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Gordon J Lithgow

Publications and source records attributed to Gordon J Lithgow.

18 recordsLinked to original sources
PubMed2006

Why aging isn't regulated: a lamentation on the use of language in aging literature.

Aging research has a problem. The field is expanding rapidly but our understanding of aging is clouded because of the language we use when describing genes that influence aging. As researchers from different disciplines gather to solve aging problems, different terms are being used to describe genetic affects. Genetic alterations can bring about enormous changes in lifespan but the significance of these experiments is debated; either the results are hailed as spectacular breakthroughs or alternatively considered laboratory artifacts unlikely to reveal useful knowledge about aging. How could this have come about and what do we need to do about it? I suggest we need to listen to exactly what each other is saying and also think carefully about how we are using key terms when describing our results. Rather than a scholarly review of this important issue, this article is intended to prompt debate. Consequently, "the gloves are off".

Aging↗
PubMed2006

Lifespan extension of Caenorhabditis elegans following repeated mild hormetic heat treatments.

Mild hormetic heat treatments early in life can significantly increase the lifespan of the nematode C. elegans. We have examined the effects of heat treatments at different ages and show that treatments early in life cause the largest increases in lifespan. We also find that repeated mild heat treatments throughout life have a larger effect on lifespan compared to a single mild heat treatment early in life. We hypothesize that the magnitude of the hormetic effect is related to the levels of heat shock protein expression. Following heat treatment young worms show a dramatic increase in the levels of the small heat shock protein HSP-16 whereas old worms are a 100-fold less responsive. The levels of the heat shock proteins HSP-4 and HSP-16 correlate well with the effects on lifespan by the hormetic treatments.

Adaptation, Physiological↗
PubMed2006

Checkpoint proteins control survival of the postmitotic cells in Caenorhabditis elegans.

Checkpoints are evolutionarily conserved signaling mechanisms that arrest cell division and alter cellular stress resistance in response to DNA damage or stalled replication forks. To study the consequences of loss of checkpoint functions in whole animals, checkpoint genes were inactivated in the nematode C. elegans. We show that checkpoint proteins are not only essential for normal development but also determine adult somatic maintenance. Checkpoint proteins play a role in the survival of postmitotic adult cells.

Adaptation, Physiological↗
PubMed2006

The nuclear hormone receptor DAF-12 has opposing effects on Caenorhabditis elegans lifespan and regulates genes repressed in multiple long-lived worms.

The orphan nuclear hormone receptor gene daf-12 in Caenorhabditis elegans plays a key role in the regulation of development and determination of adult longevity. To understand the effects of daf-12 on aging we characterized the lifespan of loss-of-function and gain-of-function daf-12 alleles that have been identified on the basis of their effects on dauer development. We find that these mutations have opposing effects on longevity and resistance to oxidative and thermal stress which makes daf-12 the first gene with alleles that can extend or shorten lifespan. We find that the shortened lifespan of the loss-of-function mutation is due to accelerated aging in young adulthood rather than an adverse effect of the mutation on development. Microarray analysis of worms carrying the two alleles revealed a relatively small number of genes differentially expressed between the two genotypes. Comparison of the expression profiles with the profiles associated with dauer formation and long-lived daf-2 mutants revealed that while the profiles are largely different, there is significant overlap among the genes down-regulated, but not up-regulated, in all profiles. Several of these genes down-regulated in multiple long-lived worms have known effects on lifespan, and many of the genes belong to a family of poorly characterized genes that are strongly down-regulated in dauers, daf-2 mutants, and long-lived daf-12 mutants. Our results point to daf-12 modulating aging and stress responses in part through the repression of specific genes, and emphasize the role that the repression of genes that curtail maximal lifespan plays in lifespan determination.

Amino Acid Sequence↗
PubMed2006

DAF-12-dependent rescue of dauer formation in Caenorhabditis elegans by (25S)-cholestenoic acid.

