[tt] [Fwd: [GRG] PEPCK Mice Live and Reproduce Twice as Long as Control Mice, Eat 60% More]

[Brian Atkins]

-------- Original Message --------
Subject: [GRG] PEPCK Mice Live and Reproduce Twice as Long as Control Mice,	Eat 
60% More
Date: Fri, 18 Apr 2008 12:22:28 -0700 (PDT)
From: Gregory M Fahy <gfahy at sbcglobal.net>
Reply-To: Gerontology Research Group <grg at lists.ucla.edu>
To: Gerontology Research Group <grg at lists.ucla.edu>

To the LA-GRG:

   It appears that the lifespan of the mouse has been doubled using a simple 
biochemical intervention.  We have heard before that the PCPCK mouse may live 
longer than normal mice despite being 25-times more energetic (i.e., it runs 25 
times farther than control mice at the same speed), but now we have more 
evidence for this and, amazingly, for the ability of female mice of this strain 
to reproduce until about ~35 months of age, when most control animals are long 
dead.

   Clues to the reason for the lifespan extension include very low insulin 
levels (therefore, more self-repair), an apparent switch from glucose to fat as 
an energy source (related to lower use of the insulin pathway), and major 
expansions of mitochondria (perhaps preventing or diluting out aging changes 
there).

   Fortunately, a true lifespan study is now underway.

   -- Greg

   Reference:  Biochimie. 2008 Apr 1 [Epub ahead of print]  PMID: 18394430
Born to run; the story of the PEPCK-C(mus) mouse.
     Hanson RW, Hakimi P.
     Department of Biochemistry, Case Western Reserve University School
of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4935, United
States.

   Commentary from the article (emphasis added):

   "A second surprising result was the apparent extended longevity of the
PEPCK-Cmus mice; they lived almost 2 years longer than the controls
and had normal litters of pups at 30-35 months of age (most mice stop
being reproductively active at 12-18 months). We use the word
"apparent" because we have not as yet carried out a detailed aging
study, involving multiple mice, which are followed at regular
intervals over their lifetime; this type of study is currently in
underway in our laboratory so hopefully we will be able to state
unequivocally that the PEPCK-Cmus mice do live longer than controls.
However, the available evidence is strong enough to warrant some
speculation as to why these mice have such an extended life span. This
is especially important since the mice violate one of the pillars of
aging research, namely that limiting food intake increases longevity.
This general principle is supported by studies with species from flies
to rats, and seems well grounded in the literature. If correct, the
results with the PEPCK-Cmus mice imply that it is not the number of
calories consumed, but what happens to these calories one they are
consumed! The mice eat almost twice as much as control animals but
because of their hyperactivity, utilize the excess calories to satisfy
their energy demands. Perhaps the new paradigm in aging research
should be that sustained activity extends life span. At this point,
both the extended life span and the prolonged reproductive capacity of
the PEPCK-Cmus mice need detailed study before hard conclusions,
rather than speculation, will be forthcoming."


   Abstract (emphasis added):

     In order to study the role of the cytosolic form of
phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) in
skeletal muscle, PEPCK-C(mus) mice were created by introducing the
cDNA for the enzyme, linked to the human alpha-skeletal actin gene
promoter, into their germ line. Two founder lines generated by this
procedure were bred together, creating a line of mice that have
9.0units/g skeletal muscle, as compared to 0.080units/g in muscle from
control animals. The mice were more active than controls in their
cages and could run for up to 5km, at a speed of 20m/min without
stopping (control mice run for 0.2km at the same speed). Male PEPCK-
C(mus) mice are extremely aggressive, as well as hyperactive. During
strenuous exercise, they use fatty acids as a fuel more efficiently
than do controls and produce far less lactate than do control animals,
perhaps due to the greatly increased number of mitochondria in their
skeletal muscle. PEPCK-C(mus) mice also store up to five-times more
triglyceride in their skeletal muscle, but have only marginal amounts
of triglyceride in their adipose tissue depots, despite eating 60%
more than controls. The concentration of leptin and insulin the blood
of 8-12 months of PEPCK-C(mus) mice is far lower than noted in the
blood of control animals of the same age. These mice live longer than
controls and the females remain reproductively active for as long as
35 months. The possible reasons for the profound alteration in
activity and longevity caused the introduction of a simple metabolic
enzyme into the skeletal muscle of the mice will be discussed.


-- 
Brian Atkins
Singularity Institute for Artificial Intelligence
http://www.singinst.org/
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