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Bart P Braeckman

Publications and source records attributed to Bart P Braeckman.

15 recordsLinked to original sources
PubMed2006

Genetic control of longevity in C. elegans.

The nematode Caenorhabditis elegans has proven to be a very useful tool for studying the genetics of longevity. Over 70 genes have been found to influence lifespan in this worm. Those related to the Ins/IGF signaling pathway are among the best studied and will be focused on in this review. The master regulator of this pathway, the forkhead transcription factor DAF-16, can activate an enhanced life maintenance program in response to environmental and gonadal inputs. DAF-16 up- and downregulates expression of many genes leading to metabolic alterations and increased stress and microbial resistance. This is generally confirmed by biochemical and physiological data. Longevity mutants are not hypometabolic and probably produce more reactive oxygen species than wild type. However, their high antioxidant capacity may result in lower oxidative damage. Enhanced molecular turnover rates may also play a role in their longevity phenotype.

Animals↗
PubMed2006

The dietary restriction effect in C. elegans and humans: is the worm a one-millimeter human?

Dietary restriction (DR) lengthens life span in wide range of vertebrate and invertebrate species. The molecular mechanism by which DR increases life span and the universality of its effects (and hence its applicability to humans) are currently debated in gerontology. This article addresses these two problems from both an experimental perspective, using the nematode C. elegans as a model system, and a theoretical viewpoint, by appealing to recent mechanistic and evolutionary models of aging. Molecular mechanisms of aging are analysed by contrasting the rate of living/oxidative stress hypothesis with the metabolic stability/longevity hypothesis, a new model of aging which postulates that the robustness of metabolic networks, rather than metabolic rate per se, is the major determinant of aging. Studies of food-restricted worms are shown to be consistent with the metabolic stability/longevity hypothesis. The universality of the effects of DR is addressed in terms of directionality theory, an evolutionary model, which is based on the analytical fact that the robustness or the stability of demographic networks determines Darwinian fitness. Directionality theory, in conjunction with the metabolic stability hypothesis, predicts that DR will have negligible effects on equilibrium species (late age of sexual maturity, small size of progeny sets and broad reproductive span) and large effects on opportunistic species (early age of maturity, large size of progeny sets, narrow reproductive span). Empirical studies using C. elegans (an opportunistic species) and computational studies on human populations (an equilibrium species) are shown to be consistent with these predictions.

Aging↗
PubMed2005

DAF-2 pathway mutations and food restriction in aging Caenorhabditis elegans differentially affect metabolism.

In Caenorhabditis elegans, metabolism and life expectancy respond to environmental cues of food availability and temperature. Several genes act in a neuroendocrine, DAF-2, insulin/IGF-1 receptor-like pathway in which reduced signaling affects metabolism and increases longevity. Here we describe the effect of reduced DAF-2 signaling on several parameters of metabolism including rates of oxygen consumption and heat output, the calorimetric/respirometric ratio, ATP levels, XTT reduction capacity and accumulation of lipofuscin. We also asked whether the DAF-2 signaling pathway mediates the metabolic and longevity effects of axenic culture medium. We show that both interventions act either antagonistically or in concert, depending on the parameter examined and that axenic culture medium, unlike DAF-2 signaling, does not need DAF-16 for generating these effects. In addition, we provide evidence that DAF-2 signaling controls mitochondrial bioenergetics by adjusting the rate of ATP synthesis to the rate of ATP utilization and by regulating the heat-producing proton leak pathway.

Adenosine Triphosphate↗
PubMed2005

Metabolism, physiology and stress defense in three aging Ins/IGF-1 mutants of the nematode Caenorhabditis elegans.

The insulin/insulin-like growth factor-1 (Ins/IGF-1) pathway regulates the aging rate of the nematode Caenorhabditis elegans. We describe other features of the three Ins/IGF-1 mutants daf-2, age-1 and aap-1. We show that the investigated Ins/IGF-1 mutants all have a reduced body volume, reduced reproductive capacity, increased ATP concentrations and an elevated stress resistance. We also observed that heat production is lower in these mutants, although the respiration rate was similar or higher compared with wild-type individuals, suggesting a metabolic shift in these mutants.

Adenosine Triphosphate↗
PubMed2004

Metabolic rate is not reduced by dietary-restriction or by lowered insulin/IGF-1 signalling and is not correlated with individual lifespan in Drosophila melanogaster.