Population density, temperature and food availability all regulate the formation of the Caenorhabditis elegans dauer larva by modulating endocrine signaling pathways. The orphan nuclear receptor DAF-12 is pivotal for the decision to form a dauer or to undergo normal reproductive development. The DAF-12 ligand has been predicted to be a sterol that is metabolized by DAF-9, a cytochrome P450. Here we chemically characterize purified lipophilic nematode extracts and show that the ligand for DAF-12 contains a carboxyl moiety and is likely to be derived from a sterol. Using a candidate ligand approach we find that the C27 bile acid cholestenoic acid (5-cholesten-3beta-ol-(25S)-carboxylic acid) promotes reproductive growth in dauer-constitutive mutants in a daf-9- and daf-12-dependent manner. Furthermore, we find that cholestenoic acid can act as a DAF-12 ligand by activating DAF-12 in a cell-based transcription assay. Analysis of dauer-rescuing lipophilic extracts from nematodes by gas chromatography-mass spectrometry indicates the presence of several regioisomers of cholestenoic acid that are distinct from Delta(5)-cholestenoic acid and are not present in extracts from daf-9 mutants. These data suggest that carboxylated sterols may be key determinants of life history.

Animals↗
PubMed2006

Using Caenorhabditis elegans as a model for aging and age-related diseases.

During the last three decades the soil nematode C. elegans has become a prominent model organism for studying aging. Initially research in the C. elegans aging field was focused on the genetics of aging and single gene mutations that dramatically increased the life span of the worm. Undoubtedly, the existence of such mutations is one of the main reasons for the popularity of the worm as model system for studying aging. However, today many different approaches are being used in the C. elegans aging field in addition to genetic manipulations that influence life span. For example, environmental manipulations such as caloric restriction and hormetic treatments, evolutionary studies, population studies, models of age-related diseases, and drug screening for compounds that extend life span are now being investigated using this nematode. This review will focus on the most recent developments in C. elegans aging research with the aim of illustrating the diversity of the field.

Aging↗
PubMed2005

Manganous ion supplementation accelerates wild type development, enhances stress resistance, and rescues the life span of a short-lived Caenorhabditis elegans mutant.

Relative to iron and copper we know very little about the cellular roles of manganese. Some studies claim that manganese acts as a radical scavenger in unicellular organisms, while there have been other reports that manganese causes Parkinson's disease-like syndrome, DNA fragmentation, and interferes with cellular energy production. The goal of this study was to uncover if manganese has any free radical scavenging properties in the complex multicellular organism, Caenorhabditis elegans. We measured internal manganese in supplemented worms using inductively coupled plasma mass spectrometry (ICP-MS) and the data obtained suggest that manganese supplemented to the growth medium is taken up by the worms. We found that manganese did not appear to be toxic as supplementation did not negatively effect development or fertility. In fact, supplementation at higher levels accelerated development and increased total fertility of wild type worms by 16%. Manganese-supplemented wild type worms were found to be thermotolerant and, under certain conditions, long-lived. In addition, the oxidatively challenged C. elegans strain mev-1's short life span was significantly increased after manganese supplementation. Although manganese appears to be beneficial to C. elegans, the mode of action remains unclear. Manganese may work directly as a free radical scavenger, as it has been postulated to do so in unicellular organisms, or may work indirectly by up regulating several protective factors.

Animals↗
PubMed2005

The C. elegans ortholog of mammalian Ku70, interacts with insulin-like signaling to modulate stress resistance and life span.

The mammalian Ku heterodimer has important roles in DNA double strand break repair, telomere maintenance, cell cycle checkpoint-arrest, tumor suppression, and cellular stress resistance. To investigate the evolutionarily conserved functions of Ku, we knocked down expression by RNA interference (RNAi) of Ku genes in C. elegans. We found that C. elegans Ku70 (CKU-70) is required for resistance to genotoxic stress, regulates cytotoxic stress responses, and influences aging. The latter effects are dependent on an IGF-1/insulin-like signaling pathway previously shown to affect life span. Reduction of CKU-70 activity amplifies the aging phenotype of long-lived insulin receptor daf-2 mutations in a daf-16-dependent manner. These observations support the view that organismal stress resistance determines life span and Ku70 modulates these effects.

