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1.
J Gerontol A Biol Sci Med Sci ; 63(8): 798-808, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18772467

ABSTRACT

Protein damage that accumulates during aging can be mitigated by a repair methyltransferase, the l-isoaspartyl-O-methyltransferase. In Caenorhabditis elegans, the pcm-1 gene encodes this enzyme. In response to pheromone, we show that pcm-1 mutants form fewer dauer larvae with reduced survival due to loss of the methyltransferase activity. Mutations in daf-2, an insulin/insulin-like growth factor-1-like receptor, and daf-7, a transforming growth factor-beta-like ligand, modulate pcm-1 dauer defects. Additionally, daf-2 and daf-7 mutant dauer larvae live significantly longer than wild type. Although dauer larvae are resistant to many environmental stressors, a proportionately larger decrease in dauer larvae life spans occurred at 25 degrees C compared to 20 degrees C than in adult life span. At 25 degrees C, mutation of the daf-7 or pcm-1 genes does not change adult life span, whereas mutation of the daf-2 gene and overexpression of PCM-1 increases adult life span. Thus, there are both overlapping and distinct mechanisms that specify dauer and adult longevity.


Subject(s)
Aging/metabolism , Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/physiology , Cell Cycle Proteins/physiology , Gene Expression Regulation, Developmental/physiology , Methyltransferases/physiology , Aging/genetics , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Cell Cycle Proteins/genetics , Epistasis, Genetic , Forkhead Transcription Factors , Gene Expression Regulation, Developmental/genetics , Genes, Helminth , Larva/physiology , Longevity/genetics , Longevity/physiology , Methyltransferases/genetics , Mutation , Pheromones , Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics , Receptor, Insulin/physiology , Signal Transduction , Transcription Factors/physiology , Transforming Growth Factor beta/physiology
2.
Aging Cell ; 7(3): 291-304, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18267002

ABSTRACT

Coenzyme Q(n) is a fully substituted benzoquinone containing a polyisoprene tail of distinct numbers (n) of isoprene groups. Caenorhabditis elegans fed Escherichia coli devoid of Q(8) have a significant lifespan extension when compared to C. elegans fed a standard 'Q-replete'E. coli diet. Here we examine possible mechanisms for the lifespan extension caused by the Q-less E. coli diet. A bioassay for Q uptake shows that a water-soluble formulation of Q(10) is effectively taken up by both clk-1 mutant and wild-type nematodes, but does not reverse lifespan extension mediated by the Q-less E. coli diet, indicating that lifespan extension is not due to the absence of dietary Q per se. The enhanced longevity mediated by the Q-less E. coli diet cannot be attributed to dietary restriction, different Qn isoforms, reduced pathogenesis or slowed growth of the Q-less E. coli, and in fact requires E. coli viability. Q-less E. coli have defects in respiratory metabolism. C. elegans fed Q-replete E. coli mutants with similarly impaired respiratory metabolism due to defects in complex V also show a pronounced lifespan extension, although not as dramatic as those fed the respiratory deficient Q-less E. coli diet. The data suggest that feeding respiratory incompetent E. coli, whether Q-less or Q-replete, produces a robust life extension in wild-type C. elegans. We believe that the fermentation-based metabolism of the E. coli diet is an important parameter of C. elegans longevity.


Subject(s)
Caenorhabditis elegans/physiology , Culture Media/chemistry , Escherichia coli/metabolism , Longevity/physiology , Animals , Biological Assay , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Escherichia coli/genetics , Mutation , Ubiquinone/metabolism
3.
J Biol Chem ; 279(52): 54655-62, 2004 Dec 24.
Article in English | MEDLINE | ID: mdl-15485840

ABSTRACT

We demonstrate biochemically that the genes identified by sequence similarity as orthologs of the mitochondrial import machinery are functionally conserved in Caenorhabditis elegans. Specifically, tin-9.1 and tin-10 RNA interference (RNAi) treatment of nematodes impairs import of the ADP/ATP carrier into isolated mitochondria. Developmental phenotypes are associated with gene knock-down of the mitochondrial import components. RNAi of tomm-7 and ddp-1 resulted in mitochondria with an interconnected morphology in vivo, presumably due to defects in the assembly of outer membrane fission/fusion components. RNAi of the small Tim proteins TIN-9.1, TIN-9.2, and TIN-10 resulted in a small body size, reduced number of progeny produced, and partial embryonic lethality. An additional phenotype of the tin-9.2(RNAi) animals is defective formation of the somatic gonad. The biochemical demonstration that the protein import activity is reduced, under the same conditions that yield the defects in specific tissues and lethality in a later generation, suggests that the developmental abnormalities observed are a consequence of defects in mitochondrial inner membrane biogenesis.


Subject(s)
Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/growth & development , Membrane Transport Proteins/physiology , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Animals , Biological Transport , Caenorhabditis elegans/genetics , Caenorhabditis elegans/ultrastructure , Caenorhabditis elegans Proteins/genetics , Membrane Transport Proteins/genetics , Mitochondria/chemistry , Mitochondria/metabolism , Mitochondria/ultrastructure , Mitochondrial ADP, ATP Translocases/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology
4.
J Biol Chem ; 278(51): 51735-42, 2003 Dec 19.
Article in English | MEDLINE | ID: mdl-14530273

