Exploiting the experimental strengths of animal model systems to elucidate genetic, cellular and biochemical mechanisms of aging may ultimately influence design of novel interventions that could reduce or delay age-related degenerative processes in humans. We are studying the C. elegans model system to decipher aging mechanisms. We have noted that the bodies of aging nematodes feature vacuoles and cellular inclusions reminiscent of those that occur during necrotic-like injury-induced cell death. That degenerative cell death may play an important role in the aging process is suggested by an exciting preliminary observation we made--a mutation that blocks injury-induced neurodegeneration also markedly extends lifespan. This intriguing link between cell death and aging underlies our goals to: 1) characterize age- related vacuolation and to define the contribution of necrotic cell death to C. elegans aging; 2) investigate the role of necrotic death suppressor des(bz29) in C. elegans lifespan; and 3) identify and molecularly characterize additional degeneration suppressor mutants that influence lifespan. This study is of fundamental interest because damage to cellular DNA, proteins and organelles is known to accumulate in aging cells and to contribute to their dysfunction, but whether injury-induced cell death contributes in a critical way to the aging of an organism has remained an unanswered question. Moreover, our planned work will identify specific molecules that can markedly influence lifespan, extending our understanding of how organisms age at the molecular level. In complementary studies we will characterize a mutation that may accelerate senescence in C. elegans. Mutations in the human Werner's syndrome helicase and in the related yeast SGS1 helicase produce symptoms of accelerated aging. We have generated a deletion within the C. elegans ceWRN gene and plan to characterize this mutation to establish the first C. elegans model for progeria. We will test the ceWRNdelta strain for lifespan, genetic instability and for rescue by human or yeast transgenes. Establishment of a nematode model for accelerated aging disorders should extend understanding of the action of helicase family members in senescence and at the same time may facilitate generation of novel data on what may be a conserved aging mechanism.