Aging↗
PubMed2004

Fitness cost of extended lifespan in Caenorhabditis elegans.

An insulin/IGF-I-like signalling pathway determines the rate of aging of the adult nematode, Caenorhabditis elegans. Mutations in genes encoding this pathway can result in a doubling of lifespan. While such mutations may appear to have little effect on development or fertility, evolutionary theory predicts that large increases in lifespan will not be optimal for fitness. We demonstrate by laboratory natural selection that partial loss of function of the insulin receptor-like protein DAF-2 results in dramatically reduced fitness even under laboratory conditions. Despite long-lived mutants appearing healthy, they exhibit a heavy fitness cost consistent with an evolutionary theory of aging.

Aging↗
PubMed2004

S.W.A.T.--SOD weapons and tactics.

The accumulation of damage caused by reactive oxygen species (ROS) is held to be one of the underlying causes of age-related decline and has been shown to be involved in a number of pathological states. Inherent defense mechanisms have evolved to limit this damage by reducing the levels of ROS, which are produced mainly by the mitochondria in aerobic organisms. One such defense is superoxide dismutase 1 (SOD1). It is well established that oxidative stress results in increased transcription and translation of the SOD1 gene, but it is now known that an additional level of posttranslational control exists. A recent paper describes the presence of an inactive pool of SOD1 whose activation is wholly reliant on the presence of superoxide or oxygen and a specific copper-containing chaperone. This mechanism highlights the importance of rapid responses in the fight against oxidative stress.

Antioxidants↗
PubMed2004

Lipophilic regulator of a developmental switch in Caenorhabditis elegans.

Abstract In Caenorhabditis elegans, the decision to develop into a reproductive adult or arrest as a dauer larva is influenced by multiple pathways including insulin-like and transforming growth factor beta (TGFbeta)-like signalling pathways. It has been proposed that lipophilic hormones act downstream of these pathways to regulate dauer formation. One likely target for such a hormone is DAF-12, an orphan nuclear hormone receptor that mediates these developmental decisions and also influences adult lifespan. In order to find lipophilic hormones we have generated lipophilic extracts from mass cultures of C. elegans and shown that they rescue the dauer constitutive phenotype of class 1 daf-2 insulin signalling mutants and the TGFbeta signalling mutant daf-7. These extracts are also able to rescue the lethal dauer phenotype of daf-9 mutants, which lack a P450 steroid hydroxylase thought to be involved in the synthesis of the DAF-12 ligand; extracts, however, have no effect on a DAF-12 ligand binding domain mutant that is predicted to be ligand insensitive. The production of this hormone appears to be DAF-9 dependent as extracts from a daf-9;daf-12 double mutant do not exhibit this activity. Preliminary fractionation of the lipophilic extracts shows that the activity is hydrophobic with some polar properties, consistent with a small lipophilic hormone. We propose that the dauer rescuing activity is a hormone synthesized by DAF-9 that acts through DAF-12.

Alleles↗
PubMed2003

An automated high-throughput assay for survival of the nematode Caenorhabditis elegans.

Many genetic or environmental manipulations that extend life span in the nematode Caenorhabditis elegans (C. elegans) also enhance survival following acute stresses such as oxidative damage and thermal stress. This coupling of stress response and aging mechanisms has proved a useful tool in identifying new genes that affect the aging process without the need for performing lengthy life span analyses. Therefore, it is likely that this approach may also be applied to the identification of pharmacological agents that extend life span through enhanced resistance to oxygen radicals or other stressors. To facilitate high-throughput drug screens in the nematode, we have developed a microtitre plate survival assay that uses uptake of the fluorescent dye SYTOX green as a marker of nematode death. An increase in throughput compared with the conventional survival assay was achieved by combining automated worm-handling technology with automated real-time fluorescence detection. We have validated this assay by examining survival during acute heat stress and protection against oxidative stress with the superoxide dismutase/catalase mimetic Euk-134. We propose that this novel method of survival analysis will accelerate the discovery of new pharmacological interventions in aging and oxidative stress.

Aging↗
PubMed2003

M142.2 (cut-6), a novel Caenorhabditis elegans matrix gene important for dauer body shape.

