Genetics of lifespan in C. elegans: molecular diversity, physiological complexity, mechanistic simplicity

Hekimi, Siegfried; Burgess, Jason; Bussière, Frédéric; Meng, Yan; Bénard, Claire

doi:10.1016/s0168-9525(01)02523-9

Cited by 64 publications

(39 citation statements)

References 48 publications

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“…Hence recent human mortality improvement is often greater than that achieved by manipulated strains of model organisms relative to the wild type, especially when single mutations or physiological pathways are manipulated. However, experiments that simultaneously manipulate multiple pathways in organisms such as yeast and nematode worms can achieve much greater life span extensions (23,24). The majority of laboratory studies where mammals are the model organism have been done on mice and yield percentage life span increases less than those gained by humans (23).…”

Section: Resultsmentioning

confidence: 99%

Human mortality improvement in evolutionary context

Bürger

Baudisch

Vaupel

2012

Proc. Natl. Acad. Sci. U.S.A.

134

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Life expectancy is increasing in most countries and has exceeded 80 in several, as low-mortality nations continue to make progress in averting deaths. The health and economic implications of mortality reduction have been given substantial attention, but the observed malleability of human mortality has not been placed in a broad evolutionary context. We quantify the rate and amount of mortality reduction by comparing a variety of human populations to the evolved human mortality profile, here estimated as the average mortality pattern for ethnographically observed hunter-gatherers. We show that human mortality has decreased so substantially that the difference between hunter-gatherers and today's lowest mortality populations is greater than the difference between huntergatherers and wild chimpanzees. The bulk of this mortality reduction has occurred since 1900 and has been experienced by only about 4 of the roughly 8,000 human generations that have ever lived. Moreover, mortality improvement in humans is on par with or greater than the reductions in mortality in other species achieved by laboratory selection experiments and endocrine pathway mutations. This observed plasticity in age-specific risk of death is at odds with conventional theories of aging.biodemography | cross-species comparison | life history evolution | phenotypic plasticity | human lifespan

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Section: Resultsmentioning

confidence: 99%

Human mortality improvement in evolutionary context

Bürger

Baudisch

Vaupel

2012

Proc. Natl. Acad. Sci. U.S.A.

134

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“…Testing the ROS toxicity theory of aging: From the point of view of evolutionary theory, it is a reasonable hypothesis to speculate that aging is due to the accumulation of unrepaired damage, as there is an expected trade-off between reproduction and the costs associated with somatic maintenance (Hekimi et al 2001b). Toxicity from the ROS produced in mitochondria is an obvious candidate for an important source of damage in this process (Sohal 2002;Droge 2003).…”

Section: Discussionmentioning

confidence: 99%

“…A variety of Caenorhabditis elegans mutants display an increased, or shortened, life span compared to the wild type under standard conditions (Lakowski and Hekimi 1998;Guarente and Kenyon 2000;Hekimi et al 2001b;Tissenbaum and Guarente 2002;Hekimi and Guarente 2003;Boehm and Slack 2005;Kenyon 2005). In life-span studies in a variety of organisms, it is frequently found that increased or decreased life span is associated with changes in the biology of reactive oxygen species (ROS) (Beckman and Ames 1998;Golden et al 2002;Droge 2003;Hekimi and Guarente 2003;Balaban et al 2005), and this is also true for a variety of C. elegans mutants (Vanfleteren and Braeckman 1999;Feng et al 2001;Senoo-Matsuda et al 2001;Hekimi and Guarente 2003;Shibata et al 2003;de Castro et al 2004;Kayser et al 2004;Sedensky and Morgan 2006) and wild-type animals treated by RNA interference (RNAi) (Dillin et al 2002;Lee et al 2003).…”

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confidence: 99%

A Measurable Increase in Oxidative Damage Due to Reduction in Superoxide Detoxification Fails to Shorten the Life Span of Long-Lived Mitochondrial Mutants of Caenorhabditis elegans

Yang¹,

Li²,

2007

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SOD-1 and SOD-2 detoxify superoxide in the cytoplasm and mitochondria. We find that, although several long-lived mutants of Caenorhabditis elegans have increased SOD levels, this phenomenon does not correlate with life span or growth rate. Furthermore, although disruption of sod-1 or -2 expression produces numerous phenotypes, including increased sensitivity to paraquat and increased oxidative damage to proteins (except in daf-2 mutants), this fails to shorten the life span of these long-lived mutants. In fact, sod-1(RNAi) increases the life span of daf-2 mutants and sod-2(RNAi) that of clk-1 mutants. Our results suggest that increased superoxide detoxification and low oxidative damage are not crucial for the longevity of the mutants examined, with the possible exception of daf-2, where our results are inconclusive. These results are surprising because several of the long-lived mutants that we examined specifically affect mitochondrial electron transport, a process whose involvement in life-span determination is believed to be related to superoxide generation. We discuss the significance of our findings in light of the oxidative stress theory of aging.

