Page 98 - 79_02

A.
Gómez
et
col.

modifying
genes
related
to
oxidative
stress,
including
genes
coding
for
desaturase

and
elongase
enzymes,
as
well
as
those
controlling
peroxisomal
ß-­-oxidation,
and
are

rate
limiting
for
the
synthesis
of
the
highly
peroxidizable
22:6n-­-3
FA.
Lower

desaturase/elongase/peroxisomal
ß-­-oxidation
activities
induced
by
the
AT-­-blockade

(via
low
AC
and
high
p-­-ERK)
would
decrease
22:6-­-n3
formation
from
its
less

unsaturated
18:3n-­-3
dietary
precursor.

Concerning
cellular
signaling,
AMPK
responds
to
high
intracellular
levels
of

AMP,
and
activates
(besides
others)
the
expression
of
SIRT1
(Silent
information

regulator
1)
(53).
SIRT1
regulates
energy
metabolism,
cell
apoptosis,
cell

proliferation
and
inflammation,
as
well
as
stress
resistance
by
means
of
FOXO,
p53

and
NF-­-B
signaling,
increasing
the
intracellular
concentration
of
NAD+.
SIRT1
is

increased
in
caloric
restriction
(life-­-extending)
models,
and
can
activate
cellular

stress
resistance,
playing
an
anti-­-aging
role
(54).
In
our
study,
SIRT1
levels
were

higher
after
the
atenolol
treatment
in
the
heart,
which
indicates
that
the
blocking
of

AC
inactivates
the
AMPc.
That
would
increase
SIRT1
expression
through
the
ensuing

changes
in
intracellular
levels
of
AMP
then
of
AMPK.

Nrf2
is
the
“master
regulator”
of
the
antioxidant
response
modulating
the

expression
of
many
several
antioxidant-­-codifying
genes
(55),
and
TFAM
is
a
regulator

of
mtDNA
transcription,
whose
lack
leads
to
severe
respiratory
chain
deficiency
(56).

Since
it
is
now
well
known
that
long-­-lived
animals
have
lower
tissue
levels
of

antioxidant
enzymes
and
other
endogenous
antioxidants
(57)
and
less
endogenous

DNA
base
excision
repair
(BER)
activity
(58),
which
are
secondary
events
to
the

lower
rate
of
mtROSp
of
long-­-lived
animal
species
(59,
37),
it
is
not
strange
that
Nrf2

and
TFAM
were
decreased
after
atenolol
treatment.

Finally,
although
our
results
show
an
improvement
in
parameters
related

with
longevity,
a
low
DBI,
PI,
protein
oxidation
and
lipoxidation
in
mitochondria
from

both
tissues,
and
in
mtDNA
oxidative
damage
(in
the
case
of
heart),
this
was
not

enough
to
increase
longevity,
as
it
is
evident
form
the
survival
curves
finally
obtained,

since
atenolol
treated
mice
did
not
live
longer
than
the
control
animals.
Although

mean
life
span
was
similar
in
both
groups,
only
at
the
end
of
the
life
span
and
in
very

old
animals
(equivalent
to
70-­-80
years
old
humans)
survival
was
somewhat

decreased
after
long-­-term
treatment
with
atenolol.
This
can
be
due
to
a
deleterious

secondary
effect
of
the
drug.
All
ß-­-blockers
act
by
decreasing
blood
pressure/heart

rate
(60),
and
that
is
known
to
be
advantageous
for
coronary
disease
patients,
or
for

those
surviving
after
heart
attacks
or
other
serious
cardiovascular
illnesses.

However,
recent
meta-­-analyses
in
humans
are
suggesting
that
in
the
case
of
old

hypertensive
patient’s
atenolol
can
decrease
instead
of
increase
survival
(61).
When

old
patients
are
treated
with
ß-­-blockers
(atenolol
is
used
in
around
75%
of
cases)

rigid
arteries
typical
of
old
people
can
result
in
sporadically
too
low
diastolic
or

systolic
blood
pressures,
which,
together
with
the
aged
myocardium
of
old
people

268