The link between resting metabolic rate and aging, measured as adult lifespan, was investigated in Drosophila melanogaster by (i) comparing lifespan and metabolic rate of individual flies, (ii) examining the effect of dietary-restriction on the metabolic rate of adult flies, and (iii) comparing the metabolic rate of wild-type and insulin/IGF-1 signalling mutant chico1 flies. The resting oxygen consumption of 65 individually housed and fully fed Drosophila was measured weekly throughout their lifetime. There was no significant difference in the mass-specific rate of oxygen consumption between cohorts that differed in lifespan. Nor was there any statistical correlation between mass-specific oxygen consumption and lifespan of individual Drosophila. The average mass-specific rate of oxygen consumption at 25 degrees C was 3.52+/-0.07 microl O2 mg(-1) h(-1). Variation in mass-specific metabolic rate explained only 4% of variation in individual life span in these flies. Contrary to predictions from the 'rate of living' theory of aging lifetime oxygen consumption was not constant and the lifespan of individual flies accounted for 91% of their lifetime oxygen consumption. An average Drosophila consumes about 3 ml O2 during its adult life. Dietary-restriction had no effect on mass-specific resting metabolic rate both when measured as oxygen consumption by respirometry and when measured as heat production by microcalorimetry. The mass-specific resting heat production of fully fed adult flies at 25 degrees C averaged 17.3+/-0.3 microW mg(-1). Similarly there was no difference in mass-specific metabolic rate of wild-type flies and longliving chico1 insulin/IGF-1 signalling mutant flies, either when measured as oxygen consumption or heat production. Thus, individual variation in lifespan in wild-type flies, and life extension by dietary-restriction and reduced insulin/IGF-1 signalling is not attributable to differences in metabolic rate.

Aging↗
PubMed2003

Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans.

Dietary restriction (DR) increases life span in a wide variety of animals. In Caenorhabditis elegans both reduced bacterial concentration (BDR) and culture on non-bacterial, semi-defined, axenic food sources (ADR) increased longevity. An Ins/IGF-1-like (IIF) signalling pathway has been shown to specify life span in C. elegans and it has been suggested that this IIF signalling pathway mediates life extension via DR. We show that both ADR and BDR act independently with mutations in the IIF pathway to increase longevity, stress resistance, and specific activities of superoxide dismutase and catalase. Moreover, these effects are not dependent on daf-16, which is known to suppress other mutations that act through the IIF pathway. We conclude that DR extends life span by mechanisms distinct from those specified by the IIF pathway.

Animals↗
PubMed2002

Assaying metabolic activity in ageing Caenorhabditis elegans.

Accurate measures of physiological and metabolic condition could provide more insight into how longevity genes and signalling pathways affect global metabolic activity and life span. The present study is essentially a methodological treatise in which we describe and evaluate a number of methods to assess changes of metabolic activity in ageing Caenorhabditis elegans. Oxygen consumption and CO(2) production rate assays, and measurement of the heat output by microcalorimetry are performed using live worms. For other assays, frozen (-75 degrees C) samples can be used. A lucigenin-mediated light production assay provides information on the metabolic capacity (scope for metabolic activity) of the worms just before freezing. Assaying ATP and ADP levels provides a measure of the instantly available energy. The XTT assay measures the activity of enzymes that can reduce XTT. Blue fluorescence emitted at 420-470 nm is a potentially useful biomarker of the rate of ageing. A protein quantification protocol for normalising all data for quantitative comparisons is presented. We illustrate how these methods can validate or disprove models of gene action inferred from molecular identification.

Aging↗
PubMed2002

No reduction of energy metabolism in Clk mutants.

Mutation in any of the four clock genes (clk-1, clk-2, clk-3, gro-1) causes an average slowing down of many temporal processes, and an increase of mean life span. The latter effect has been linked to the slow phenotype, and it has been reasoned that any reduction of the rate of living would reduce the load of oxidative damage, which is thought to drive the ageing process. To test this model we measured several parameters describing metabolic output in wild type worms and all four Clk mutants. We found no gross changes in metabolic output, as assessed from oxygen consumption and heat production rates, lucigenin-mediated light production capacity, ATP content, and lipofuscin autofluorescence. Catalase and superoxide dismutase (SOD) were variably altered, but not cooperatively, as would be expected to enhance reactive oxygen species (ROS) scavenging activity. Thus we conclude that the prolonged life span of Clk mutants cannot be attributed to reduced metabolic rate or an increased activity of the major antioxidant enzymes catalase and SOD.

