X-Message-Number: 29423
Date: Sat, 14 Apr 2007 16:16:27 -0700 (PDT)
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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

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