X-Message-Number: 29421
Date: Sat, 14 Apr 2007 16:23:12 -0700 (PDT)
From: 
Subject: engineered negligible senescence Part IV

[Effective intervention in human aging may not be as far off as one
might suppose, provided information is acted on in a timely manner.]

J Gerontol A Biol Sci Med Sci. 2005 Nov;60(11):1386-93.
Prevention of accelerated cell aging in Werner syndrome using a p38
mitogen-activated protein kinase inhibitor.
Davis T, Baird DM, Haughton MF, Jones CJ, Kipling D. D.Phil, Department
of Pathology, School of Medicine, Cardiff University, Heath Park,
Cardiff CF14 4XN, United Kingdom.
  We investigated the role of p38 mitogen-activated protein kinase
(MAPK) signalling in the accelerated aging of Werner Syndrome
(WS) fibroblasts by use of SB203580, a cytokine-suppressive
anti-inflammatory drug that targets p38 activity. SB203580 treatment
reverts the aged morphology of young WS fibroblasts to that seen in young
normal fibroblasts. In addition, SB203580 increases the life span and
growth rate of WS fibroblasts to within the normal range. In young WS
cells, p38 is activated coincident with an up-regulation of p21(WAF1),
and a reduction in the levels of both activated p38 and p21(WAF1) are seen
following treatment with SB203580. As these effects are not seen in young
normal cells, our data suggest that the abbreviated replicative life span
of WS cells is due to a stress-induced, p38-mediated growth arrest that
is independent of telomere erosion. With some p38 inhibitors
already in clinical trials, our data suggest a potential route to drug
intervention in a premature aging syndrome.
PMID: 16339323

Biogerontology. 2005;6(5):313-23.
Effect of S-adenosylmethionine on age-induced hepatocyte damage in old
Wistar rats.
Castillo C, Salazar V, Ariznavarreta C, Fossati M, Tresguerres JA, Vara E.
Laboratory of Experimental Endocrinology, Department of Physiology, School
of Medicine, Complutense University, Avda. Complutense s/n, 28040, Madrid,
Spain.
    Aging is accompanied by changes in the morphology and physiology of
organs and tissues, such as the liver. This process might be due to the
accumulation of oxidative damage induced by reactive oxygen (ROS) and
reactive nitrogen species (RNS). Hepatocytes are very rich in
mitochondria and have a high respiratory rate, so they are exposed to
large amounts of ROS and permanent oxidative stress. S-Adenosylmethionine
(SAMe) is an endogenous metabolite that has shown to exert protective
effects on different experimental pathological models in which free
radicals are involved. The aim of this study was to investigate the effect
of SAMe on age-induced damage in hepatocytes. For this purpose, male and
female Wistar rats of 18 and 2 months of age were used. Cells were
isolated and, after incubation in the presence or in the absence of SAMe,
different parameters were measured. Aging induced a significant increase
in nitric oxide, carbon monoxide and cGMP, and a reduction in reduced
glutathione, ATP and phosphatidylcholine synthesis, as well as in
methionine- adenosyl-transferase and methyl-transferase
activities. Incubation of old cells with SAMe prevented all these age-related
changes, reaching values in some of the parameters similar to those found
in young animals. In conclusion, SAMe seems to have beneficial effects
against age-induced damage in hepatocytes.
PMID: 16463108

Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12873-8. Epub 2005 Aug 29.
Blocking protein farnesyltransferase improves nuclear shape in
fibroblasts from humans with progeroid syndromes.
Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL, Miner JH,
Young SG, Fong LG. Department of Medicine and Division of Cardiology,
David Geffen School of Medicine, University of California, Los Angeles,
CA 90095, USA.
    Defects in the biogenesis of lamin A from its farnesylated precursor,
prelamin A, lead to the accumulation of prelamin A at the nuclear
envelope, cause misshapen nuclei, and result in progeroid syndromes. A
deficiency in ZMPSTE24, a protease involved in prelamin A processing,
leads to prelamin A accumulation, an absence of mature lamin A,
misshapen nuclei, and a lethal perinatal progeroid syndrome: restrictive
dermopathy (RD). Hutchinson-Gilford progeria syndrome (HGPS) is caused
by a mutant prelamin A that cannot be processed to lamin A. The hallmark
cellular abnormality in RD and HGPS is misshapen nuclei. We hypothesized
that the farnesylation of prelamin A is important for its targeting to
the nuclear envelope in RD and HGPS and that blocking farnesylation
would ameliorate the nuclear shape abnormalities. Indeed, when RD
fibroblasts were treated with a farnesyltransferase inhibitor (FTI),
prelamin A was partially mislocalized away from the nuclear envelope,
and the frequency of nuclear shape abnormalities was reduced (P < 0.0001).
A FTI also mislocalized prelamin A and improved nuclear shape in
Zmpste24-deficient mouse embryonic fibroblasts (P < 0.0001) and improved
nuclear shape in human HGPS fibroblasts (P < 0.0001). Most remarkably, a
FTI significantly improved nuclear shape in two fibroblast cell lines
from atypical progeria patients with lamin A missense mutations in the
absence of prelamin A accumulation (P = 0.0003 and P < 0.0001). These
findings establish a paradigm for ameliorating the most obvious cellular
pathology in lamin-related progeroid syndromes and suggest a potential
strategy for treating these diseases.
PMID: 16129834

