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modifying genes related to oxidative stress, including genes coding for desaturase
and elongase enzymes, as well as those controlling peroxisomal β-‐oxidation, and are
rate limiting for the synthesis of the highly peroxidizable 22:6n-‐3 FA. Lower
desaturase/elongase/peroxisomal β-‐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 TFAMwere 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 β-‐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 β-‐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
