Gerontogenes mediate health and longevity in nematodes through increasing resistance to environmental toxins and stressors.

More than 40 mutants in Caenorhabditis elegans have been demonstrated to lead to increased life span (a rigorous, operational test for being a gerontogene) of 20% or more ("Age" mutants). Age mutants alter rate-limiting determinants of longevity; moreover, important genes are identified independent of prior hypotheses as to actual mode of gene action in extending longevity and/or "slowing" aging. Age mutants define as many as nine (possibly) distinct pathways and/or modes of action, as defined by primary phenotype. Three well-studied mutants (age-1, clk-1, and spe-26) alter age-specific mortality rates in characteristic fashions; in age-1 mutants, especially, the changes in mortality rates are quite dramatic. All Age mutants (so far without exception) increase response to several (but not all) stresses, including heat, UV, and reactive oxidants. We have used directed strategies, as well as random mutagenesis, to identify novel genes increasing the worm's ability to resist stress. Two genes (daf-16 and old-1) yield over-expression strains that are stress resistant and long-lived. A variety of approaches to assess transcriptional alterations associated with increased longevity are underway. We suggest that the role of the Age genes in both longevity and stress resistance indicates that a major evolutionary determinant of longevity is the ability to respond to stress.