Inhibition of adenylyl cyclase type 5 increases longevity and healthful aging through oxidative stress protection.

Stephen F Vatner,Dorothy E Vatner,Ronald E Pachon

doi:10.1155/2015/250310

Stephen F Vatner, Dorothy E Vatner + Show 1 more

Open Access

https://doi.org/10.1155/2015/250310

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Abstract

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.

Highlights

Adenylyl cyclase (AC) is a ubiquitous enzyme which regulates all organs and catalyzes the conversion of aging process; mitochondria produce less energy (ATP) to cAMP
We found that AC5 KO increases life span and protects against oxidative stress though upregulating the antioxidant, MnSOD [4], whereas MnSOD regulated the cardiomyopathy induced by chronic catecholamine stimulation through the AC5, SIRT1, FoxO3a, and MnSOD pathway [3]
The lesson from the AC5 KO model is how oxidative stress is important in mediating healthful aging, which when coupled to longevity provides a blueprint for clinical translation

Summary

Introduction

Adenylyl cyclase (AC) is a ubiquitous enzyme which regulates all organs and catalyzes the conversion of ATP to cAMP. One common mechanism that mediates longevity and healthful aging is protection against oxidative stress [4, 6, 8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. The most common cause of death in C57BL/6J mice is neoplasia, including lymphoma and other hematological and nonhematological cancers, followed by chronic kidney and heart diseases [74]. As previously described, these entities have been linked to oxidative stress, further supporting the importance of oxidative stress in limiting longevity. It is an autosomal dominant mutation involving (LMNA) gene and/or abnormal posttranslational processing (ZMPSTE24) [75, 78]

Oxidative Stress in Exercise

Oxidative Stress in Diabetes and Obesity

Oxidative Stress in Cardiomyopathy and Heart Failure

Mechanisms of AC5 KO Induced Longevity and Oxidative Stress Resistance

Summary

Clinical Translation