[Some examples of divergence between human aging and rodent aging are
with repect to telomeres, amyloid accumulation, and p66(shc).]

Mech Ageing Dev. 2005 Aug;126(8):839-44. Epub 2005 Apr 8.
p66(shc) is highly expressed in fibroblasts from centenarians.
Pandolfi S, Bonafe M, Di Tella L, Tiberi L, Salvioli S, Monti D, Sorbi S,
Franceschi C. Department of Experimental Pathology, University of
Bologna, via S. Giacomo 12, 40126 Bologna, Italy.
    p66(shc-/-) mice exhibit prolonged lifespan and increased resistance
to oxidative and hypoxic stress. To investigate p66(shc) involvement in
human longevity, p66(shc) mRNA and protein were evaluated in fibroblasts
from young people, elderly and centenarians, exposed to oxidative or
hypoxic stress. Unexpectedly, centenarians showed the highest basal levels
of p66(shc). Oxidative stress induced p66(shc) in all samples. At
variance, hypoxic stress caused p66(shc) reduction only in cells from
centenarians. These changes occurred in absence of any modification of
p66(shc) promoter methylation pattern. Intriguingly, in cells from
centenarians, p66(shc) induction was affected by p53 codon 72
polymorphism. Thus, cells from centenarians present a peculiar regulation
of p66(shc), suggesting that its role in mammalian longevity is more
complex than previously thought.
PMID: 15992607

[Engineered Reversible Cryostasis is not yet available. A precursor
called cryonics is currently used as a processing option for the
treatment of corpses. By comparison, ERC would typically be used to place
still living human beings into an ultra-low temperature "hibernation".
Although ERC subjects would be suffering from a terminal disease, they
would still be both medically and legally alive both before and after
treatment. If there was any doubt on this matter, any ERC subject could
be resusitated, and show up in court to prove this legally. After
technical development of ERC, it is anticipated that there may be a
further 10 year delay before legal hurtles are overcome to allow still
living human beings to become ERC subjects.]

Ann N Y Acad Sci. 2004 Jun;1019:559-63.
The arrest of biological time as a bridge to engineered negligible
senescence.
Lemler J, Harris SB, Platt C, Huffman TM. Alcor Life Extension
Foundation, 7895 E. Acoma Drive, Scottsdale, AZ 85260, USA.
    Biological systems can remain unchanged for several hundred years at
cryogenic temperatures. In several hundred years, current rapid
scientific and technical progress should lead to the ability to reverse
any biological damage whose reversal is not forbidden by physical law. We
therefore explore whether contemporary people facing terminal conditions
might be preserved well enough today for their eventual recovery to be
compatible with physical law. The ultrastructure of the brain can now be
excellently preserved by vitrification, and solutions needed for
vitrification can now be distributed through organs with retention of
organ viability after transplantation. Current law requires a few minutes
of cardiac arrest before cryopreservation of terminal patients, but dogs
and cats have recovered excellent brain function after 16-60 min of
complete cerebral ischemia. The arrest of biological time as a bridge to
engineered negligible senescence, therefore, appears consistent with
current scientific and medical knowledge.
PMID: 15247086

[Quote from the paper listed below: "Approaches to reduce chemical
toxicity of a CPA solution without dimishing its glass-forming tendancy
include using a combination of CPAs with different mechanisms of
toxicity, using agents that antagonize each other's toxicity and using
reduced temperatures of exposure". Note that pretreatment of cells to
modulate cryoprotectant toxicity is an avenue which has NOT been
significantly explored in published papers. I will shortly be pretreating
brine shrimp to see if this might be a viable approach to reducing
cryoprotectant toxicity. Various additives to the cryoprotectant
solutions will also be tried.]

