Long-‐life supplementation with atenolol…
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(16,17). The negative relationship between membrane fatty acid composition and
longevity has been observed in all the animal models studied, including mammals,
birds, rodents, honeybees, mussels, and humans (18, 19): the longer the longevity of
a species, the smaller the degree of unsaturation of the FAs present in their cellular
membranes.
Recently, many mammalian models of extended lifespan caused single gene-‐
mutations have been developed (20, 21). Most of them are related to insulin/IGF-‐1-‐
like signaling pathways (22). But there are others like Agtr1a–/– (Angiotensine II
type 1 receptors targeted disrupted) mice (23) and AC5KO (adenylyl cyclase 5
Knockout) mice (1) that also show increased medium and maximum longevity.
In the AC5KO model, extension of lifespan in 129/SvJ-‐C57BL/6 mice has been
obtained through the disruption of β-‐adrenergic receptor signaling at the Type 5
adenylyl cyclase (AC5) level (1). This mouse showed increased mean and maximum
longevity, from 25 to 33 months, and from 33 to 37 months, respectively, and also
showed improvements in parameters related to bone and heart age-‐related
deterioration. These improvements seem to be signaled to the nucleus through the
Raf/ MEK/ extra cellular signal-‐regulated kinase (p-‐ERK) pathway, which was
increased in heart and other tissues of the AC5KO mice, together with increases in
the protein levels of MnSOD (manganese superoxide dismutase) in heart, kidney and
brain, suggesting that a decrease in oxidative stress is involved in the mechanisms
responsible for the aging delaying effect.
Two years ago we discovered that the AC5KO model can be mimicked, at least
on the short-‐term, with the drug atenolol, by treating C57BL/6 normal mice during
15 days with this β1-‐selective blocker simply added to drinking water (2). In the
present study we test the long-‐term effects of this drug given to mice in their drinking
water throughout their whole life, using 128 male mice studied during their whole
life span (more than 3 years) under SPF conditions. Based on the successful results of
our previous short-‐term studies (2), we hypothesized that atenolol would chronically
decrease the global degree of unsaturation of heart and skeletal muscle (SKM)
mitochondrial membranes of mice to levels almost similar to those of species with
one order of magnitude higher longevity, and would decrease specific markers of
oxidative stress due to lowered in vivo lipid peroxidation. In this investigation it is
tested for the first time whether modifying one of the only two known correlates of
longevity (the double bond index of mitochondrial membranes, DBI) can decrease
highly specific markers of oxidative stress in two post-‐mitotic tissues of a mammal
and whether it can modify its longevity.
In those life-‐long atenolol-‐treated animals and their controls we studied
physiological parameters including rectal temperature, basal metabolic rate, heart
rate and blood pressure (at 18 and 35 months of age). Concerning oxidative stress,
we measured the rate of ROS production in isolated functional mitochondrial
