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1.
PLoS One ; 12(5): e0176798, 2017.
Article in English | MEDLINE | ID: mdl-28459841

ABSTRACT

Nrf2/skn-1, a transcription factor known to mediate adaptive responses of cells to stress, also regulates energy metabolism in response to changes in nutrient availability. The ability to locate food sources depends upon chemosensation. Here we show that Nrf2/skn-1 is expressed in olfactory interneurons, and is required for proper integration of multiple food-related sensory cues in Caenorhabditis elegans. Compared to wild type worms, skn-1 mutants fail to perceive that food density is limiting, and display altered chemo- and thermotactic responses. These behavioral deficits are associated with aberrant AIY interneuron morphology and migration in skn-1 mutants. Both skn-1-dependent AIY autonomous and non-autonomous mechanisms regulate the neural circuitry underlying multisensory integration of environmental cues related to energy acquisition.


Subject(s)
Appetitive Behavior/physiology , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , DNA-Binding Proteins/metabolism , Interneurons/metabolism , Sensation/physiology , Transcription Factors/metabolism , Animals , Animals, Genetically Modified , Brain/cytology , Brain/metabolism , Caenorhabditis elegans/cytology , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Cell Movement/physiology , DNA-Binding Proteins/genetics , Feeding Behavior/physiology , Interneurons/cytology , Mice, Inbred C57BL , Mutation , NF-E2-Related Factor 2/metabolism , Olfactory Perception/physiology , Sensory Receptor Cells/metabolism , Transcription Factors/genetics
2.
Sci Rep ; 7: 46208, 2017 04 11.
Article in English | MEDLINE | ID: mdl-28397803

ABSTRACT

Aging is a major international concern that brings formidable socioeconomic and healthcare challenges. Small molecules capable of improving the health of older individuals are being explored. Small molecules that enhance cellular stress resistance are a promising avenue to alleviate declines seen in human aging. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in C. elegans, an animal model of aging which shares many major longevity pathways with mammals. Tomatidine improves many C. elegans behaviors related to healthspan and muscle health, including increased pharyngeal pumping, swimming movement, and reduced percentage of severely damaged muscle cells. Microarray, imaging, and behavioral analyses reveal that tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy. This mechanism occurs in C. elegans, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions for diseases of aging.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , DNA-Binding Proteins/metabolism , Longevity/physiology , Mitophagy/drug effects , NF-E2-Related Factor 2/metabolism , Signal Transduction/drug effects , Tomatine/analogs & derivatives , Transcription Factors/metabolism , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Gene Expression Regulation/drug effects , Longevity/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Muscles/drug effects , Muscles/physiology , Organelle Biogenesis , Reactive Oxygen Species/metabolism , Stress, Physiological/drug effects , Tomatine/pharmacology , Transcriptome/genetics
3.
Cell Metab ; 24(4): 566-581, 2016 10 11.
Article in English | MEDLINE | ID: mdl-27732836

ABSTRACT

Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.


Subject(s)
Ataxia Telangiectasia/pathology , DNA Repair/drug effects , Health , Longevity/drug effects , Mitophagy/drug effects , NAD/pharmacology , Animals , Ataxia Telangiectasia Mutated Proteins/deficiency , Ataxia Telangiectasia Mutated Proteins/metabolism , Behavior, Animal , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/ultrastructure , Cells, Cultured , Disease Models, Animal , Gene Knockdown Techniques , Homeostasis/drug effects , Metabolomics , Mice , Neurons/drug effects , Neurons/metabolism , Phenotype , Phthalazines/pharmacology , Piperazines/pharmacology , Proteomics , Rats, Sprague-Dawley , Signal Transduction/drug effects , Sirtuin 1/metabolism
4.
Age (Dordr) ; 35(3): 689-703, 2013 Jun.
Article in English | MEDLINE | ID: mdl-22610697