Cryobiology. 2007 Feb;54(1):1-12. Epub 2006 Dec 12.
Cryopreservation of rat precision-cut liver and kidney slices by rapid
freezing and vitrification.
de Graaf IA, Draaisma AL, Schoeman O, Fahy GM, Groothuis GM, Koster
HJ. Pharmacokinetics and Drug Delivery, Groningen University Institute
for Drug Exploration, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
    Precision-cut tissue slices of both hepatic and extra-hepatic origin
are extensively used as an in vitro model to predict in vivo drug
metabolism and toxicity. Cryopreservation would greatly facilitate their
use. In the present study, we aimed to improve (1) rapid freezing and
warming (200 degrees C/min) using 18% Me(2)SO as cryoprotectant and
(2) vitrification with high molarity mixtures of cryoprotectants, VM3 and
VS4, as methods to cryopreserve precision-cut rat liver and kidney
slices. Viability after cryopreservation and subsequent 3-4h of
incubation at 37 degrees C was determined by measuring ATP content and by
microscopical evaluation of histological integrity. Confirming earlier
studies, viability of rat liver slices was maintained at high levels by
rapid freezing and thawing with 18% Me(2)SO. However, vitrification of
liver slices with VS4 resulted in cryopreservation damage despite the fact
that cryoprotectant toxicity was low, no ice was formed during cooling
and devitrification was prevented. Viability of liver slices was not
improved by using VM3 for vitrification. Kidney slices were found not to
survive cryopreservation by rapid freezing. In contrast, viability of
renal medullary slices was almost completely maintained after
vitrification with VS4, however vitrification of renal cortex slices with
VS4 was not successful, partly due to cryoprotectant toxicity. Both
kidney cortex and medullary slices were vitrified successfully with VM3
(maintaining viability at 50-80% of fresh slice levels), using an
optimised pre-incubation protocol and cooling and warming rates that
prevented both visible ice-formation and cracking of the formed glass. In
conclusion, vitrification is a promising approach to cryopreserve
precision-cut (kidney) slices.
PMID: 17166492

[Here's another example of the extremely slow pace of transmission of
information to scientists. Back in 1988 the Gynaephora groenlandica larva
were discovered to be nature's most freeze resistant animal. By all rights,
cryobiologists should have bumped into each other researching this animal
to discover its chilly secret. However for the next two decades nothing
happened. There are still currently a grand total of zero references to
this animal in the journal Cryobiology. I talked to one of the world's
premier cryobiologists recently about these "Woollybear caterpillars".
He admitted he had never heard of them! Yes, he was very interested, and
thankful for the information. This slow pace of information transmission
is partly the reason I agree with conservative cryobiologists, that it may
take over 50 years to achieve ERC. Cryobiologists have had a few decades
to advance their art, while Mother Nature has had billions of years to
evolve the exceptionally high freeze resistance of the woollybear
caterpillar.]

J Comp Physiol [B]. 1988;158(2):175-83.
Glycerol metabolism in a freeze-tolerant arctic insect: an in vivo 13C
NMR study.Kukal O, Serianni AS, Duman JG.
Department of Biological Sciences, University of Notre Dame, Indiana 46556.
  Freeze-tolerance in larvae of Gynaephora groenlandica is enhanced by
the accumulation of glycerol in the winter. Since summer larvae remain
freeze-tolerant despite the lack of glycerol, we investigated glycerol
metabolism as a function of acclimation and body temperature using
noninvasive 13C NMR spectroscopy. Major constituents of hemolymph isolated
from cold- and warm-acclimated larvae were identified with the aid of
standard NMR spectra and confirmed by TLC and GLC. Spectra obtained on
live, warm-acclimated larvae showed the presence of lipids, glycogen,
glucose, trehalose and amino acids. Similar spectra of cold-acclimated or
previously frozen larvae showed the additional presence of glycerol. In
vitro time-lapse 13C spectra of D-[1-13C]glucose added separately to
hemolymph or extracted fat body tissue showed that glycerol is
synthesized from glucose in the fat body tissue and distributed to the
peripheral tissue via hemolymph. In vivo time-lapse 13C spectra of cold-
and warm-acclimated larvae were obtained after injection with
D-[1-13C]glucose to monitor the production of labeled metabolic
intermediates and end-products. [13C]Glycerol was produced between -30
degrees C and 30 degrees C but accumulated only below 5 degrees C. Above 5
degrees C glycerol was degraded and the 13C label incorporated mainly
into glycogen. The mechanism underlying temperature control of glycerol
biosynthesis and degradation may provide a clue to the role of glycerol
in enhancing freeze-tolerance in these insects.
PMID: 3170824

[Further quote from the above paper:
"However, cold-acclimation (-15 C, -30 C) enhanced cold tolerance in the
larvae so they were able to tolerate temperatures lower than -70 C (the
lowest temperature tested, no mortality resulted;"]


Guess how many citations there are for "Gynaephora groenlandica" on
Pubmed. 600? 60? 6?
Check out the answer with this link>>
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

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