Page 113 - 79_04

Reduction
in
mitochondrial
membrane
peroxidizability
index…

the
long-­-lived
AC5
KO
mice
was
probably
AIF
independent.
On
the
other
hand
the

atenolol
treatment
did
not
modify
SIRT3
values,
which
would
agree
with
the

absence
of
changes
in
mitROS
production
rate
observed
in
our
study.
SIRT3
has

been
reported
to
increase
the
activity
of
complex
I
through
direct
interaction
and

deacetylation
of
several
of
its
subunits
(27).
Finally,
the
unchanged
content

observed
for
SIRT5
also
agree
with
the
absence
of
changes
in
oxidative
metabolism

(oxygen
consumption)
observed
in
the
present
work.

In
conclusion,
the
results
of
the
present
investigation,
together
with

previous
reports
in
mice
(1,
38)
suggest
that
ß-­-adrenergic
receptor
signaling

blockade
can
be
a
useful
model
looking
for
pharmacologically-­-induced
decreases
in

oxidative
stress
and
possible
increases
in
lifespan.
Atenolol
treatment
improved

parameters
related
to
oxidative
stress
and
longevity
such
as
membrane
fatty
acid

unsaturation
degree,
the
peroxidizability
index
and
protein
lipoxidation
in
a
time

period
as
short
as
fifteen
days.
It
would
be
very
interesting
to
further
investigate

the
effect
of
atenolol
in
different
organs
(other
than
the
heart),
species
and
times
of

action,
and
to
clarify
the
cellular
signaling
mechanisms
by
which
this
ß-­-blocker

decreases
fatty
acid
unsaturation.
The
interruption
of
the
beta-­-adrenergic
receptor

signaling
pathway
in
AC5
KO
mice
resulted
in
delaying
bone
and
heart
aging
and

increasing
mean
and
maximum
longevity.
Those
beneficial
changes
seemed
to
be

under
the
stimulation
of
the
Raf/MEK/ERK
signalling
pathway.
Previous
studies

also
observed
that
atenolol-­-treated
mice
had
higher
levels
of
p-­-ERK
(38).
That

could
suggest
that
the
decrease
in
fatty
acid
unsaturation
and
oxidative
stress

induced
by
atenolol
could
be
due
to
changes
in
gene
expression
activated
by

increases
in
ERK-­-dependent
signalling.
Finally,
lowering
oxidative
stress
with

atenolol
can
be
easier
to
implement
in
humans
than
caloric
restriction.
Atenolol

seems
to
be
a
rather
well
tolerated
drug,
which
has
been
used
for
decades
in
large

human
populations
without,
apparently,
important
side
effects.

5.
ACKNOWLEDGMENTS

This
study
was
supported
in
part
by
I+D
grants
from
the
Spanish
Ministry
of

Science
and
Innovation
(BFU2008-­-00335/BFI;
BFU2011-­-23888)
to
G.B;
and
grants

from
the
Spanish
Ministry
of
Science
and
Innovation
(BFU2009-­-11879/BFI),
and

the
Generalitat
of
Catalonia
(2009SGR735)
to
R.P.
A.
G.,
I.
S-­-R
and
J.
G.
received

predoctoral
fellowships
from
the
Ministry
of
Education
and
Science.

6.
REFERENCES

1.

Yan,
L.;
Vatner,
D.E.;
O’Connor,
J.P.;
Ivessa,
A.;
Ge,
H.;
Chen,
W.;
Hirotani,
S.;
Ishikawa,
Y.;

Sadoshima,
J.;
Vatner,
S.F..
Type
5
adenylyl
cyclase
disruption
increases
longevity
and

protects
against
stress.
Cell
2007;
130,
247–258.

629