ABSTRACT

We present an initial molecular characterization of a morphological transition between two early aging states. In previous work, an age score reflecting physiological age was developed using a machine classifier trained on images of worm populations at fixed chronological ages throughout their lifespan. The distribution of age scores identified three stable post-developmental states and transitions. The first transition occurs at day 5 post-hatching, where a significant percentage of the population exists in both state I and state II. The temperature dependence of the timing of this transition (Q 10 ~ 1.17) is too low to be explained by a stepwise process with an enzymatic or chemical rate-limiting step, potentially implicating a more complex mechanism. Individual animals at day 5 were sorted into state I and state II groups using the machine classifier and analyzed by microarray expression profiling. Despite being isogenic, grown for the same amount of time, and indistinguishable by eye, these two morphological states were confirmed to be molecularly distinct by hierarchical clustering and principal component analysis of the microarray results. These molecular differences suggest that pharynx morphology reflects the aging state of the whole organism. Our expression profiling yielded a gene set that showed significant overlap with those from three previous age-related studies and identified several genes not previously implicated in aging. A highly represented group of genes unique to this study is involved in targeted ubiquitin-mediated proteolysis, including Skp1-related (SKR), F-box-containing, and BTB motif adaptors.


Subject(s)
Aging/physiology , Caenorhabditis elegans Proteins/chemistry , Caenorhabditis elegans/growth & development , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Cell Cycle Proteins/chemistry , Cell Cycle Proteins/genetics , Cullin Proteins/chemistry , Cullin Proteins/genetics , Oligonucleotide Array Sequence Analysis
5.
BMC Physiol ; 11: 11, 2011 Jul 12.
Article in English | MEDLINE | ID: mdl-21749693

ABSTRACT

BACKGROUND: Evolutionary theories of aging propose that longevity evolves as a competition between reproduction and somatic maintenance for a finite pool of resources. Reproduction is thought to shorten lifespan by depleting resources from processes promoting somatic maintenance. Maternal yolk production, vitellogenesis, represents a significant maternal cost for reproduction and is suppressed under genetic and environmental conditions that extend lifespan. However, little is known about the pathways regulating vitellogenesis in response to prolongevity cues. RESULTS: In order to identify mechanisms that suppress vitellogenesis under prolongevity conditions, we studied factors regulating vitellogenesis in C. elegans nematodes. In C. elegans, vitellogenesis is depressed in the absence of insulin-like signaling (IIS). We found that the C. elegans daf-2/IIS pathway regulates vitellogenesis through two mechanisms. vit-2 transcript levels in daf-2 mutants were indirectly regulated through a germline-dependent signal, and could be rescued by introduction of daf-2(+) sperm. However, yolk protein (YP) levels in daf-2 mutants were also regulated by germline-independent posttranscriptional mechanisms. CONCLUSIONS: C. elegans vitellogenesis is regulated transcriptionally and posttranscriptionally in response to environmental and reproductive cues. The daf-2 pathway suppressed vitellogenesis through transcriptional mechanisms reflecting reproductive phenotypes, as well as distinct posttranscriptional mechanisms. This study reveals that pleiotropic effects of IIS pathway mutations can converge on a common downstream target, vitellogenesis, as a mechanism to modulate longevity.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/growth & development , Gene Expression Regulation, Developmental , Receptor, Insulin/metabolism , Vitellogenesis/genetics , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Female , Gene Expression Regulation , Genetic Pleiotropy/physiology , Longevity/genetics , Longevity/physiology , Male , Mutation , Receptor, Insulin/genetics , Signal Transduction , Spermatozoa/metabolism , Transcription, Genetic
6.
PLoS One ; 6(3): e17369, 2011 Mar 09.
Article in English | MEDLINE | ID: mdl-21408062

