Sirtuin regulation in calorie restriction

The beneficial effects of calorie restriction diet in extending lifespan and preventing diseases have long been recognized. Recent genetic and molecular studies in model organisms began to uncover the molecular regulation of calorie restriction response, with the gene SIR2 playing an essential role. This article summarizes the latest development on how mammalian SIR2 homologs coordinately regulate the calorie restriction response.     

The role of Sirt1: At the crossroad between promotion of longevity and protection against Alzheimer's disease neuropathology

Sirt1, a mammalian member of the sirtuin gene family, holds great potential for promoting longevity, preventing against disease and increasing cell survival. For example, studies suggest that the beneficial impact of caloric restriction in promoting longevity and cellular function may be mediated, in part, by Sirt1 through mechanisms involving PGC-1α, which plays important role in the regulation of cellular metabolism and inflammatory and antioxidant responses. Sirt1 may also interfere with mechanisms implicated in pathological disorders. We will present recent evidence indicating that Sirt1 may protect against Alzheimer's disease by interfering with the generation of β-amyloid peptides. We will discuss Sirt1 as a potential novel target, in addition to the development of Sirt1 activators for the prevention and treatment of Alzheimer's disease.     

DNA polymerase proofreading: Multiple roles maintain genome stability

DNA polymerase proofreading is a spell-checking activity that enables DNA polymerases to remove newly made nucleotide incorporation errors from the primer terminus before further primer extension and also prevents translesion synthesis. DNA polymerase proofreading improves replication fidelity ∼ 100-fold, which is required by many organisms to prevent unacceptably high, life threatening mutation loads. DNA polymerase proofreading has been studied by geneticists and biochemists for > 35 years. A historical perspective and the basic features of DNA polymerase proofreading are described here, but the goal of this review is to present recent advances in the elucidation of the proofreading pathway and to describe roles of DNA polymerase proofreading beyond mismatch correction that are also important for maintaining genome stability.     

Proteome and radioimmunoassay analyses of pituitary hormones and proteins in response to feed restriction of dairy cows

The hypothalamic-pituitary system controls homeostasis during feed energy reduction. In order to examine which pituitary proteins and hormone variants are potentially associated with metabolic adaptation, pituitary glands from ad libitum and energy restrictively fed dairy cows were characterized using RIA and 2-DE followed by MALDI-TOF-MS. We found 64 different spots of regulatory hormones: growth hormone (44), preprolactin (16), luteinizing hormone (LH) (1), thyrotropin (1), proopiomelanocortin (1) and its cleavage product lipotropin (1), but none of these did significantly differ between feeding groups. Quantification of total pituitary LH and prolactin concentrations by RIA confirmed the results obtained by proteome analysis. Also, feed energy restriction provoked increasing non-esterified fatty acid, decreasing prolactin, but unaltered glucose, LH and growth hormone plasma concentrations. Energy restriction decreased the expression of glial fibrillary acidic protein, triosephosphate isomerase, purine-rich element-binding protein A and elongation factor Tu, whereas it increased expression of proline synthetase co-transcribed homolog, peroxiredoxin III, β-tubulin and annexin A5 which is involved in the hormone secretion process. Our results indicate that in response to feed energy restriction the pituitary reservoir of all posttranslationally modified hormone forms remains constant. Changing plasma hormone concentrations are likely attributed to a regulated releasing process from the gland into the blood.     

The Cambrian explosion triggered by critical turning point in genome size evolution

The Cambrian explosion is a grand challenge to science today and involves multidisciplinary study. This event is generally believed as a result of genetic innovations, environmental factors and ecological interactions, even though there are many conflicts on nature and timing of metazoan origins. The crux of the matter is that an entire roadmap of the evolution is missing to discern the biological complexity transition and to evaluate the critical role of the Cambrian explosion in the overall evolutionary context. Here, we calculate the time of the Cambrian explosion by a “C-value clock”; our result quite fits the fossil records. We clarify that the intrinsic reason of genome evolution determined the Cambrian explosion. A general formula for evaluating genome size of different species has been found, by which the genome size evolution can be illustrated. The Cambrian explosion, as a major transition of biological complexity, essentially corresponds to a critical turning point in genome size evolution.     

Mitochondrial metabolism during fasting-induced daily torpor in mice

During fasting, mice (Mus musculus) undergo daily bouts of torpor, considerably reducing body temperature (T_b) and metabolic rate (MR). We examined females of different laboratory strains (Balb/c, C57/6N, and CD1) to determine whether liver mitochondrial metabolism is actively reduced during torpor. In all strains, we found that state 3 (phosphorylating) respiration rate measured at 37 °C was reduced up to 35% during torpor for at least one of the substrates (glutamate and succinate) used to fuel respiration. The extent of this suppression varied and was correlated with T_b at sampling. This suggests that, at the biochemical level, the transition to and from a hypometabolic torpid state is gradual. In fasted non-torpid animals, T_b and MR still fluctuated greatly: T_b dropped by as much as 4 °C and MR was reduced up to 25% compared to fed controls. Changes in T_b and MR in fasted, non-torpid animals were correlated with changes in mitochondrial state 3 respiration rate measured at 37 °C. This suggests that fasting mice may conserve energy even when not torpid by occasionally reducing T_b and mitochondrial oxidative capacity to reduce MR. Furthermore, proton conductance was higher in torpid compared to non-torpid animals when measured at 15 °C (the lower limit of torpid T_b). This pattern is similar to that reported previously for daily torpor in Phodopus sungorus.     

Blockade of sphingosine 1-phosphate receptor 2 signaling attenuates streptozotocin-induced apoptosis of pancreatic β-cells

Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that acts through five cognate G protein-coupled receptors (S1P₁-S1P₅) and regulates many critical biological processes. Recent studies indicated that S1P at nanomolar concentrations significantly reduces cytokine-induced apoptosis of pancreatic β-cells in which genes for S1P₁-S1P₄ are co-expressed. However, the S1P receptor subtype(s) involved in this effect remains to be clarified. In this study, we investigated the potential role of S1P₂ in streptozotocin (STZ)-induced apoptosis of pancreatic β-cells and progression of diabetes. S1P₂-deficient (S1P₂^-/-) mice displayed a greater survive ability, lower blood glucose levels, and smaller numbers of TUNEL-positive apoptotic β-cells to administration of a high dose of STZ than wild-type (WT) mice. S1P₂^-/- mice showed higher insulin/glucose ratios (an index of relative insulin deficiency) and larger insulin-positive islet areas to administration of a low dose of STZ than WT mice. Moreover, administration of JTE-013, a S1P₂-specific antagonist, to WT mice ameliorated STZ-induced blood glucose elevation and reduced the incidence of diabetes. Our findings indicate that blockade of S1P₂ signaling attenuates STZ-induced apoptosis of pancreatic β-cells and decreases the incidence of diabetes.