A Review of Adenylyl Cyclase Type 5 and Longevity in Mice

Gene therapy to remove adenylyl cyclase type 5 (AC5) was shown to increase mouse longevity a few years back, and researchers have since been working to better understand the mechanisms involved. Like many longevity mutations, this gene is involved in many crucial low-level cellular processes, and researchers are interested in producing drugs to mimic some of the effects of a full gene therapy:

G-protein coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are 9 isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress.

Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function, but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/SIRT1/FoxO3a pathway.

Conversely, disrupting AC5, i.e., AC5 knockout (KO) protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5-KO results in a 30% increase in healthy lifespan, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver and brain that are both protected against diabetes and obesity. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes and obesity. Thus, AC5 inhibition has novel, potential therapeutic applicability to several diseases, not only in the heart, but also in aging, diabetes and obesity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23624627

Comments

What I don't understand about these studies is that the researchers don't seem to attempt integrating studies. If study A extends life by 2 years and study B does it for 1 year and study C does it for 2.5 years, then wouldn't it make sense to try study A+B+C to extend life? A "cocktail" of drugs/interactions to extend life. I've NEVER read an article of someone trying this.

Even if combining studies extends life for 3+ years, for example, that would be a huge jump over one individual study.

Is it an ego thing? Are they so fractured in knowing each other that knowledge isn't shared?

Perhaps SENS Foundation could facilitate this?

Posted by: Rob W at May 3rd, 2013 10:08 AM

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