Reduction in mitochondrial membrane peroxidizability index…
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heterogeneous animals like the Wistar rat, and to ascertain whether β-‐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 β-‐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.
