Dominant
mec-4(d) alleles induce swelling and degeneration of the touch cells. This degenerative cell death is characterized by cellular swelling, distention of subcellular organelles and chromatin clumping. Other cellular insults, such as expression of constitutively activated GaS (Korswagen HC et al (1997) Genes & Development 11: 1493-1503) or human bA4 protein (Link CD (1995) Proc. Natl. Acad. Sci. USA. 92: 9368-9372) also induce the formation of vacuoles. Interestingly, aged animals exhibit vacuolar structures throughout their bodies. Since neurodegeneration underlies dysfunction of nervous system in the situations of injury and aging-related diseases, we have been interested in identifying genes involved in the degenerative process. We have previously reported that ectopic expression of the toxic
mec-4(d) allele can induce degeneration in several cell types. Expression of
mec-4(d) from an integrated array of
punc-8mec-4(d) causes swelling and degeneration of some interneurons and many ventral cord neurons, resulting in severe paralysis. Using this behavioral phenotype, we have identified suppressor mutations that block the deleterious effects of
mec-4(d): suppressors restore normal or near normal locomotion by preventing cell death. The genes identified by these mutations are called des genes (degeneration suppressor). In a screen of 10,000 mutagenized animals, we isolated 16 independent death suppressors. 4 alleles of
mec-6, an expected suppressor of ectopically expressed
mec-4(d), were identified. 8 strong suppressors appear to affect previously unidentified genes. Two of the strongest suppressors, defined by
bz29 and
bz30 in one case, and
bz31 in another, are particularly interesting because they can suppress degeneration induced by different cellular insults (mutant degenerins, constitutively activated GaS, etc).
bz29 and
bz31 fail to complement, but map to different positions. This is also the case for
bz30 and
bz31. The observed non-allelic non-complementation suggests involvement of both des genes in the same pathway. We have identified candidate rescuing cosmids for each gene. Given the high incidence of vacuoles in aging animals, we were curious whether animals in which degenerative cell death is blocked by mutation might age differently. We hypothesized that if vacuolar degeneration contributed to aging and if the des mutations blocked all cellular vacuolation, des mutants might have altered lifespans. Indeed, we find that both alleles of one des gene,
bz29 and
bz30, affect aging-- mutants live significantly longer than wild type. Lifespan extension is comparable to that seen with
age-1(
hx546). Our results suggest that degenerative cell death contributes to nematode aging.