Project 1. Genes, Diet & Longevity in C. elegans

Genetic approaches have recently made enormous strides toward defining mechanisms by which life span is determined in several “lower” organisms. The most dramatic advances have come from studies of the nematode C. elegans, with important contributions also from budding yeast (Saccharomyces cerevisiae) and the fruitfly Drosophila melanogaster. Many disparate phenomena associated with aging and differences in life span among species are beginning to fall into place under the broad canopy of metabolically generated free radical stress and its sequelae, and the defenses and adaptations that have evolved to deal with them. The first mutations demonstrated to extend life in a metazoan were discovered in C. elegans, and currently life-extending mutations have been shown in over 60 C. elegans genes, far more than in any other organism. This is clearly the proofing ground for discovery of genes regulating longevity, and most genes reported to extend life in other species when mutated, were tested precisely because they had previously been shown to do so in the nematode.

Our own laboratory has discovered a dozen genetic loci (QTLs, or quantitative trait loci), that are polygenic determinants of life span. Four of these are included in this Project, along with 14 mutations extending life, in order to include natural genetic variants in our panel.

Aims and Rationale

Project 1 will examine a panel of 14 long-lived mutant strains, four naturally occurring polymorphisms, and two dietary means of life-extension in C. elegans. We are seeking common mechanisms -- e.g., effects on respiration, metabolic profiles, and antioxidant defenses -- that may account for the extended longevity and (in many but not all cases) accompanying reduction in sensitivity to oxidative and other stresses.

We have used QTL mapping (inference of quantitative trait loci based on linkage) to identify new genetic determinants of longevity and stress resistance, testing the hypothesis that these functions reside in the same genes and thus are modified conjointly in evolution. These loci may reflect natural variation in primarily higher-level or (more likely) lower-level molecular effectors. At the metabolic level of analysis, the various agents of life extension may be seen to comprise a handful of successful mechanisms.

We have identified two mutated alleles of a C. elegans gene, which extend adult lifespan by 10- to 11-fold. We have found that these alleles confer markedly enhanced resistance to some stresses, but not to others. Moreover, they elicit overlapping but distinct patterns of gene expression, to less longevitous alleles of the same gene; that is, some downstream genes are elevated or suppressed similarly in all hypomorphic alleles, whereas others are allele-specific.

Slide Presentation of Recent Data

Robert J. Shmookler Reis, D.Phil, Project Leader and Program P.I.

Srinivas Ayyadevara, Ph.D., Co-Investigator

Ramani Alla, M.Sc., Research Technician