Page 84 - 79_02

A.
Gómez
et
col.

sólo
en
animales
viejos
que
coincide
con
meta-­-análisis
recientes
en
pacientes

humanos.

Palabras
clave:
Estrés
oxidativo;
ß-­-bloqueante;
Frecuencia
cardíaca.

1.
INTRODUCTION

TA
new
mammalian
longevity
model
based
on
ß-­-adrenergic
receptor

signaling
interruption
at
the
level
of
adenylyl
cyclase
has
reported
decreased
bone

and
heart
aging
and
increases
in
mean
and
maximum
longevity
in
AC5
KO
(adenylyl

cyclase
5
Knockout)
mice
(1).
We
have
previously
mimicked
this
model
with
the
ß-­-
blocker
atenolol
in
short-­-term
studies
(2),
in
which
we
have
successfully
modified

one
of
the
only
two
known
traits
correlating
with
longevity
in
the
right
sense:
the
low

degree
fatty
acid
unsaturation
of
the
cellular
membranes
of
the
tissues
of
long-­-lived

animals.

Comparative
gerontological
studies
have
already
unveiled
two
traits
that
can

explain
the
different
(maximum)
longevity
of
different
mammals:
long-­-lived
animal

species
have
a
low
rate
of
mitochondrial
reactive
oxygen
species
production

(mitROSp)
(3,
4)
and
a
low
unsaturation
degree
of
membrane
fatty
acids
(5,
6).

The
first
of
these
two
factors,
mitROSp,
can
be
experimentally
decreased
with

dietary
manipulations
like
caloric
restriction
(7,
8),
protein
restriction
(9)
and

methionine
restriction
(10).
But
the
second
one,
the
unsaturation
degree
of

membrane
fatty
acids,
is
more
difficult
to
modify.
Increasing
dietary
saturated
fatty

acids
have
unhealthy
effects
on
plasma
cholesterol
levels,
and
the
tissue
global
FA

(fatty
acid)
unsaturation
is
homeostatically
regulated
in
mammalian
tissues
through

control
of
gene
expression
(11).
Deficiency
of
essential
PUFAs
in
the
diet
leads
to

strong
compensatory
increases
in
tissue
mead
acid
(20:3n-­-9,
synthesized
from

18:1n-­-9),
a
known
diagnostic
marker
of
essential
FA
deficiency,
or
to
increases
in

MUFAs
like
16:1n-­-7
and
18:1n-­-9
(12).
Homeostatic
changes
like
these
are

responsible
for
the
failure
to
effectively
change
tissue
DBI
after
feeding
the
animals

with
diets
differing
in
FA
unsaturation
(13,
14).

A
low
unsaturation
degree
is
most
important
for
developing
a
high
longevity

because
membrane
fatty
acid
double
bounds
are
most
susceptible
to
oxidative
attack

due
to
two
reasons:
a)
oxygen
and
many
radical
species
are
several
times
more

soluble
in
lipid
membrane
bilayers
than
in
the
aqueous
solution
(15);
b)
the

sensitivity
of
membranes
to
lipid
peroxidation
increases
strongly
as
a
function
of
the

number
of
double
bonds
per
fatty
acid
molecule.
A
lower
total
number
of
double

bounds
of
membrane
fatty
acids
make
these
molecules
more
resistant
to
lipid

peroxidation.
Polyunsaturated
fatty
acids
(PUFAs)
exhibit
the
highest
sensitivity
to

ROS
induced
oxidative
damage
among
cellular
macromolecules,
and
this
sensitivity

increases
as
a
function
of
the
number
of
double
bonds
per
fatty
acid
molecule

254