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“…To better investigate this question, we studied clk-1 daf-2 double mutants (21). The effect of clk-1 mutations on lifespan is greatest in combination with mutations in daf-2, as mutations in clk-1 can approximately double the lifespan increase of daf-2 mutants (14,21,24).…”

Section: Maternally Rescued Daf-2 Clk-1 Double Mutants Have Increasedmentioning

confidence: 99%

Molecular Mechanism of Maternal Rescue in the clk-1 Mutants of Caenorhabditis elegans

Burgess

Hihi

Bénard

et al. 2003

Journal of Biological Chemistry

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The clk-1 mutants of Caenorhabditis elegans display an average slowing down of physiological rates, including those of development, various behaviors, and aging. clk-1 encodes a hydroxylase involved in the biosynthesis of the redox-active lipid ubiquinone (co-enzyme Q), and in clk-1 mutants, ubiquinone is replaced by its biosynthetic precursor demethoxyubiquinone. Surprisingly, homozygous clk-1 mutants display a wild-type phenotype when issued from a heterozygous mother. Here, we show that this maternal effect is the result of the persistence of small amounts of maternally derived CLK-1 protein and that maternal CLK-1 is sufficient for the synthesis of considerable amounts of ubiquinone during development. However, gradual depletion of CLK-1 and ubiquinone, and expression of the mutant phenotype, can be produced experimentally by developmental arrest. We also show that the very long lifespan observed in daf-2 clk-1 double mutants is not abolished by the maternal effect. This suggests that, like developmental arrest, the increased lifespan conferred by daf-2 allows for depletion of maternal CLK-1, resulting in the expression of the synergism between clk-1 and daf-2. Thus, increased adult longevity can be uncoupled from the early mutant phenotypes, indicating that it is possible to obtain an increased adult lifespan from the late inactivation of processes required for normal development and reproduction.The clk-1 gene of Caenorhabditis elegans encodes a 187-amino acid protein that is orthologous to yeast Coq7p as well as to rodent and human sequences (1). CLK-1 is necessary for ubiquinone (coenzyme Q, or Q) 1 biosynthesis. Q n is a prenylated benzoquinone (the numerical subscript denotes the number of isoprene repeats, which is a species-specific trait) that is primarily involved in numerous redox reactions in the cell, including those in the mitochondrial electron transport chain. In its reduced form, Q is an antioxidant, preventing lipid peroxidation in biological membranes (2, 3). In the absence of CLK-1, worms and mice are defective in Q biosynthesis (4 -6) and accumulate the Q precursor, demethoxyubiquinone (DMQ 9 ) (5, 6). Yet, mitochondrial respiration is not strongly affected in clk-1 mutants, indicating that DMQ can substitute for some, but not all, of the Q functions in vivo (5-9).Despite the presence of DMQ, clk-1 mutants require Q from their bacterial food source to proceed through development and become fertile adults (4, 10). Indeed, when clk-1 mutants are transferred onto a Q 8 -deficient E. coli strain before the early larval stages, they arrest development at the second larval stage, and when the animals are transferred onto Q 8 -deficient bacteria later in development, they become sterile adults. This fact strongly suggests that DMQ 9 cannot functionally replace Q 9 for all of its cellular roles, and that at least some Q is required, which can be provided as Q 8 in the diet. Thus, the viability and overall good health of the clk-1 mutants seems to rely on a combination of endogenously produced DM...

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Genetics of lifespan in C. elegans: molecular diversity, physiological complexity, mechanistic simplicity

Cited by 64 publications

References 48 publications

Human mortality improvement in evolutionary context

Human mortality improvement in evolutionary context

A Measurable Increase in Oxidative Damage Due to Reduction in Superoxide Detoxification Fails to Shorten the Life Span of Long-Lived Mitochondrial Mutants of Caenorhabditis elegans

Molecular Mechanism of Maternal Rescue in the clk-1 Mutants of Caenorhabditis elegans

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