Abstract
Transparent, easily-maintained, amenable to genetic manipulation, and living for only a few weeks, the nematode Caenorhabditis elegans is a leading animal model for the study of the determinants of lifespan. The original genetic screen for increased longevity identified a mutant, age-1, with a defect in one component of a signal transduction pathway. This pathway functioned as a genetic switch and governed the decision whether to enter a specialized larval form, dauer, that enables the worm to withstand the scarcity of food or other stressful conditions. These age-1 worms had an increased tendency to become dauers, but if they did not adopt the dauer developmental pathway, they lived longer than wild type worms. age-1 and other longevity mutants with dauer phenotypes are vigorous, indicating that they do not suffer from a significant energy deficit, and stress resistant. Mutation of genes encoding mitochondrial components was found to be another means of extending the lifespan of the worm, although the associated phenotypes suggest a deficiency of available energy. While there are now many documented genetic manipulations which can extend the worm's lifespan, it has been difficult to come to definite conclusions as to the mechanism (s) by which lifespan is extended. The most carefully studied mutant strains have complex changes in gene expression and metabolism making it difficult to ascertain what changes are critical.
The free radical theory of aging is the dominant biochemical theory of aging, and the phenotypes of the well-characterized longevity mutants worm can be accommodated to it. However discrete interventions to lower reactive oxygen species, or mitigate their effects, have not produced consistent easily-interpretable results in terms of lifespan extension. It has become clear that the insulin-dependent signalling mechanism that regulates lifespan in the worm functions in the context of a complex endocrine system and the hormonal control of aging is an emerging focus of research in worms and higher organisms.