A Review of Adenylyl Cyclase Type 5 Inhibition and Longevity

Inhibiting adenylyl cyclase type 5 (AC5) has been demonstrated to extend life in mice. This open access review paper covers what is known of the mechanisms involved:

Adenylyl cyclase (AC) is a ubiquitous enzyme which regulates all organs and catalyzes the conversion of ATP to cAMP. There are nine major mammalian AC isoforms; types 5 and 6 are the major isoforms in the heart. Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against obesity, the cardiomyopathy induced by aging, diabetes, and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection.

Inhibition of AC5 naturally becomes an important mechanism for clinical translation. There have been recent clinical studies supporting our findings in the AC5 KO model. The clinical genome wide association studies have identified single nucleotide polymorphisms (SNPs) in the ADCY5 gene associated with increased type 2 diabetes risk, which is the inverse of AC5 inhibition and therefore consistent with our findings. However, it is difficult to isolate the specific action of one gene in human genome studies, as we have done by disrupting the AC5 gene in mice. Unfortunately disrupting the AC5 gene in patients is not feasible and therefore it becomes necessary to identify a pharmacological inhibitor of AC5. One example of a pharmacological compound that replicates many of the features of AC5 inhibition is an FDA approved antiviral drug, Vidarabine, which protects against the development of cardiomyopathy in mice. However, this drug is not purely an AC5 inhibitor and has the disadvantage that it cannot be administered orally. Accordingly, further work is required to develop a nontoxic AC5 inhibitor that is soluble and can be given to patients orally.

Link: http://dx.doi.org/10.1155/2015/250310


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