Although limiting energy availability extends lifespan in many organisms, it is not understood how lifespan is coupled to energy levels. We find that the AMP:ATP ratio, a measure of energy levels, increases with age in Caenorhabditis elegans and can be used to predict life expectancy. The C. elegans AMP-activated protein kinase ␣ subunit AAK-2 is activated by AMP and functions to extend lifespan. In addition, either an environmental stressor that increases the AMP:ATP ratio or mutations that lower insulin-like signaling extend lifespan in an aak-2-dependent manner. Thus, AAK-2 is a sensor that couples lifespan to information about energy levels and insulin-like signals.Supplemental material is available at http://www.genesdev.org.Received August 27, 2004; revised version accepted October 18, 2004. Interventions that limit energy availability extend lifespan in an array of organisms (Weindruch and Sohal 1997;Osiewacz 2002;Tissenbaum and Guarente 2002). A common method to limit energy is dietary restriction, which leads to lifespan extension in organisms as diverse as yeasts, nematodes, and rodents (Lakowski and Hekimi 1998;Longo and Finch 2003). However, little is known about how aging is coupled to information about the energy state of the animal.In humans, aging is accompanied by an increase in mitochondrial dysfunction in muscle (Petersen et al. 2003), which is expected to lower cellular energy levels. Similarly, senescent human fibroblasts have a higher AMP:ATP ratio, a sensitive measure of energy levels, than do young fibroblasts (Hardie and Hawley 2001;Wang et al. 2003). We speculated that animals actively sense changes in energy levels and respond by adjusting their lifespan. To investigate this possibility, we studied the role of an AMP-activated protein kinase (AMPK) in the regulation of lifespan in Caenorhabditis elegans.AMPK belongs to a conserved family of eukaryotic protein kinases that function as energy sensors to coordinate the response to conditions that lower energy levels (Hardie and Hawley 2001). For example, when energy availability is limited in rodents, AMPK functions to restore normal energy levels by stimulating glucose uptake in skeletal muscle and glycolysis in the heart and by promoting feeding by regulating a hypothalamic circuit (Marsin et al. 2000;Mu et al. 2001;Andersson et al. 2004;Minokoshi et al. 2004). AMPK is activated by AMP and inhibited by ATP via an allosteric mechanism. Thus, AMPK is a sensor of low energy levels and becomes active when the AMP:ATP ratio is high. AMPK is a heterotrimeric complex that consists of a catalytic ␣ subunit and regulatory ␤ and ␥ subunits. Here, we report that the C. elegans AMPK ␣ subunit AAK-2 is activated by AMP and functions to extend lifespan. We find that a high-temperature pulse (HTP), an environmental stressor that lowers energy levels, extends lifespan and lowers fertility in an aak-2-dependent manner. Insulin-like signaling regulates lifespan in C. elegans, Drosophila, and rodents (Tissenbaum and Guarente 2002); and we find that aa...

Introduction: Australia is a country with a relatively small rural population dispersed over an enormous area. Issues similar to how best to deliver health services and recruit health professionals to rural areas exist in other countries. For professional and lifestyle reasons, most specialist doctors (including emergency medicine specialists), choose to live and work in major metropolitan centres. Outside the major Australian cities, most presentations to emergency departments are dealt with by 'nonspecialist' doctors, often with limited specialist back up. Recruitment of suitably trained medical staff is increasingly difficult.There is increasing reliance on overseas trained doctors from widely varying backgrounds. In Canada and New Zealand, family medicine trained emergency medicine doctors are a significant proportion of the workforce in rural and regional emergency departments. Aim: To undertake a detailed investigation of the non-specialist emergency medicine doctors in Australia, and examine strategies to secure a more highly trained emergency medicine workforce for rural and regional Australia.

BackgroundWe and others have demonstrated previously that ghrelin receptor (GhrR) knock out (KO) mice fed a high fat diet (HFD) have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI-E) clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity.ResultsConsistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd), and decreased hepatic glucose production (HGP). HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice.ConclusionsThese results indicate that improved glucose homeostasis of GhrR KO mice is characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. GhrR KO mice have an intact 1st phase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of GhrR KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the GhrR KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge.

Essentially complete backbone and side-chain 1H, 15N and 13C resonance assignments for the 185-amino-acid cytokine interleukin-6 (IL-6) are presented. NMR experiments were performed on uniformly [15N]- and [15N,13C]-labeled recombinant human IL-6 (rIL-6) using a variety of heteronuclear NMR experiments. A combination of 13C-chemical shift, amide hydrogen-bond exchange, and 15N-edited NOESY data allowed for analysis of the secondary structure of IL-6. The observed secondary structure of IL-6 is composed of loop regions connecting five alpha-helices, four of which are consistent in their length and disposition with the four-helix bundle motif present in other related cytokines and previously postulated for IL-6. In addition, the topology of the overall fold was found to be consistent with a left-handed up-up-down-down four-helix bundle based on a number of long-range interhelical NOEs. The results presented here provide deeper insight into structure-function relationships among members of the four-helix bundle family of proteins.