ABSTRACT

Insulin/IGF-I-like signaling (IIS) has both cell autonomous and non-autonomous functions. In some cases, targets through which IIS regulates cell-autonomous functions, such as cell growth and metabolism, have been identified. In contrast, targets for many non-autonomous IIS functions, such as C. elegans dauer morphogenesis, remain elusive. Here, we report the use of genomic and genetic approaches to identify potential non-autonomous targets of C. elegans IIS. First, we used transcriptional microarrays to identify target genes regulated non-autonomously by IIS in the intestine or in neurons. C. elegans IIS controls expression of a number of stress response genes, which were differentially regulated by tissue-restricted IIS. In particular, expression of sod-3, a MnSOD enzyme, was not regulated by tissue-restricted IIS on the microarrays, while expression of hsp-16 genes was rescued back to wildtype by tissue restricted IIS. One IIS target regulated non-autonomously by age-1 was cyp-35B1/dod-13, encoding a cytochrome P450. Genetic analysis of the cyp-35B1 promoter showed both DAF-16 and HSF-1 are direct regulators. Based on these findings, we propose that hsf-1 may participate in the pathways mediating non-autonomous activities of age-1 in C. elegans.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/genetics , Cytochrome P-450 Enzyme System/genetics , Gene Expression Regulation , Insulin/metabolism , Receptor, Insulin/metabolism , Transcription Factors/metabolism , Animals , Caenorhabditis elegans Proteins/metabolism , Cytochrome P-450 Enzyme System/metabolism , Forkhead Transcription Factors , Gene Expression Profiling , Intestinal Mucosa/metabolism , Larva , Mutation/genetics , Oligonucleotide Array Sequence Analysis , Organ Specificity/genetics , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Regulatory Sequences, Nucleic Acid/genetics , Sequence Deletion/genetics , Signal Transduction/genetics , Stress, Physiological/genetics , Transcription, Genetic , Two-Hybrid System Techniques
7.
Proc Natl Acad Sci U S A ; 107(16): 7413-8, 2010 Apr 20.
Article in English | MEDLINE | ID: mdl-20368426

ABSTRACT

Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in C. elegans because knockouts of the O-GlcNAc cycling enzymes are viable and fertile. Using anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays on wild-type and mutant strains, we detected over 800 promoters where O-GlcNAc cycling occurs, including microRNA loci and multigene operons. Intriguingly, O-GlcNAc-marked promoters are biased toward genes associated with PIP3 signaling, hexosamine biosynthesis, and lipid/carbohydrate metabolism. These marked genes are linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways in C. elegans. Whole-genome transcriptional profiling of the O-GlcNAc cycling mutants confirmed dramatic deregulation of genes in these key pathways. As predicted, the O-GlcNAc cycling mutants show altered lifespan and UV stress susceptibility phenotypes. We propose that O-GlcNAc cycling at promoters participates in a molecular program impacting nutrient-responsive pathways in C. elegans, including stress, pathogen response, and adult lifespan. The observed impact of O-GlcNAc cycling on both signaling and transcription in C. elegans has important implications for human diseases of aging, including diabetes and neurodegeneration.


Subject(s)
Acetylglucosamine/genetics , Caenorhabditis elegans/genetics , Longevity/genetics , Animals , Caenorhabditis elegans/metabolism , Carbohydrates/chemistry , Chromatin/genetics , Chromatin/metabolism , Epigenesis, Genetic , Gene Expression Profiling , Immune System , Insulin/metabolism , Lipids/chemistry , Operon , Phosphorylation , Promoter Regions, Genetic , Signal Transduction
8.
PLoS One ; 3(7): e2821, 2008 Jul 30.
Article in English | MEDLINE | ID: mdl-18665238

ABSTRACT

Aging is associated with functional and structural declines in many body systems, even in the absence of underlying disease. In particular, skeletal muscles experience severe declines during aging, a phenomenon termed sarcopenia. Despite the high incidence and severity of sarcopenia, little is known about contributing factors and development. Many studies focus on functional aspects of aging-related tissue decline, while structural details remain understudied. Traditional approaches for quantifying structural changes have assessed individual markers at discrete intervals. Such approaches are inadequate for the complex changes associated with aging. An alternative is to consider changes in overall morphology rather than in specific markers. We have used this approach to quantitatively track tissue architecture during adulthood and aging in the C. elegans pharynx, the neuromuscular feeding organ. Using pattern recognition to analyze aged-grouped pharynx images, we identified discrete step-wise transitions between distinct morphologies. The morphology state transitions were maintained in mutants with pharynx neurotransmission defects, although the pace of the transitions was altered. Longitudinal measurements of pharynx function identified a predictive relationship between mid-life pharynx morphology and function at later ages. These studies demonstrate for the first time that adult tissues undergo distinct structural transitions reflecting postdevelopmental events. The processes that underlie these architectural changes may contribute to increased disease risk during aging, and may be targets for factors that alter the aging rate. This work further demonstrates that pattern analysis of an image series offers a novel and generally accessible approach for quantifying morphological changes and identifying structural biomarkers.


