β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

Abstract

Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease allcause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality.Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P< 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans.

Lifespan effects of simple and complex nutraceutical combinations fed isocalorically to mice

“…These results suggest that screening drugs and supplements in lower eucaryotes may be confounded by high false discovery rates. However, our experience has been that many compounds which extend mouse lifespan also extend the lifespan of Drosophila (e.g., Spindler et al 2013c). …”

“…Second, therapeutics may have both negative and positive effects on lifespan and healthspan. Beginning treatment at a later age may reduce the accumulated toxic effects of a potential therapeutic (Spindler et al 2013c). Third, rapamycin, the most efficacious model therapeutic yet found in mice, is approximately equally effective whether administration is begun at 9 or 20 months of age (Miller et al 2011).…”

“…6 Lifespan of mice fed a diet containing Ortho Core or a control diet Fig. 7 Lifespan of mice fed a diet containing Ortho Mind or a control diet mean body weight estimates became increasingly unstable as days on diet increased, because the number of mice diminished with time (Spindler et al 2013b;Spindler et al 2013c). Because the ratio of food consumption to body weight was not consistently different between groups, the supplements do not appear to change energy adsorption or utilization.…”

Mechanisms of action of compounds that mimic beneficial effects of calorie restriction such as lifespan extension: Is taurine a promising candidate?

“…Among the β-blockers, it was recently reported that metoprolol and nebivolol extend the lifespan of mice 21) . It has been hypothesized that this lifespan extension effect is the result of an off-target effect different from that of the original target molecule of the drug.…”

“…The versatility of taurine thus makes it a promising CRM candidate compound. Notably, taurine has already been shown to reduce tunicamycin-induced endoplasmic reticulum stress and extend the lifespan of lower organisms (C. elegans) 44) , offering further promise as a CRM for higher Telmisartan Antihypertensive AT1 possible 20) Metoprolol Antihypertensive ACE yes 21) Rapamycin Immunosuppressive mTOR yes 22) Rikkunshito Neuropeptide Y activator GHS-R yes 33) Taurine Anti-congestive heart failure various yes 44) 205 JPFSM : Effects of calorie restriction mimetics organisms. Table 1 provides a summary of the CRM candidates described in this review that are currently in clinical use or being clinically trialed for various age-related diseases.…”