Page 85 - 79_02

Long-­-life
supplementation
with
atenolol…

(16,17).
The
negative
relationship
between
membrane
fatty
acid
composition
and

longevity
has
been
observed
in
all
the
animal
models
studied,
including
mammals,

birds,
rodents,
honeybees,
mussels,
and
humans
(18,
19):
the
longer
the
longevity
of

a
species,
the
smaller
the
degree
of
unsaturation
of
the
FAs
present
in
their
cellular

membranes.

Recently,
many
mammalian
models
of
extended
lifespan
caused
single
gene-­-
mutations
have
been
developed
(20,
21).
Most
of
them
are
related
to
insulin/IGF-­-1-­-
like
signaling
pathways
(22).
But
there
are
others
like
Agtr1a–/–
(Angiotensine
II

type
1
receptors
targeted
disrupted)
mice
(23)
and
AC5KO
(adenylyl
cyclase
5

Knockout)
mice
(1)
that
also
show
increased
medium
and
maximum
longevity.

In
the
AC5KO
model,
extension
of
lifespan
in
129/SvJ-­-C57BL/6
mice
has
been

obtained
through
the
disruption
of
ß-­-adrenergic
receptor
signaling
at
the
Type
5

adenylyl
cyclase
(AC5)
level
(1).
This
mouse
showed
increased
mean
and
maximum

longevity,
from
25
to
33
months,
and
from
33
to
37
months,
respectively,
and
also

showed
improvements
in
parameters
related
to
bone
and
heart
age-­-related

deterioration.
These
improvements
seem
to
be
signaled
to
the
nucleus
through
the

Raf/
MEK/
extra
cellular
signal-­-regulated
kinase
(p-­-ERK)
pathway,
which
was

increased
in
heart
and
other
tissues
of
the
AC5KO
mice,
together
with
increases
in

the
protein
levels
of
MnSOD
(manganese
superoxide
dismutase)
in
heart,
kidney
and

brain,
suggesting
that
a
decrease
in
oxidative
stress
is
involved
in
the
mechanisms

responsible
for
the
aging
delaying
effect.

Two
years
ago
we
discovered
that
the
AC5KO
model
can
be
mimicked,
at
least

on
the
short-­-term,
with
the
drug
atenolol,
by
treating
C57BL/6
normal
mice
during

15
days
with
this
ß1-­-selective
blocker
simply
added
to
drinking
water
(2).
In
the

present
study
we
test
the
long-­-term
effects
of
this
drug
given
to
mice
in
their
drinking

water
throughout
their
whole
life,
using
128
male
mice
studied
during
their
whole

life
span
(more
than
3
years)
under
SPF
conditions.
Based
on
the
successful
results
of

our
previous
short-­-term
studies
(2),
we
hypothesized
that
atenolol
would
chronically

decrease
the
global
degree
of
unsaturation
of
heart
and
skeletal
muscle
(SKM)

mitochondrial
membranes
of
mice
to
levels
almost
similar
to
those
of
species
with

one
order
of
magnitude
higher
longevity,
and
would
decrease
specific
markers
of

oxidative
stress
due
to
lowered
in
vivo
lipid
peroxidation.
In
this
investigation
it
is

tested
for
the
first
time
whether
modifying
one
of
the
only
two
known
correlates
of

longevity
(the
double
bond
index
of
mitochondrial
membranes,
DBI)
can
decrease

highly
specific
markers
of
oxidative
stress
in
two
post-­-mitotic
tissues
of
a
mammal

and
whether
it
can
modify
its
longevity.

In
those
life-­-long
atenolol-­-treated
animals
and
their
controls
we
studied

physiological
parameters
including
rectal
temperature,
basal
metabolic
rate,
heart

rate
and
blood
pressure
(at
18
and
35
months
of
age).
Concerning
oxidative
stress,

we
measured
the
rate
of
ROS
production
in
isolated
functional
mitochondrial

255