Acridines↗
PubMed2002

No reduction of metabolic rate in food restricted Caenorhabditis elegans.

Dietary restriction (DR) is the most consistent means of extending life span throughout the animal kingdom. Multiple mechanisms by which DR may act have been proposed but none are clearly predominant. We asked whether metabolic rate and stress resistance is altered in Caenorhabditis elegans in response to DR. DR was imposed in two complementary ways: by growing wild-type worms in liquid medium supplemented with reduced concentrations of bacteria and by using eat-2 mutants, which have a feeding defect. Metabolic rate was not reduced when we fed wild-type worms reduced food and was up-regulated in the eat-2 mutants in liquid culture, as assessed by oxygen consumption rate and heat production. The specific activity levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase showed small increases when we reduced food in wild-type worms, but restricted worms acquired no elevated protection against paraquat and hydrogen peroxide. eat-2 mutants showed elevated specific activities of SOD and catalase relative to wild type in liquid culture. These results indicate that the effects imparted by DR and the eat-2 mutation are not identical, and they contradict, at least in C. elegans, the widespread belief that CR acts by lowering the rate of metabolism.

Aging↗
PubMed2002

Axenic growth up-regulates mass-specific metabolic rate, stress resistance, and extends life span in Caenorhabditis elegans.

Culture in axenic medium causes two-fold increases in the length of development and adult life span in Caenorhabditis elegans. We asked whether axenic medium imposes dietary restriction (ADR), and causes changes in metabolic activity and stress resistance. Eat mutants, which have a reduced food intake, were studied in parallel with wild-type worms to assess potential synergistic actions of axenic culture and food restriction. We found that axenic culture enhances metabolic activity as assessed by mass-specific oxygen consumption rate and heat production. Axenic culture also caused higher activities of the antioxidant enzymes superoxide dismutase and catalase, and led to increased resistance to high temperature, which was further exacerbated by mutation in eat-2. These results show that axenic medium up-regulates a variety of somatic maintenance functions including oxidative and thermal stress resistance and that food restriction due to axenic growth and to mutation in eat-2 are very similar but not identical.

Aging↗
PubMed2002

Assessing metabolic activity in aging Caenorhabditis elegans: concepts and controversies.

It is widely believed that normal by-products of oxidative metabolism and the subsequent molecular damage inflicted by them couple the aging process to metabolic rate. Accordingly, high metabolic rates would be expected to accelerate aging, and life-extending interventions are often assumed to act by attenuating metabolic rate. Notorious examples in Caenorhabditis elegans are food restriction, mutation in the Clock genes and several genes of the insulin-like signalling pathway. Here we discuss how metabolic rate can be accurately measured and normalized, and how to deal with differences in body size. These issues are illustrated using experimental data of the long-lived mutant strains clk-1(e2519) and daf-2(e1370). Appropriate analysis shows that metabolic rates in wildtype and in the clk-1 mutant are very similar. In contrast, the metabolic rate profiles point to a metabolic shift toward enhanced efficiency of oxidative phosphorylation in the daf-2 worms.

Aging↗
PubMedDate not supplied

Ageing is reversed, and metabolism is reset to young levels in recovering dauer larvae of C. elegans.

The nematode Caenorhabditis elegans responds to unfavourable environmental conditions by arresting development and entering diapause as a dauer larva. Dauers can survive several times the normal life span and the duration of the dauer state has no effect on postdauer life span. This led to the suggestion that dauers are non-ageing, and that dauers eventually perish as the consequence of depletion of stored nutrients. We have investigated physiological changes associated with long-term diapause survival, and found that dauer larvae slowly develop senescence-like symptoms, including decrease of metabolic capacity, aconitase enzyme activity, and ATP stores, and increase of lipofuscin- and oxidised flavin-specific fluorescence. However, these changes are reversed when the dauers recover. Thus senescence can occur before attainment of reproductive maturity, and furthermore, is reversible. Other life processes, including respiration rate and heat output, remain unaltered over four weeks of diapause at 24 degrees C. Possible determinants of the enhanced life maintenance include increased resistance to oxidative stress provided by enhanced superoxide dismutase and catalase activities, and a shift to a highly reducing redox status.

Adenosine Triphosphate↗