Reduction in mitochondrial membrane peroxidizability index…
629
the long-‐lived AC5 KO mice was probably AIF independent. On the other hand the
atenolol treatment did not modify SIRT3 values, which would agree with the
absence of changes in mitROS production rate observed in our study. SIRT3 has
been reported to increase the activity of complex I through direct interaction and
deacetylation of several of its subunits (27). Finally, the unchanged content
observed for SIRT5 also agree with the absence of changes in oxidative metabolism
(oxygen consumption) observed in the present work.
In conclusion, the results of the present investigation, together with
previous reports in mice (1, 38) suggest that β-‐adrenergic receptor signaling
blockade can be a useful model looking for pharmacologically-‐induced decreases in
oxidative stress and possible increases in lifespan. Atenolol treatment improved
parameters related to oxidative stress and longevity such as membrane fatty acid
unsaturation degree, the peroxidizability index and protein lipoxidation in a time
period as short as fifteen days. It would be very interesting to further investigate
the effect of atenolol in different organs (other than the heart), species and times of
action
,
and to clarify the cellular signaling mechanisms by which this β-‐blocker
decreases fatty acid unsaturation. The interruption of the beta-‐adrenergic receptor
signaling pathway in AC5 KO mice resulted in delaying bone and heart aging and
increasing mean and maximum longevity. Those beneficial changes seemed to be
under the stimulation of the Raf/MEK/ERK signalling pathway. Previous studies
also observed that atenolol-‐treated mice had higher levels of p-‐ERK (38). That
could suggest that the decrease in fatty acid unsaturation and oxidative stress
induced by atenolol could be due to changes in gene expression activated by
increases in ERK-‐dependent signalling. Finally, lowering oxidative stress with
atenolol can be easier to implement in humans than caloric restriction. Atenolol
seems to be a rather well tolerated drug, which has been used for decades in large
human populations without, apparently, important side effects.
5. ACKNOWLEDGMENTS
This study was supported in part by I+D grants from the Spanish Ministry of
Science and Innovation (BFU2008-‐00335/BFI; BFU2011-‐23888) to G.B; and grants
from the Spanish Ministry of Science and Innovation (BFU2009-‐11879/BFI), and
the Generalitat of Catalonia (2009SGR735) to R.P. A. G., I. S-‐R and J. G. received
predoctoral fellowships from the Ministry of Education and Science.
6. REFERENCES
1.
Yan, L.; Vatner, D.E.; O’Connor, J.P.; Ivessa, A.; Ge, H.; Chen, W.; Hirotani, S.; Ishikawa, Y.;
Sadoshima, J.; Vatner, S.F.. Type 5 adenylyl cyclase disruption increases longevity and
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