Loss of adenylyl cyclase gene increases life span and protects the aging heart. August 10th, 2007

Loss of adenylyl cyclase gene increases life span and protects the aging heart. August 10th, 2007

August 10th, 2007 By Farhad Abtahian, M.D. Ph.D. [mailto:fabtahian@partners.org]

Disruption of the type 5 adenylyl cyclase (AC5) gene in mice protects against aging changes in the heart and results in increased lifespan. Adenylyl cyclase is a key component of signaling downstream of beta-adrenergic receptors which are activated by increased sympathetic nervous system activity. Because elevated beta-adrenergic signaling has deleterious effects on the heart, interfering with the adrenergic system is a cornerstone of therapy for patients with heart failure. In a recent study published in Cell, Yan et al. show that AC5 is not only important for age related cardiac changes but may play an important role in determining life span[1].

Most models of increasing longevity in mammals have been focused on mechanisms related to the regulation of metabolism. Caloric restriction is probably the best studied such model. In this work, Yan et al. show that AC5 also has a significant influence on longevity. AC5 deficient (AC5 KO) mice have increased lifespan, with a median survival to 33 months of age compared to 25 months for wild type (WT) mice. Increased longevity may not be a consequence of decreased calorie consumption as young AC5 KO mice actually consume more calories than WT mice.

Previous studies had revealed that loss of AC5 provides protection against pressure overload and development of heart failure, in part, by limiting myocardial apoptosis[2]. Comparing WT and AC5 KO mice, Yan et al. now show that old AC5 KO mice do not develop left ventricular (LV) hypertrophy, maintain LV ejection fraction comparable to young mice, and show very little evidence of age related cardiac myocyte apoptosis or myocardial fibrosis (two hallmarks of aging cardiomyopathy). Furthermore, cardiac myocytes isolated from AC5 KO are resistant to both oxidative stress and DNA damage by UV light. Yan et al. suggest the cardio-protective effect of the loss of AC5 is at least partly due to activation of the Raf/MEK/ERK signaling pathway resulting in an up regulation of anti-apoptotic and anti-oxidative stress elements. The beneficial effects of AC5 deficiency extend beyond the heart as the bones of AC5 KO mice have increased density and mechanical strength.

An overload of sympathetic nervous system activity has long been known to contribute to the progression of heart failure. Not surprisingly, loss of AC5 protects against development of heart failure in response to stress (e.g. pressure overload or excess catecholamine stimulation). In addition, it seems that interfering with beta-adrenergic signaling (by loss of AC5) protects against the simple effects of aging on at least the heart and bones in part by activation of anti-apoptotic and anti-oxidative stress pathways. Consequentially, lifespan is increased. The work of Yan et al. suggest that inhibiting catecholamine signaling may not only protect heart failure patients but provide a mechanism for preventing a host of age related pathologies.


 * 1) ref1 pmid=17662940
 * 2) ref2 pmid=12904575