ABSTRACT

Caenorhabditis elegans clk-1 mutants lack coenzyme Q9 and accumulate the biosynthetic intermediate demethoxy-Q9. A dietary source of ubiquinone (Q) is required for larval growth and development of the gonad and germ cells. We considered that uptake of the shorter Q8 isoform present in the Escherichia coli food may contribute to the Clk phenotypes of slowed development and reduced brood size observed when the animals are fed Q-replete E. coli. To test the effect of isoprene tail length, N2 and clk-1 animals were fed E. coli engineered to produce Q7, Q8, Q9, or Q10. Wild-type nematodes showed no change in reproductive fitness regardless of the Qn isoform fed. clk-1(e2519) fed the Q9 diet showed increased egg production; however, this diet did not improve reproductive fitness of the clk-1(qm30) animals. Furthermore, animals with the more severe clk-1(qm30) allele become sterile and their progeny inviable when fed Q7-containing bacteria. The content of Q7 in the mitochondria of clk-1 animals was decreased relative to Q8, suggesting less effective transport of Q7 to the mitochondria, impaired retention, or decreased stability. Additionally, regardless of E. coli diet, clk-1(qm30) animals contain a dysfunctional dense form of mitochondria. The gonads of clk-1(qm30) worms fed Q7-containing food were severely shrunken and disordered. The differential fertility of clk-1 mutant nematodes fed Q isoforms may result from changes in Q localization, altered recognition by Q-binding proteins, and/or potential defects in mitochondrial function resulting from the mutant CLK-1 polypeptide itself.


Subject(s)
Benzoquinones/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/genetics , Ubiquinone/metabolism , Animals , Benzoquinones/analysis , Caenorhabditis elegans/growth & development , Caenorhabditis elegans/physiology , Caenorhabditis elegans Proteins/physiology , Mitochondria/metabolism , Mutation , Phenotype , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Reproduction , Structure-Activity Relationship , Ubiquinone/chemistry
5.
Sci Aging Knowledge Environ ; 2003(17): PE9, 2003 Apr 30.
Article in English | MEDLINE | ID: mdl-12844535

ABSTRACT

Several genes involved in the determination of life span have been identified by mutation in the free-living soil nematode Caenorhabditis elegans. One of the key pathways studied in the context of life span is the DAF-2 pathway. The daf-2 gene is homologous to the insulin and insulin-like growth factor 1 receptor families. A downstream gene, daf-16, encodes a protein that is homologous to the forkhead transcription factor. A study by McElwee, Bubb, and Thomas, published in the current issue of Aging Cell, used genome-scale gene expression analysis to search for genes that are differentially expressed between long-lived daf-2(e1370) and short-lived daf-16(m27);daf-2(e1370) animals. In doing so, they identified candidate direct and indirect targets of DAF-16. In this Perspective, I discuss the results of this study.


Subject(s)
Aging/physiology , Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/physiology , Gene Expression Regulation , Transcription Factors/physiology , Aging/genetics , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Forkhead Transcription Factors , Genes, Helminth , Longevity/genetics , Longevity/physiology , Models, Biological , Oligonucleotide Array Sequence Analysis , Receptor, Insulin/genetics , Receptor, Insulin/physiology , Transcription Factors/genetics , Transcription, Genetic
7.
J Biol Chem ; 277(47): 45020-7, 2002 Nov 22.
Article in English | MEDLINE | ID: mdl-12324451

ABSTRACT

The Caenorhabditis elegans clk-1 mutants lack coenzyme Q(9) and instead accumulate the biosynthetic intermediate demethoxy-Q(9) (DMQ(9)). clk-1 animals grow to reproductive adults, albeit slowly, if supplied with Q(8)-containing Escherichia coli. However, if Q is withdrawn from the diet, clk-1 animals either arrest development as young larvae or become sterile adults depending upon the stage at the time of the withdrawal. To understand this stage-dependent response to a Q-less diet, the quinone content was determined during development of wild-type animals. The quinone content varies in the different developmental stages in wild-type fed Q(8)-replete E. coli. The amounts peak at the second larval stage, which coincides with the stage of arrest of clk-1 larvae fed a Q-less diet from hatching. Levels of the endogenously synthesized DMQ(9) are high in the clk-1(qm30)-arrested larvae and sterile adults fed Q-less food. Comparison of quinones from animals fed a Q-replete or a Q-less diet establishes that the Q(8) present is assimilated from the E. coli. Furthermore, this E. coli-specific Q(8) is present in mitochondria isolated from fertile clk-1(qm30) adults fed a Q-replete diet. These results suggest that the uptake and transport of dietary Q(8) to mitochondria prevent the arrest and sterility phenotypes of clk-1 mutants and that DMQ is not functionally equivalent to Q.


Subject(s)
Biological Transport/physiology , Caenorhabditis elegans Proteins , Caenorhabditis elegans/growth & development , Diet , Helminth Proteins/genetics , Mitochondria/metabolism , Ubiquinone/metabolism , Animals , Caenorhabditis elegans/cytology , Caenorhabditis elegans/genetics , Caenorhabditis elegans/physiology , Genes, Helminth , Helminth Proteins/metabolism , Larva/physiology , Mitochondria/chemistry , Mutation , Quinones/metabolism , Temperature
8.
Science ; 295(5552): 120-3, 2002 Jan 04.
Article in English | MEDLINE | ID: mdl-11778046

ABSTRACT

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.


Subject(s)
Aging , Caenorhabditis elegans/physiology , Longevity , Ubiquinone/metabolism , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Diet , Escherichia coli/genetics , Escherichia coli/metabolism , Fermentation , Forkhead Transcription Factors , Genes, Helminth , Helminth Proteins/genetics , Helminth Proteins/metabolism , Larva/growth & development , Larva/metabolism , Mitochondria/metabolism , Models, Biological , Mutation , Oxidation-Reduction , Oxygen Consumption , Phenotype , Reactive Oxygen Species/metabolism , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , Ubiquinone/administration & dosage
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