Long-‐life supplementation with atenolol…
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4. DISCUSSION
In the present work we comprehensively studied, for the first time, the
chronic effect of the β-‐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 β1-‐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 β-‐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
