Page 109 - 79_04

Reduction
in
mitochondrial
membrane
peroxidizability
index…

heterogeneous
animals
like
the
Wistar
rat,
and
to
ascertain
whether
ß-­-adrenergic

blockade,
which
increases
longevity
(1),
decreases
oxidative
stress.

Atenolol
treatment
did
not
modify
body
weight,
heart
weight
or
animal
food

intake
discarding
the
possibility
that
the
observed
changes
could
be
secondary

effects
of
caloric
restriction.
In
our
study,
atenolol
treatment
did
not
change
either

complex
I
or
III
mitROS
generation
rate,
with
their
specific
substrates

glutamate/malate
and
pyruvate/malate
and
the
inhibitors
rotenone
and
antimicyn

A.
These
results
agree
with
previous
studies
(38),
and
are
in
contrast
to
dietary,

protein
and
methionine
restriction
models
in
which
mitROS
generation
decreases

at
complex
I
(10).

Many
studies
from
different
laboratories
have
shown
that

dietary
restriction
lowers
mitROS
generation
(39).
After
testing
restriction
of

different
diet
components,
we
concluded
that
only
protein
restriction
decreased

mitROS
production
(8)
and
methionine
was
the
aminoacid
responsible
for
it
(9).

Dietary,
protein
and
methionine
restriction
also
increased
maximum
longevity.

Thus
ß-­-adrenergic
blockade
does
not
seem
to
follow
the
same
pattern
as
these

three
types
of
restriction
and
probably
the
increase
in
longevity
observed
in
AC5

KO
mice
would
not
be
related
to
a
reduced
mitROS
generation
rate.
In
relation
to

the
lack
of
effect
of
atenolol
treatment
on
mitROS
generation,
the
level
of
8-­-oxodG

in
mtDNA
(which
indicates
the
balance
between
mtDNA
oxidative
damage
and

repair)
did
not
change
in
the
heart
of
atenolol
treated
rats.
Both
parameters,

mitROS
generation
and
8-­-oxodG
levels
in
mtDNA,
change
together
and
in
similar

direction
in
different
models
of
dietary
restriction
studied
and
both
are
lower
in

long-­-lived
compared
to
short-­-lived
animal
species
(40).

Since
atenolol
did
not
modify
mitROS
generation
or
mtDNA
oxidative

damage,
we
focused
on
the
other
oxidative
stress
longevity-­-related
parameter:
the

fatty
acid
unsaturation
degree.
Membrane
phospholipids
are
susceptible
to

oxidative
alterations
due
to
physico-­-chemical
properties
of
the
membrane
bilayer,

in
which
oxygen
and
free
radicals
are
more
soluble
than
in
the
aqueous
medium
.

For
this
reason
membrane
lipids
are
highly
sensitive
to
oxidative
damage.
On
the

other
hand,
PUFA
residues
of
phospholipids
are
extremely
sensitive
to
oxidation,

and
this
sensitivity
increases
exponentially
as
a
function
of
the
number
of
double

bonds
per
fatty
acid
molecule
(15).
It
has
been
observed
in
many
different
animal

species
(5)
that
the
total
number
of
double
bonds
(DBI)
and
the
peroxidizability

index
(PI)
from
membrane
fatty
acids
are
lower
in
long-­-lived
than
in
short-­-lived

animals.
A
low
membrane
fatty
acid
unsaturation
degree
is
also
present
in

extraordinarily
long-­-lived
animals
like
birds
(41,42),
naked
mole-­-rats
(43),

echidna
(44)
and
queen
honeybees
(45).
This
also
occurs
in
long-­-lived
wild-­-
derived
strains
of
mice
compared
to
genetically
heterogeneous
laboratory
mice

(46).
In
our
study,
atenolol
treatment
significantly
decreased
the
PI
(15.20%
total

decrease)
and
tended
to
decrease
the
DBI
(6.49%
total
decrease)
in
the
rat
heart.

625