X-Message-Number: 29423 Date: Sat, 14 Apr 2007 16:16:27 -0700 (PDT) From: Subject: engineered negligible senescence Part II Appendix: Rejuvenation Res. 2005 Fall;8(3):135-7. H(2)S-induced ectothermy: relevance to aging. Muller F.Department of Cellular Biology, University of Texas Health Science Center, San Antonio, Texas 78284, USA. Many biogerontologists privately agree that "engineered negligible senescence" (ENS) is possible given enough time and resources. However, there is great discord on the time frame by which ENS will be achievable, with the more conservative voices (including this author) arguing for the first half of the next century. This means that most people alive today will not see this happen. Blackstone et al.'s recent report, showing that low levels of the toxic gas H(2)S can seemingly turn off the internal thermal rheostat of an endothermic, non-hibernating mammal, may make it possible for those alive today to live long enough (albeit at a slowed rate) until ENS comes about. PMID: 16144467 Science. 2005 Apr 22;308(5721):518. H2S induces a suspended animation-like state in mice. Blackstone E, Morrison M, Roth MB. Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA. Mammals normally maintain their core body temperature (CBT) despite changes in environmental temperature. Exceptions to this norm include suspended animation-like states such as hibernation, torpor, and estivation. These states are all characterized by marked decreases in metabolic rate, followed by a loss of homeothermic control in which the animal's CBT approaches that of the environment. We report that hydrogen sulfide can induce a suspended animation-like state in a nonhibernating species, the house mouse (Mus musculus). This state is readily reversible and does not appear to harm the animal. This suggests the possibility of inducing suspended animation-like states for medical applications. PMID: 15845845 Am J Physiol Regul Integr Comp Physiol. 2007 Apr 4; [Epub ahead of print] AMP Does Not Induce Torpor. Swoap SJ, Rathvon MK, Gutilla MJ. Department of Biology, Williams College, Williamstown, Massachusetts, United States. Torpor, a state characterized by a well-orchestrated reduction of metabolic rate and body temperature (Tb) is employed for energetic savings by organisms throughout the animal kingdom. The nucleotide AMP has recently been purported to be a primary regulator of torpor in mice, as circulating AMP is elevated in the fasted state and administration of AMP causes severe hypothermia. However, we have found that the characteristics and parameters of the hypothermia induced by AMP were dissimilar to those of fasting-induced torpor bouts in mice. While administration of AMP induced hypothermia (min. Tb = 25.2 +/- 0.6 degrees C), similar to the depth of fasting-induced torpor (24.9 +/- 1.5 degrees C), ), ADP and ATP were equally effective in lowering Tb (min.Tb: 24.8 +/- 0.9 degrees C and 24.0 +/- 0.5 degrees C, respectively). The maximum rate of Tb fall into hypothermia was significantly faster with injection of adenine nucleotides (AMP- 0.24 +/- 0.03; ADP- 0.24 +/- 0.02; ATP- 0.25 +/- 0.03 degrees C/min) than during fasting-induced torpor (0.13 +/- 0.02 degrees C/min). Heart rate decreased from 755 +/- 15 to 268 +/- 17 bpm within one minute of AMP administration, much different from that observed during torpor (646 +/- 21 to 294 +/- 19 bpm over 35 minutes). Finally, the hypothermic effect of AMP was blunted with pre-administration of an adenosine receptor blocker, suggesting that AMP action on Tb is mediated via the adenosine receptor. These data suggest that injection of adenine nucleotides into mice induces a reversible hypothermic state that is unrelated to fasting-induced torpor. Key words: Core body temperature, Adenosine, hibernation, heart rate. PMID: 17409259 Appetite. 2004 Feb;42(1):91-8. Fat-depleted CLA-treated mice enter torpor after a short period of fasting.Bouthegourd JC, Martin JC, Gripois D, Roseau S, Tome D, Even PC. UMR INRA/INA P-G 914, Physiologie de la Nutrition et du Comportement Alimentaire, Institut National de la Recherche Agronomique, 16, rue Claude Bernard, 75231 Paris Cedex 05, France. Resting energy expenditure (Resting-EE), EE with treadmill exercise, and post-prandial thermogenesis were continuously monitored by indirect calorimetry during a 24 h recording session in control (CT) and CLA-treated (CLA) (1% CLA in the food, by weight) C57Bl/6 male mice. After 15 days of CLA treatment, the fat content of CLA mice had fallen to 20% of that in CT mice. CLA mice were able to face the energy challenge of exercise but used less lipid than CT mice. Resting-EE values fell during the post-exercise period. The thermogenic response to a calibrated test meal given 5 h after the run abolished the differences in EE and substrate oxidation between CT and CLA mice. However, 2.5 h after ingestion of the test meal onward, CT mice gradually increased their lipid oxidation to sustain resting-EE levels. In contrast, CLA mice did not increase their lipid oxidation and their resting-EE levels fell significantly until they entered into torpor. Blood leptin was low but similar in CT and CLA-treated mice suggesting that leptin is not critical to induce torpor. We suggest that the durable inhibition of lipid oxidation in fasting CLA mice was an adaptive behaviour devoted at sparing the residual adipose deposits. PMID: 15036787 Med Hypotheses. 