Mutations that increase the longevity of the soil nematode Caenorhabditis elegans could define genes involved in a process specific for aging. Alternatively, these mutations could reduce animal metabolic rate and increase longevity as a consequence. In ectotherms, longevity is often negatively correlated with metabolic rate. Consistent with these observations, environmental conditions that reduce the metabolic rate of C. elegans also extend longevity. We found that the metabolic rate of long-lived C. elegans mutants is reduced compared with that of wild-type worms and that a genetic suppressor that restored normal longevity to longlived mutants restored normal metabolic rate. Thus, the increased longevity of some long-lived C. elegans mutants may be a consequence of a reduction in their metabolic rate, rather than an alteration of a genetic pathway that leads to enhanced longevity while maintaining normal physiology. The actual mechanism responsible for the inverse correlation between metabolic rate and longevity remains unknown.

In general ectothermic organisms grow larger at both lower temperatures and higher latitudes. Adult size in the soil nematode Caenorhabditis elegans reared at 10°C was approximately 33% greater than worms grown at 25°C. Nematode egg size and fish red blood cell size showed similar size increases at lower temperatures. These results indicate that body size differences in many ectotherms may simply be a consequence of developmental processes that cause cells to grow larger at lower temperatures. This would provide a general explanation for the increased size of ectotherms at lower temperatures independent of species-specific ecology.

In general ectothermic organisms grow larger at both lower temperatures and higher latitudes. Adult size in the soil nematode Caenorhabditis elegans reared at 10°C was approximately 33% greater than worms grown at 25°C. Nematode egg size and fish red blood cell size showed similar size increases at lower temperatures. These results indicate that body size differences in many ectotherms may simply be a consequence of developmental processes that cause cells to grow larger at lower temperatures. This would provide a general explanation for the increased size of ectotherms at lower temperatures independent of species-specific ecology.

Mitochondrial encephalomyopathies are common and devastating multisystem genetic disorders characterized by neuromuscular dysfunction and tissue degeneration. Point mutations in the human mitochondrial ATP6 gene are known to cause several related mitochondrial disorders: NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh's syndrome), and FBSN (familial bilateral striatal necrosis). We identified a pathogenic mutation in the Drosophila mitochondrial ATP6 gene that causes progressive, adult-onset neuromuscular dysfunction and myodegeneration. Our results demonstrate ultrastructural defects in the mitochondrial innermembrane, neural dysfunction, and a marked reduction in mitochondrial ATP synthase activity associated with this mutation. This Drosophila mutant recapitulates key features of the human neuromuscular disorders enabling detailed in vivo studies of these enigmatic diseases.

Relatively simple model organisms such as yeast, fruit-flies and the nematode, Caenorhabditis elegans , have proven to be invaluable resources in biological studies. An example is the widespread use of C. elegans to investigate the complex process of ageing. An important issue when interpreting results from these studies is the similarity of the observed C. elegans mortality pattern in the laboratory to that expected in its natural environment. We found that the longevity of C. elegans under more natural conditions is reduced up to 10‐fold compared with standard laboratory culture conditions. Additionally, C. elegans mutants that live twice as long as wild-type worms in laboratory conditions typically die sooner than wild-type worms in a natural soil. These results indicate that conclusions regarding extended longevity drawn from standard laboratory assays may not extend to animals in their native environment.

SUMMARYThis study examined the metabolic response of Drosophila melanogaster exposed to O 2 concentrations ranging from 0 to 21% and at 100%. The metabolic rate of flies exposed to graded hypoxia remained nearly constant as O 2 tensions were reduced from normoxia to ~3 kPa. There was a rapid, approximately linear reduction in fly metabolic rate at P O2 s between 3 and 0.5 kPa. The reduction in metabolic rate was especially pronounced at P O2 levels <0.5 kPa, and at a P O2 of 0.1 kPa fly metabolic rate was reduced ~10-fold relative to normoxic levels. The metabolic rate of flies exposed to anoxia and then returned to normoxia recovered to pre-anoxic levels within 30 min with no apparent payment of a hypoxia-induced oxygen debt. Flies tolerated exposure to hypoxia and/or anoxia for 40 min with nearly 100% survival. Fly mortality increased rapidly after 2 h of anoxia and >16 h exposure was uniformly lethal. Flies exposed to pure O 2 for 24 h showed no apparent alteration of metabolic rate, even though such O 2 tensions should damage respiratory enzymes critical to mitochondria function. Within a few hours the metabolic rate of flies recovering from exposure to repeated short bouts of anoxia was the same as flies exposed to a single anoxia exposure.

Mutations affecting the Na+, K+ ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na+, K+ ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na+, K+ ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na+, K+ ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. Importantly, all of these mutations cause neurological phenotypes and, akin to the mutations that cause RDP and FHM, these new alleles are missense mutations. All of these alleles exhibit progressive stress-induced locomotor impairment suggesting neuromuscular dysfunction, yet neurodegeneration is observed in an allele-specific manner. Surprisingly, studies of longevity demonstrate that mild hypomorphic mutations in the sodium pump significantly improve longevity, which was verified using the Na+, K+ ATPase antagonist ouabain. The isolation and characterization of a series of new missense alleles of ATPalpha in Drosophila provides the foundation for further studies of these neurological diseases and the role of sodium pump impairment in animal longevity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-009-0673-2) contains supplementary material, which is available to authorized users.

In a recent study examining the relationship between longevity and metabolism in a large number of recombinant inbred Drosophila melanogaster lines, we found no indication of the inverse relationship between longevity and metabolic rate that one would expect under the classical "rate of living" model. A potential limitation in generalizing from that study is that it was conducted on experimental material derived from a single set of parental strains originally developed over 20 years ago. To determine whether the observations made with those lines are characteristic of the species, we studied metabolic rates and longevities in a second, independently derived set of recombinant inbred lines. We found no correlation in these lines between metabolic rate and longevity, indicating that the ability to both maintain a normal metabolic rate and have extended longevity may apply to D. melanogaster in general. To determine how closely our measurements reflect metabolic rates of flies maintained under conditions of life span assays, we used long-term, flow-through metabolic rate measurements and closed system respirometry to examine the effects of variables such as time of day, feeding state, fly density, mobility of the flies, and nitrogen knockout on D. melanogaster metabolic rate. We found that CO2 production estimated in individual flies accurately reflects metabolic rates of flies under the conditions used for longevity assays.