Long-‐life supplementation with atenolol…
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can increase sudden cardiac death and thus mortality. It seems that the most
important secondary effect of atenolol is the strongly decrease in heart rate that it
induces (62, 63). The meta analyses recently performed in humans agree with our
results in mice, because we did not see any differences in blood pressure or heart
rate when measured at 18 months of age, whereas heart rate was strongly and
significantly decreased in the atenolol group at 35 months of age (499 mmHg in Old
AT compared to 674 mmHg in Old controls). We believe that our results are most
important concerning future cardiologic treatments in humans since there are
available antihypertensive drugs alternative to atenolol, and they constitute the first
study of the long-‐life effects of atenolol in a large population of healthy mammal.
5. CONCLUSION
1.-‐ The long-‐life treatment with the β-‐blocker atenolol in drinking water of a
large population of mice strongly decreases the degree of fatty acid unsaturation of
skeletal muscle and mitochondrial membranes, the only parameter known, apart
from a low rate of mitochondrial ROS generation, that correlates with longevity in the
right way. 2.-‐ That change seems to be due to a large extent to a decrease in
desaturase/elongase/peroxisomal β-‐oxidation activities, which are rate limiting for
the synthesis of the highly unsaturated docosahexahenoic acid (22:6n-‐3). This fatty
acid is universally avoided in the tissue cellular membranes of long-‐lived mammalian
and bird species.
3.-‐ Those decreases are due to β-‐adrenergic blockade-‐induced increases in p-‐
ERK signaling to the nucleus, and lead to strong decreases in oxidation, glycoxidation
and lipoperoxidation of mitochondrial proteins, as well as in oxidative damage to
mtDNA (in the case of heart tissue).
4.-‐ These beneficial changes were not translated into increased (maximum)
longevity most likely due to a secondary detrimental effect of the drug on heart
frequency, and likely eventual falls in arterial pressure, only evident in very old
animals, whereas the mean life span was not altered. These effects are most relevant
for consideration of possible detrimental effects of atenolol, recently detected (meta-‐
analyses from 2008 on) only in old hypertensive human subjects.
6. ACKNOWLEDGMENTS
This investigation was supported in part by I+D grants from the Spanish
Ministry of Science and Innovation (BFU2008-‐00335/BFI) to G.Barja.
