The dauer larva state and the age-i mutation, both of which extend life-span in Caenorhabdit elegans, were tested for hyperresistance to cellular damage that may be relevant to aging. The age-i strain TJ401 displayed hyperresitance to oxidative stress relative to its parental strain. The activities of two enzymes that protect cells from oxidative damage, superoxide dismutase (SOD) and catalase, showed an age-dependent increase in mutant animals, which was not seen in the parental strain. These increases in activities paralleled the time course of the hyperresistance. The results are consistent with the age-i gene product functioning as a neptive rglator of SOD and cataase activities. In wild-type and age-i dauer larvae, elevated levels ofSOD activity, but not ofcatalase activit, were present when compared with young adults. The common increase in SOD activity prompted cloning the C. ekgans Cu/Zn SOD gene. Its position on the physical map of the genome was in the region to which the age-i gene has been genetically mapped, but it is unlikely that a mutation at the SOD locus confers the Age phenotype. Results support the free radical theory of aging by suggesting that the increased resistance to oidative stress may be among the causes of increased longevity in both strain TJ401 and in the dauer larva.Life-span is a species-specific attribute that is determined by the interaction of the environment with the genetic predisposition of the individual. There are a variety of theories on the mechanisms of aging (1-3). This work tested one mechanism of aging based on the assumption that the level of cellular defense and repair is sufficient yet unlikely to provide the maximum obtainable cellular protection. This assumption is derived from the premise that each species has evolved a unique repertoire of cellular defense and repair mechanisms to maintain the soma (non-germ-cell tissues) while striving to maximize the success of its reproductive strategy. If accumulated cellular damage causes aging, then an increased life-span may result from improved defense and repair capacities (although it may be at the expense of reproductive capacity). It is feasible to test this hypothesis for specific types of damage potentially relevant to aging because protective cellular mechanisms such as DNA repair, heat shock response, and protection against free radical species have been extensively characterized (4-6).The experiments reported here test the prediction that increased resistance to oxidative damage could lead to increased life-span. The free radical theory of aging postulates that free radical reactions are a basic cause ofaging, and these reactions are influenced by genetic and environmental factors (7). The free radical theory is generally supported by correlations between the life-span of various species and either their metabolic rates or their incurred level of oxidative damage (8, 9). In addition, correlations between decreased life-span and decreased levels of enzymes involved in protection from oxidative damage h...

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The isoprenylated benzoquinone coenzyme Q is a redox-active lipid essential for electron transport in aerobic respiration. Here, we show that withdrawal of coenzyme Q (Q) from the diet of wild-type nematodes extends adult life-span by approximately 60%. The longevity of clk-1, daf-2, daf-12, and daf-16 mutants is also extended by a Q-less diet. These results establish the importance of Q in life-span determination. The findings suggest that Q and the daf-2 pathway intersect at the mitochondria and imply that a concerted production coupled with enhanced scavenging of reactive oxygen species contributes to the substantial life-span extension.

The nematode Caenorhabditis elegans responds to overcrowding and scarcity of food by arresting development as a dauer larva, a nonfeeding, long-lived, stress-resistant, alternative third-larval stage. Previous work has shown that mutations in the genes daf-2 (encoding a member of the insulin receptor family) and age-1 (encoding a PI 3-kinase) result in constitutive formation of dauer larvae (Daf-c), increased adult longevity (Age), and increased intrinsic thermotolerance (Itt). Some daf-2 mutants have additional developmental, behavioral, and reproductive defects. We have characterized in detail 15 temperature-sensitive and 1 nonconditional daf-2 allele to investigate the extent of daf-2 mutant defects and to examine whether specific mutant traits correlate with each other. The greatest longevity seen in daf-2 mutant adults was approximately three times that of wild type. The temperature-sensitive daf-2 mutants fell into two overlapping classes, including eight class 1 mutants, which are Daf-c, Age, and Itt, and exhibit low levels of L1 arrest at 25.5°. Seven class 2 mutants also exhibit the class 1 defects as well as some or all of the following: reduced adult motility, abnormal adult body and gonad morphology, high levels of embryonic and L1 arrest, production of progeny late in life, and reduced brood size. The strengths of the Daf-c, Age, and Itt phenotypes largely correlated with each other but not with the strength of class 2-specific defects. This suggests that the DAF-2 receptor is bifunctional. Examination of the null phenotype revealed a maternally rescued egg, L1 lethal component, and a nonconditional Daf-c component. With respect to the Daf-c phenotype, the dauer-defective (Daf-d) mutation daf-12(m20) was epistatic to daf-2 class 1 alleles but not the severe class 2 alleles tested. All daf-2 mutant defects were suppressed by the daf-d mutation daf-16(m26). Our findings suggest a new model for daf-2, age-1, daf-12, and daf-16 interactions.