Subject(s)
Aging , Caenorhabditis elegans/physiology , Gene Expression Regulation , Animals , Biomarkers , Caenorhabditis elegans Proteins/metabolism , Cellular Senescence , Genes, Helminth , Image Processing, Computer-Assisted , Longevity , Models, Biological , Pharynx/metabolism , Serotonin/deficiency , Time Factors
9.
PLoS One ; 2(11): e1240, 2007 Nov 28.
Article in English | MEDLINE | ID: mdl-18043747

ABSTRACT

BACKGROUND: Dietary restriction (DR) and reduced insulin/IGF-I-like signaling (IIS) are two regimens that promote longevity in a variety of organisms. Genetic analysis in C. elegans nematodes has shown that DR and IIS couple to distinct cellular signaling pathways. However, it is not known whether these pathways ultimately converge on overlapping or distinct targets to extend lifespan. PRINCIPAL FINDINGS: We investigated this question by examining additional effects of DR in wildtype animals and in daf-2 mutants with either moderate or severe IIS deficits. Surprisingly, DR and IIS had opposing effects on these physiological processes. First, DR induced a stress-related change in intestinal vesicle trafficking, termed the FIRE response, which was suppressed in daf-2 mutants. Second, DR did not strongly affect expression of a daf-2- and stress-responsive transcriptional reporter. Finally, DR-related growth impairment was suppressed in daf-2 mutants. CONCLUSIONS: These findings reveal that an important biological function of DAF-2/IIS is to enhance growth and survival under nutrient-limited conditions. However, we also discovered that levels of DAF-2 pathway activity modified the effects of DR on longevity. Thus, while DR and IIS clearly affect lifespan through independent targets, there may also be some prolongevity targets that are convergently regulated by these pathways.


Subject(s)
Aging/metabolism , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Diet , Insulin/metabolism , Receptor, Insulin/metabolism , Signal Transduction , Stress, Physiological/metabolism , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Mutation , RNA Interference
10.
Dev Biol ; 303(2): 434-47, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17257591

ABSTRACT

In C. elegans, insulin signaling affects development, lifespan and stress resistance. Several studies have shown that insulin signaling affects lifespan in an endocrine-like manner from different cells, while the major downstream target of insulin, the FOXO transcription factor encoded by daf-16, may act preferentially in intestinal cells to prolong lifespan. This discrepancy raised the possibility that insulin may have both endocrine and cell-intrinsic outputs. Here, we further investigated the types of cells capable of producing endocrine outputs of insulin and also identified a new cell-intrinsic insulin output. We found that insulin signaling within groups of neurons promoted wildtype lifespan, showing that the endocrine outputs of insulin were not restricted to specific cells. In contrast, DAF-16 appeared to have a greater effect on lifespan when expressed in a combination of tissues. These results suggest that insulin signaling may regulate DAF-16 through cell-intrinsic and endocrine pathways. We also found that an insulin-dependent response to fasting in intestinal cells was preferentially regulated by intestinal insulin signaling and was less responsive to insulin signaling from non-intestinal cells. Together, these results show that C. elegans insulin signaling has endocrine as well as tissue-specific outputs which could influence lifespan in a combinatorial fashion.


