Type 5 Adenylyl Cyclase Disruption Increases Longevity and Protects Against Stress

Yan, Lin; Vatner, Dorothy E.; O’Connor, J. P.; Ivessa, Andreas S.; Ge, Hui; Chen, Wei; Hirotani, Shinichi; Ishikawa, Yoshihiro; Sadoshima, Junichi; Vatner, Stephen F.

doi:10.1016/j.cell.2007.05.038

Cited by 308 publications

(344 citation statements)

References 65 publications

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“…Chronic or overstimulation of the adrenergic pathways adversely affects myocyte growth and function, produces hypertension (Port and Bristow 2001;Taylor and Bristow 2004), and is a prognostic indicator in heart failure (Esler et al 1997). Mouse models of chronically enhanced β1AR, G protein, and protein kinase PKA activity suffer from increased mortality and decreased resistance to stress (see discussion in Yan et al 2007). Sympathetic nervous system and βAR activity increase with age, and this increase may hasten the development of age-related cardiomyopathies (Lakatta 1993;Swynghedauw et al 1995).…”

Section: Discussionmentioning

confidence: 99%

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

Spindler

Mote

et al. 2013

AGE

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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.

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Section: Discussionmentioning

confidence: 99%

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

Spindler

Mote

et al. 2013

AGE

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“…A number of "aging genes" have been identified for which mutations significantly increase mouse lifespan and delay the onset of age-related disease (Prop1, Pit1, Ghr,Ghrhr,Irs1,Irs2,PappA,Clk1,Shc1,Igf1r,Kl,Adcy5,Surf1,Insr,Ucp2,Gpx4) (Brown-Borg et al, 1996;Kopchick and Laron, 1999;Migliaccio et al, 1999;Flurkey et al, 2001;Bluher et al, 2003;Holzenberger et al, 2003;Kurosu et al, 2005;Liu et al, 2005;Conti et al, 2006;Conover and Bale, 2007;Dell'Agnello et al, 2007;Ran et al, 2007;Taguchi et al, 2007;Yan et al, 2007;Selman et al, 2008). The extent to which these genes interact with CR-regulated pathways is unclear (Miller et al, 2002;Tsuchiya et al, 2004;Bonkowski et al, 2006;Swindell, 2007).…”

Section: Other "Aging Genes" Lack Unique Network Propertiesmentioning

confidence: 99%

Genes regulated by caloric restriction have unique roles within transcriptional networks

Swindell

2008

Mechanisms of Ageing and Development

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Caloric restriction (CR) has received much interest as an intervention that delays age-related disease and increases lifespan. Whole-genome microarrays have been used to identify specific genes underlying these effects, and in mice, this has led to the identification of genes with expression responses to CR that are shared across multiple tissue types. Such CR-regulated genes represent strong candidates for future investigation, but have been understood only as a list, without regard to their broader role within transcriptional networks. In this study, co-expression and network properties of CR-regulated genes were investigated using data generated by more than 600 Affymetrix microarrays. This analysis identified groups of co-expressed genes and regulatory factors associated with the mammalian CR response, and uncovered surprising network properties of CR-regulated genes. Genes downregulated by CR were highly connected and located in dense network regions. In contrast, CR-upregulated genes were weakly connected and positioned in sparse network regions. Some network properties were mirrored by CR-regulated genes from invertebrate models, suggesting an evolutionary basis for the observed patterns. These findings contribute to a systems-level picture of how CR influences transcription within mammalian cells, and point towards a comprehensive understanding of CR in terms of its influence on biological networks.

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“…Therefore, the demonstration of improved exercise performance in the AC5 KO model is particularly germane, as this is also a model for longevity (Yan et al ., 2007), and protects against cardiovascular stress (Okumura et al ., 2003; Lai et al ., 2013), diabetes, and obesity (Ho et al ., 2015). In view of the important link between exercise and longevity, it is surprising that of 20 mouse models we reviewed, only two studied exercise and found it to be increased.…”

Section: Discussionmentioning

confidence: 99%

“…However, the overwhelming preponderance of data in patients support the concept that exercise improves not only healthy lifespan, but also longevity, as it clearly is protective against cardiovascular disease, diabetes, and obesity, all of which are known to reduce lifespan. As the AC5 KO mice exhibit longevity and protection against diabetes, obesity, and cardiovascular disease (Yan et al ., 2007, 2014; Lai et al ., 2013; Ho et al ., 2015) along with enhanced exercise performance demonstrated in the current investigation, this model replicates the human paradigm of healthful aging. Conversely, enhanced β adrenergic signaling results in diminished lifespan, not only in transgenic animal models, for example, overexpression of Gsα (Iwase et al ., 1996, 1997), but also in human aging studies with increased β2 adrenergic receptor genotype, where longevity is diminished (Zhao et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The most widely recognized physiological mechanism to improve exercise performance is enhanced sympathetic and beta adrenergic receptor stimulation and increased adenylyl cyclase (AC) activity (Esposito et al ., 2008), whereas reducing sympathetic stimulation is generally thought to impair exercise performance. We found that inhibiting beta adrenergic signaling at the level of AC, by disrupting the AC isoform type 5 (AC5), that is, AC5 knock out (KO), enhances longevity (Yan et al ., 2007). In view of the above, it becomes a natural question as to whether inhibiting AC5 improves exercise performance.…”

Section: Introductionmentioning

confidence: 99%

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Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

et al. 2015

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SummaryThe most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β‐AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac‐ and skeletal muscle‐specific AC5 KO's, where exercise performance was no longer improved by the cardiac‐specific AC5 KO, but was by the skeletal muscle‐specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti‐oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy‐3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.

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Type 5 Adenylyl Cyclase Disruption Increases Longevity and Protects Against Stress

Cited by 308 publications

References 65 publications

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

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

Genes regulated by caloric restriction have unique roles within transcriptional networks

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

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