Combined statin and angiotensin-converting enzyme (ACE) inhibitor treatment increases the lifespan of long-lived F1 male mice.

Stephen R Spindler,James M Flegal,Patricia L Mote

doi:10.1007/s11357-016-9948-4

Stephen R Spindler, James M Flegal + Show 1 more

Open Access

https://doi.org/10.1007/s11357-016-9948-4

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Journal: GeroScience	Publication Date: Sep 2, 2016
Citations: 17	License type: CC BY 4.0

Affiliation: University of California, Riverside

Abstract

Statins, such as simvastatin, and ACE inhibitors (ACEis), such as ramipril, are standard therapies for the prevention and treatment of cardiovascular diseases. These types of drugs are commonly administered together. More recently, angiotensin II type 1 receptor (AT1R) antagonists, such as candesartan cilexetil (candesartan), have been used in the place of, or in combination with, ACEis. Here, we investigated the effects of simvastatin and ramipril single and combination therapy, and candesartan treatment on the lifespan of isocalorically fed, long-lived, B6C3F1 mice. Males were used for their relative endocrine simplicity and to minimize animal usage. The drugs were administered daily in food. The simvastatin and ramipril combination therapy significantly increased the mean and median lifespan by 9 %. In contrast, simvastatin, ramipril, or candesartan monotherapy was ineffective. All groups consumed the same number of calories. Simvastatin, alone or administered with ramipril, decreased body weight without changing caloric consumption, suggesting it may alter energy utilization in mice. Combination therapy elevated serum triglyceride and glucose levels, consistent with altered energy homeostasis. Few significant or consistent differences were found in mortality-associated pathologies among the groups. Simvastatin treatment did not reduce normal serum cholesterol or lipid levels in these mice, suggesting that the longevity effects may stem from the pleiotropic, non-cholesterol-related, effects of statins. Together, the results suggest that statins and ACEis together may enhance mouse longevity. Statins and ACE inhibitors are generally well-tolerated, and in combination, they have been shown to increase the lifespan of normotensive, normocholesterolemic humans.

Highlights

Cardiovascular disease is the leading cause of morbidity and mortality worldwide (World Health Organization 2004)
Suppression of angiotensin II type 1 receptor (AT1R) signaling is not sufficient to induce the lifespan increase seen in the simvastatin and ramipril together (SimRam)-treated mice
Mice fed food containing simvastatin and candesartan together ate so little of the food, even when it contained bacon flavoring, that the studies had to be discontinued for humane reasons

Summary

Introduction

Cardiovascular disease is the leading cause of morbidity and mortality worldwide (World Health Organization 2004). Statins [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors], such as simvastatin, reduce the biosynthesis of the isoprenoids used for cholesterol biosynthesis (Spindler et al 2012a; Edwards and Ericsson 1999). Statins have been shown by meta-analyses to reduce cardiovascular death by 20–30 % (Taylor et al 2011). These health benefits appear to stem from both reduced serum cholesterol levels (Ludman et al 2009) and reduced protein isoprenylation [e.g., (Spindler et al 2012a)]. The pleiotropic effects of reduced isoprenoid biosynthesis are independent of their effects on cholesterol levels (Spindler et al 2012a; Ludman et al 2009). Simvastatin’s non-cholesterol-related, pleotropic effects increase the lifespan and health span of Drosophila by decreasing protein isoprenylation (Spindler et al 2012a)

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