Subject(s)
Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/physiology , Insulin/physiology , Aging/genetics , Animals , Animals, Genetically Modified , Caenorhabditis elegans/cytology , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Caenorhabditis elegans Proteins/genetics , Fasting , Forkhead Transcription Factors , Genes, Helminth , Longevity/genetics , Models, Biological , Mutation , Neurons/physiology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/physiology , Signal Transduction , Transcription Factors/genetics , Transcription Factors/physiology
11.
BMC Dev Biol ; 6: 45, 2006 Oct 04.
Article in English | MEDLINE | ID: mdl-17020605

ABSTRACT

BACKGROUND: In the nematode, Caenorhabditis elegans, a conserved insulin-like signaling pathway controls larval development, stress resistance and adult lifespan. AGE-1, a homolog of the p110 catalytic subunit of phosphoinositide 3-kinases (PI3K) comprises the major known effector pathway downstream of the insulin receptor, DAF-2. Phospholipid products of AGE-1/PI3K activate AKT/PKB kinase signaling via PDK-1. AKT/PKB signaling antagonizes nuclear translocation of the DAF-16/FOXO transcription factor. Reduced AGE-1/PI3K signaling permits DAF-16 to direct dauer larval arrest and promote long lifespan in adult animals. In order to study the downstream effectors of AGE-1/PI3K signaling in C. elegans, we conducted a genetic screen for mutations that suppress the constitutive dauer arrest phenotype of age-1(mg109) animals. RESULTS: This report describes mutations recovered in a screen for suppressors of the constitutive dauer arrest (daf-C) phenotype of age-1(mg109). Two mutations corresponded to alleles of daf-16. Two mutations were gain-of-function alleles in the genes, akt-1 and pdk-1, encoding phosphoinositide-dependent serine/threonine kinases. A fifth mutation, mg227, located on chromosome X, did not correspond to any known dauer genes, suggesting that mg227 may represent a new component of the insulin pathway. Genetic epistasis analysis by RNAi showed that reproductive development in age-1(mg109);akt-1(mg247) animals was dependent on the presence of pdk-1. Similarly, reproductive development in age-1(mg109);pdk-1(mg261) animals was dependent on akt-1. However, reproductive development in age-1(mg109); mg227 animals required only akt-1, and pdk-1 activity was dispensable in this background. Interestingly, while mg227 suppressed dauer arrest in age-1(mg109) animals, it enhanced the long lifespan phenotype. In contrast, akt-1(mg247) and pdk-1(mg261) did not affect lifespan or stress resistance, while both daf-16 alleles fully suppressed these phenotypes. CONCLUSION: A screen for suppressors of PI3K mutant phenotypes identified activating mutations in two known pathway components, providing insights into their regulation. In particular, the interdependence of akt-1 and pdk-1, even in activated forms, supports the existence of AGE-1-independent pathways for these phospholipid-dependent kinases. Phenotypic analysis of these alleles shows that the larval and adult outputs of AGE-1/PI3K are fully separable in these mutants.


Subject(s)
Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/physiology , Phosphatidylinositol 3-Kinases/physiology , Receptor, Insulin/physiology , Signal Transduction/physiology , Adaptation, Physiological/genetics , Adaptation, Physiological/physiology , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cell Nucleus/metabolism , Cytoplasm/metabolism , Forkhead Transcription Factors , Gene Expression Regulation, Developmental , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Longevity/genetics , Longevity/physiology , Mutation/genetics , Oxidative Stress/physiology , Phenotype , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/physiology , RNA Interference , Receptor, Insulin/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Signal Transduction/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Transfection/methods
12.
Ageing Res Rev ; 5(2): 196-208, 2006 May.
Article in English | MEDLINE | ID: mdl-16707280

