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Oxidative Medicine and Cellular Longevity
Volume 2015, Article ID 250310, 13 pages
Review Article

Inhibition of Adenylyl Cyclase Type 5 Increases Longevity and Healthful Aging through Oxidative Stress Protection

Departments of Cell Biology & Molecular Medicine and Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA

Received 2 January 2015; Revised 10 March 2015; Accepted 13 March 2015

Academic Editor: Vincent Pialoux

Copyright © 2015 Stephen F. Vatner et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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 diabetes, obesity, and the cardiomyopathy induced by aging, diabetes, and cardiac stress and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection. For example, chronic beta adrenergic receptor stimulation induced cardiomyopathy was rescued by AC5 KO. Conversely, in AC5 transgenic (Tg) mice, where AC5 is overexpressed in the heart, the cardiomyopathy was exacerbated and was rescued by enhancing oxidative stress resistance. Thus, the AC5 KO model, which resists oxidative stress, is uniquely designed for clinical translation, since it not only increases longevity and exercise, but also protects against diabetes, obesity, and cardiomyopathy. Importantly, inhibition of AC5’s action to prolong longevity and enhance healthful aging, as well as its mechanism through resistance to oxidative stress, is unique among all of the nine AC isoforms.