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 le ad to increased life span (a rigorous, operational test for being a geronto gene) of 20% or more ("Age" mutants). Age mutants alter rate-limiting deter minants 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) dist inct pathways and/or modes of action, as defined by primary phenotype. Thre e well-studied mutants (age-1, clk-1, and spe-26) alter age-specific mortal ity rates in characteristic fashions; in age-1 mutants, especially, the cha nges 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 abilit y to resist stress. Two genes (daf-16 and old-1) yield over-expression stra ins that are stress resistant and long-lived. A variety of approaches to as sess transcriptional alterations associated with increased longevity are un derway. We suggest that the role of the Age genes in both longevity and str ess resistance indicates that a major evolutionary determinant of longevity is the ability to respond to stress. (C) 2000 Elsevier Science Inc. All ri ghts reserved.