ABSTRACT

Uncoupling proteins (UCPs), which dissipate the mitochondrial proton gradient, have the ability to decouple mitochodrial respiration from ATP production. Since mitochondrial electron transport is a major source of free radical production, it is possible that UCP activity might impact free radical production. Free radicals can react with and damage cellular proteins, DNA and lipids. Accumulated damage from oxidative stress is believed to be a major contributor to cellular decline during aging. If UCP function were to impact mitochondrial free radical production, then one would expect to find a link between UCP activity and aging. This theory has recently been tested in a handful of organisms whose genomes contain UCP1 homologs. Interestingly, these experiments indicate that UCP homologs can affect lifespan, although they do not support a simple relationship between UCP activity and aging. Instead, UCP-like proteins appear to have a variety of effects on lifespan, and on pathways implicated in lifespan regulation. One possible explanation for this complex picture is that UCP homologs may have tissue-specific effects that complicate their effects on aging. Furthermore, the functional analysis of UCP1 homologs is incomplete. Thus, these proteins may perform functions in addition to, or instead of, mitochondrial uncoupling. Although these studies have not revealed a clear picture of UCP effects on aging, they have contributed to the growing knowledge base for these interesting proteins. Future biochemical and genetic investigation of UCP-like proteins will do much to clarify their functions and to identify the regulatory networks in which they are involved.


Subject(s)
Carrier Proteins/metabolism , Energy Metabolism/physiology , Longevity/physiology , Membrane Proteins/metabolism , Mitochondria/metabolism , Aging/metabolism , Aging/physiology , Animals , Ion Channels , Mitochondrial Proteins , Models, Biological , Oxidative Phosphorylation , Uncoupling Protein 1
13.
Mech Ageing Dev ; 126(10): 1090-6, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15893362

ABSTRACT

Reactive oxygen species (ROS) are generated by mitochondrial respiration and can react with and damage cellular components. According to the free radical theory of aging, oxidative damage from mitochondrial ROS is a major cause of cellular decline during aging. Mitochondrial uncoupling proteins (UCPs) uncouple ATP production from electron transport and can be stimulated by free radicals, suggesting UCPs may perform a cytoprotective function. The nematode, Caenorhabditis elegans, contains one UCP-like protein, encoded by the ucp-4 gene. We have investigated the genetic requirement for ucp-4 in normal aging and stress resistance. Consistent with the hypothesis that ucp-4 encodes a putative uncoupling protein, animals lacking ucp-4 function contained elevated ATP levels. However, the absence of ucp-4 function did not affect adult lifespan or survival in the presence of thermal or oxidative stress. Together, these results demonstrate that ucp-4 is a negative regulator of ATP production in C. elegans, but is not required for normal lifespan.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/genetics , Longevity/genetics , Membrane Transport Proteins/genetics , Mitochondria/genetics , Adenosine Triphosphate/genetics , Adenosine Triphosphate/metabolism , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/metabolism , Electron Transport/genetics , Membrane Transport Proteins/metabolism , Mitochondria/metabolism , Mitochondrial Uncoupling Proteins , Oxygen Consumption/genetics , Reactive Oxygen Species/metabolism
14.
J Gerontol A Biol Sci Med Sci ; 59(12): 1251-60, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15699524

ABSTRACT

Many behavioral responses require the coordination of sensory inputs with motor outputs. Aging is associated with progressive declines in both motor function and muscle structure. However, the consequences of age-related motor deficits on behavior have not been clearly defined. Here, we examined the effects of aging on behavior in the nematode, Caenorhabditis elegans. As animals aged, mild locomotory deficits appeared that were sufficient to impair behavioral responses to sensory cues. In contrast, sensory ability appeared well maintained during aging. Age-related behavioral declines were delayed in animals with mutations in the daf-2/insulin-like pathway governing longevity. A decline in muscle tissue integrity was correlated with the onset of age-related behavioral deficits, although significant muscle deterioration was not. Treatment with a muscarinic agonist significantly improved locomotory behavior in aged animals, indicating that improved neuromuscular signaling may be one strategy for reducing the severity of age-related behavioral impairments.


Subject(s)
Aging/psychology , Caenorhabditis elegans/physiology , Locomotion , Muscles/physiology , Acetylcholine/metabolism , Aging/physiology , Animals , Caenorhabditis elegans Proteins , Motor Neurons/physiology , Muscarinic Agonists/pharmacology , Muscle Contraction/drug effects , Muscles/pathology , Mutation , Nicotinic Agonists/pharmacology , Receptor, Insulin/genetics , Sensation
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