The cuticle of the nematode Caenorhabditis elegans is a collagenous extracellular matrix which forms the exoskeleton and defines the shape of the worm. We have characterized the C. elegans gene M142.2, and we show that this is a developmentally regulated gene important for cuticle structure. Transgenic worms expressing M142.2 promoter fused to green fluorescent protein showed that M142.2 is expressed in late embryos and L2d predauers, in the hypodermal cells which synthesize the cuticle. The same temporal pattern was seen by RT-PCR using RNA purified from specific developmental stages. A recombinant fragment of M142.2 was expressed in Escherichia coli and used to raise an antiserum. Immunohistochemistry using the antiserum localized M142.2 to the periphery of the alae of L1 and dauers, forming two longitudinal ribbons over the hypodermal cells. Loss-of-function of M142.2 by RNAi resulted in a novel phenotype: dumpy dauers which lacked alae. M142.2 therefore plays a major role in the assembly of the alae and the morphology of the dauer cuticle; because of its similarity to the other cut genes of the cuticle, we have named the gene cut-6.

Amino Acid Sequence↗
PubMed2003

Does anti-aging equal anti-microbial?

Aging is the dominant risk factor for human disease in developed countries. Could it be that a wide variety of disease states all have their origins in a common mechanism? Major signaling pathways that determine the rate of aging, such as the insulin/insulin-like growth factor 1 (IGF-1) pathway, might give clues to the nature of this major disease risk factor. It has now been shown that insulin/IGF-1 signaling influences Caenorhabditis elegans resistance to bacteria in such a way that long-lived worms are stress-resistant and slow to succumb to infection. Perhaps enhanced innate immunity is a feature of genetically determined longevity.

Aging↗
PubMed2003

Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals.

Insulin-like signalling is a key determinate of lifespan in diverse species including mammals but the mechanism by which this pathway influences the rate of aging is unknown. In the roundworm Caenorhabditis elegans, mutations in the insulin-like signalling pathway extend adult lifespan and are associated with up-regulation of stress response genes including those for heat shock proteins (HSPs). We tested the hypothesis that the C. elegans insulin-like signalling pathway determines longevity through modulating HSP levels. We introduced extra copies of the gene encoding HSP-16 and this conferred stress resistance and longevity both in a wildtype and a long-lived mutant strain. The DAF-16 transcription factor is essential for maximal hsp-16 expression and for lifespan extension conferred by hsp-16. This demonstrates that lifespan is determined in part by insulin-like regulation of molecular chaperones.

Animals↗
PubMed2003

Oxidative stress in Caenorhabditis elegans: protective effects of superoxide dismutase/catalase mimetics.

The lifespan of Caenorhabditis elegans can be extended by the administration of synthetic superoxide dismutase/ catalase mimetics (SCMs) without any effects on development or fertility. Here we demonstrate that the mimetics, Euk-134 and Euk-8, confer resistance to the oxidative stress-inducing agent, paraquat and to thermal stress. The protective effects of the compounds are apparent with treatments either during development or during adulthood and are independent of an insulin/IGF-I-like signalling pathway also known to affect thermal and oxidative stress resistance. Worms exposed to the compounds do not induce a cellular stress response and no detrimental effects are observed.

Aging↗
PubMed2002

Stress resistance as a determinate of C. elegans lifespan.

It is difficult to exaggerate the progress that has been made in biogerontology over the last 15 years. As with all scientific revolutions, a few experiments in a small number of laboratories have changed the way in which we think about and design experiments. As a result of these experiments, there is much evidence to suggest that a rudimentary understanding of some of the processes that cause aging will be available in the next decade. One particular area of progress is the molecular genetics of lifespan. Although one may draw some distinctions between chronological lifespan and normal aging, extended lifespan remains one of the best indicators that an intervention in an aging process has been made. The isolation of a long-lived variant of a laboratory invertebrate is now essentially a trivial project but the information obtained from this approach is proving invaluable. As with most other biological problems, the most important experimental developments are coming from studying simple organisms in a reductionist fashion.

Aging↗