Cell death is a highly regulated process that plays important roles in normal development and in response to cellular injury. Whether injury-induced cell death, also known as necrosis, contributes in a critical way to the aging of an organism is unknown. Since aging worms exhibit many vacuolar structures that look similar to degenerative cell deaths (for example, as induced by
mec-4(d) mutations), we wondered about a possible relationship between necrotic-like cell death and aging. We identified genes required for degenerative cell death, called des genes ( de generation s uppressors), by screening for mutations that block necrosis. We hypothesized that if these mutations also suppress aging-associated vacuolation and if degenerative cell death plays a critical role in C. elegans aging, the des mutants might have extended lifespans or exhibit increased vitality late in life. We show that animals mutant in one gene, identified by alleles
bz29 and
bz30 , have an extended lifespan. We are characterizing these lines to determine extent of random vacuole formation, general locomotor activity, resistance to heat and oxidative stresses, and interaction with the dauer formation mutants that are known to affect the lifespan of adult animals. In another line of experimentation, we are attempting to identify mutations that may accelerate senescence in C. elegans . Mutations in the human Werner's syndrome helicase (WRN) and in the related yeast SGS1 helicase produce features of accelerated aging. There are four C. elegans genes that exhibit sequence similarity to the RecQ family of DNA helicases. We have generated a deletion within the C. elegans gene most similar to the Werner's gene (F18C5.2). Preliminary results indicate that these animals appear to have a normal lifespan and genetic stability. As there may be redundancy in the activity of these helicases, we are currently characterizing animals carrying both the Cewrn deletion and a mutation in another helicase family member,
him-6 1 . We are screening for deletions in the other two C. elegans DNA helicase family members. Establishment of a nematode model for accelerated aging disorders should extend understanding of the action of helicase family members in senescence. 1. Wicky, C., A. Rose and F. Mueller. 1998. European Worm Meeting Abstract.