A. Gómez et col.
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sólo en animales viejos que coincide con meta-‐análisis recientes en pacientes
humanos.
Palabras clave:
Estrés oxidativo; β-‐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
