, and thus shifts resources away from production of long-lived dauer forms toward immediate growth and reproduction.

Flies

Drosophila melanogaster has a remarkably similar pathway to C. elegans (Fig. WN20.6B). Mutations that interfere with this pathway considerably increase female life span. For example, reduced expression of Inr, which is homologous to daf-2, can increase female life span by 85%.

Yeast

Saccharomyces cerevisae, like C. elegans and Drosophila, lives longer when calories are restricted (Fig. WN20.6B). In yeast, calorie restriction causes a shift from anaerobic fermentation to aerobic respiration, which uses resources far more efficiently (one glucose molecule releases 28 adenosine triphosphate [ATP] molecules instead of the two released by fermentation; Lin et al. [2002]). As well as requiring genes for respiration, increased life span following calorie restriction requires a gene, sir-2, which suppresses transcription and recombination in the ribosomal DNA (rDNA) genes. It is thought that this gene increases life span by reducing the accumulation of harmful extrachromosomal rDNA circles. sir-2 also leads to mating, which is followed by formation of hardy spores. This gene codes for an NAD receptor, which is stimulated by increased respiration.

The homolog of sir-2 in nematodes increases life span when overexpressed; it acts via the insulin-related pathway discussed above. Leonard Guarente has suggested that sir-2 is a conserved detector of poor nutrition, which causes a shift in resources away from reproduction and toward survival. The mechanism of this shift varies between organisms. In yeast, it is via spore formation and reduced rDNA transcription, whereas in nematodes it is via the formation of hardy dauer larvae.