2006;66(3):636-42. Epub 2005 Dec 2. Cooler biologically compatible core body temperatures may prolong longevity and combat neurodegenerative disorders. Salerian AJ, Saleri NG. Washington Center for Psychiatry, 5225 Wisconsin Avenue, Suite 104, Washington, DC 20015, USA. Scientific evidence suggests the critical role of temperature in regulating three mechanisms contributing to cellular damage: Oxidative stress, oxygen demand overload and inflammation. In this article, we propose that the Arrhenius rate law has a profound impact on aging and a variety of neurodegenerative disorders including Alzheimer's disease, and we review the supporting evidence. Published studies suggest empirical correlations between temperature and lifespan of various organisms, bolstering the hypothesis that variations in lifespan may stem from differences in the mitochondrial production rates of radicals - a process also influenced by temperature. Given the exponential temperature dependency of all biochemical factors, cooler body temperatures may promote longevity and combat neurodegenerative disorders. This promises to offer extraordinary yet unexplored weapons against two formidable enemies of the human body: aging and neurodegenerative disorders. Stated in the form of a thesis referred to as Salerian and Saleri Temperature Thesis (SSTT): "Cooler biologically compatible core body temperatures prolong lifespan and are of value to combat illness". Double blind studies of SSTT in therapeutic strategies against amyotrophic lateral sclerosis (ALS) or early-stage Alzheimer's disease may offer a reasonable first stage to validate SSTT. In view of the known rapid progressive neurodegeneration associated with ALS, minute variations in core body temperature may, in fact, demonstrate statistically significant differences in disease progression. PMID: 16326025 Science. 2006 Nov 3;314(5800):825-8. Comment in: Science. 2006 Nov 3;314(5800):773-4. Transgenic mice with a reduced core body temperature have an increased life span. Conti B, Sanchez-Alavez M, Winsky-Sommerer R, Morale MC, Lucero J, Brownell S, Fabre V, Huitron-Resendiz S, Henriksen S, Zorrilla EP, de Lecea L, Bartfai T. Harold L. Dorris Neurological Research Center, Scripps Research Institute, La Jolla, CA 92037, USA. Reduction of core body temperature has been proposed to contribute to the increased life span and the antiaging effects conferred by calorie restriction (CR). Validation of this hypothesis has been difficult in homeotherms, primarily due to a lack of experimental models. We report that transgenic mice engineered to overexpress the uncoupling protein 2 in hypocretin neurons (Hcrt-UCP2) have elevated hypothalamic temperature. The effects of local temperature elevation on the central thermostat resulted in a 0.3 degrees to 0.5 degrees C reduction of the core body temperature. Fed ad libitum, Hcrt-UCP2 transgenic mice had the same caloric intake as their wild-type littermates but had increased energy efficiency and a greater median life span (12% increase in males; 20% increase in females). Thus, modest, sustained reduction of core body temperature prolonged life span independent of altered diet or CR. PMID: 17082459 [It is interesting that high doses of deuterium oxide can block the increase in lifespan that temperature reduction exerts.] Science. 1974 Feb 1;183(123):427-8. Deuterium oxide effect on temperature-dependent survival in populations of Drosophila melanogaster. Samis HV, Baird MB, Massie HR. PMID: 4203023 J Comp Physiol [B]. 1992;162(3):278-83. Effects of deuterium oxide and temperature on heart rate in Drosophila melanogaster. White LA, Ringo JM, Dowse HB. Department of Zoology, University of Maine, Orono 04469. A non-intrusive optical technique has been developed to monitor heartbeat in late third-instar Drosophila larvae. Heartbeat in this insect is an oscillation that is not temperature compensated. Deuterium oxide lengthens the period of a number of high and low frequency oscillators and clocks in a variety of organisms. To determine whether deuterium affects heart rate, flies were raised on proteated and deuterated media and their heartbeat was monitored at four temperatures ranging from 18 to 33 degrees C. The rate of heartbeat increased linearly with increasing temperature, and decreased with increasing concentrations of deuterium. There was a significant interaction between temperature and deuterium: the higher the concentration of deuterium oxide the less temperature-sensitive was the heart rate. Raising temperatures also increased the amount of "noise" in the rhythm: signal-to-noise ratio, which characterizes the amount of power in a rhythmic signal, decreased with increasing temperatures. Deuterium oxide had no effect on signal-to-noise ratio. PMID: 1319433 Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=29423