Page 95 - 79_02

Long-­-life
supplementation
with
atenolol…

4.
DISCUSSION

In
the
present
work
we
comprehensively
studied,
for
the
first
time,
the

chronic
effect
of
the
ß-­-1
blocker
atenolol
on
various
metabolic
and
oxidative
stress

parameters
during
the
whole
life
span
of
a
sufficiently
large
population
of
healthy

mice.

After
16
months
of
continuous
atenolol
treatment,
we
observed
quantitatively

important
decreases
in
the
fatty
acid
unsaturation
degree
of
mitochondrial

membranes,
as
well
as
in
protein
oxidation,
lipoxidation
and
glycoxidation
in

mitochondria
from
the
two
tissues
studied:
heart
and
SKM.
This
agrees
with
similar

changes
observed
after
15
days
of
treatment
with
the
same
dose
of
atenolol
in
mouse

heart
(2),
indicating
that
the
most
important
capacity
of
this
drug
to
lower
this

parameter
can
be
maintained
at
least
during
most
of
the
lifespan
of
the
animals.

These
results
indicate
that
blocking
of
the
ß1-­-adrenergic
signaling
pathway

improves
one
of
the
only
two
known
parameters
which
link
longevity
and
oxidative

stress,
the
DBI
and
PI
(reviewed
in
34,
35).
Strikingly,
the
potency
of
atenolol
is
so

great
that
it
can
decrease
the
DBI
of
mitochondrial
membranes
from
that
of
a
mouse

to
that
typical
of
a
mammal
of
around
40
years
in
longevity
(2),
taking
into
account

the
known
relationship
between
membrane
FA
unsaturation
and
mammalian

longevity
(34),
also
in
relation
to
the
extended
life-­-span
of
the
AC5KO
mice
(1).

In
our
longevity
experiment,
the
atenolol
treatment
did
not
modify
body

weight,
heart
and
SKM
organ
weight,
or
food
intake,
this
ruling
out
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
mtROS
generation

rate
neither
with
glutamate/malate
nor
with
pyruvate/malate
as
substrates
or
with

the
supplemented
complex
I
and
III
specific
inhibitors
rotenone
or
antimicyn
A.

These
results
agree
with
those
from
our
short-­-term
study
in
the
heart
of
atenolol-­-
treated
C57BL/6
mice
(2),
and
are
in
contrast
to
dietary,
protein
and
methionine

restriction
models
in
which
mtROSp
decreases
at
complex
I
(36).
All
of
these
dietary

manipulations
increase
longevity
and
decrease
mtROSp
without
changing
the
DBI

and
PI
(37).
However,
the
ß-­-adrenergic
signalling
blockade
seems
to
decrease
the

other
longevity-­-related
trait
(lowers
the
DBI
and
PI)
without
changing
mtROSp.

Therefore,
these
two
manipulations,
the
dietary
restrictions
and
the
atenolol

treatment,
seem
to
be
complementary.

Supporting
that
general
idea,
long-­-term
treatment
with
atenolol
did
not

change
any
of
the
mitochondrial
respiratory
chain
complexes
except
for
the
increase

in
complex
II
(70
KDa
subunit,
Flavoprotein)
in
heart
mitochondria,
mtROSp
and
the

level
of
8-­-oxodG
in
mtDNA
(which
indicates
the
balance
between
mtDNA
oxidative

damage
and
repair).
mtROSp
and
8-­-oxodG
in
mtDNA
usually
change
together
and
in

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

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