Lifelong treatment with atenolol decreases membrane fatty acid unsaturation and oxidative stress in heart and skeletal muscle mitochondria and improves immunity and behavior, without changing mice longevity

Abstract

The membrane fatty acid unsaturation hypothesis of aging and longevity is experimentally tested for the first time in mammals. Lifelong treatment of mice with the β1-blocker atenolol increased the amount of the extracellular-signal-regulated kinase signaling protein and successfully decreased one of the two traits appropriately correlating with animal longevity, the membrane fatty acid unsaturation degree of cardiac and skeletal muscle mitochondria, changing their lipid profile toward that present in much more longer-lived mammals. This was mainly due to decreases in 22:6n-3 and increases in 18:1n-9 fatty acids. The atenolol treatment also lowered visceral adiposity (by 24%), decreased mitochondrial protein oxidative, glycoxidative, and lipoxidative damage in both organs, and lowered oxidative damage in heart mitochondrial DNA. Atenolol also improved various immune (chemotaxis and natural killer activities) and behavioral functions (equilibrium, motor coordination, and muscular vigor). It also totally or partially prevented the aging-related detrimental changes observed in mitochondrial membrane unsaturation, protein oxidative modifications, and immune and behavioral functions, without changing longevity. The controls reached 3.93 years of age, a substantially higher maximum longevity than the best previously described for this strain (3.0 years). Side effects of the drug could have masked a likely lowering of the endogenous aging rate induced by the decrease in membrane fatty acid unsaturation. We conclude that it is atenolol that failed to increase longevity, and likely not the decrease in membrane unsaturation induced by the drug.

Cysteine dietary supplementation reverses the decrease in mitochondrial ROS production at complex I induced by methionine restriction

“…Activation of the Raf-ERK-MAPK has been described in long-lived mutant mice (Yan et al 2007) and in DR in rat heart (Castello et al 2011). Furthermore, ERK activation has been related to decreases in lipid-derived oxidative stress (Gómez et al 2014). However, in the present investigation no variations in ERK phosphorylation were observed in any group.…”

“…Inhibition of mTOR is documented in mammalian DR models (Wei et al 2013;Johnson et al 2015). ERK activation has been described in long-lived mutant mice (Yan et al 2007) and in DR in rats (Castello et al 2011) and has been recently related to decreases in oxidative stress (Gómez et al 2014).…”

Perspectives on the membrane fatty acid unsaturation/pacemaker hypotheses of metabolism and aging

“…Finally, treatment with atenolol, a β1-adrenergic receptor blocker, decreased unsaturation index in mice, but did not lead to a significant difference in longevity (Gómez et al, 2014). Atenolol treatment did, however, decrease oxidative damage and improved age-related behavioral functions, such as motor coordination, so the lack of longevity increase was likely related to decreases in heart rate and increases in arterial pressure variation, similar to results from an analogous study (Spindler et al, 2013;Gómez et al, 2014). In addition to the problems listed above with specific studies, some studies may not have found correlations between peroxidation index and longevity because of individuals that were not of equivalent ages, as fatty acyl composition changes with age (Hulbert, 2005).…”

“…Queen bees, which live an order of magnitude longer than workers, had a lower peroxidation index than did worker bees (Haddad et al, 2007). Finally, in many cases, higher peroxidation index and shorter lifespan were predictive of higher oxidative damage to lipids, DNA, and proteins (Aguilar-Toral et al, 2014;Gómez et al, 2014;Jeon et al, 2001;Pamplona et al, 1999aPamplona et al, , 1999cPamplona et al, , 1996.…”

“…For instance, the peroxidation index of free fatty acids, not just acyl chains, in plasma was recently found to be correlated with longevity ; this finding would not have been possible using the techniques that have been traditionally used to study the membrane pacemaker hypotheses. Some authors have started to use mass spectrometry to analyze phospholipid species (Mitchell et al, , 2007, but multiple recent studies still have used gas chromatography to analyze fatty acyl composition (AguilarToral et al, 2014;Almaida-Pagán et al, 2014;Gómez et al, 2014). By employing mass spectrometers, we could have a more complete understanding of patterns of fatty acyl composition in phospholipids and of the mechanisms behind the membrane pacemaker hypotheses of metabolism and aging.…”