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

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.

The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?

“…Interestingly, the anti-aging effects of ACE-inhibitors and ARBs were also observed in rodents with normal blood pressure values [ 48 , 51 , 52 ]. A key mechanism potentially leading to these findings is the interaction of AngII with members of the Sirtuin family [ 53 , 54 ].…”

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“…Enalapril treatment increased lifespan in Wistar rats on standard and palatable hyper lipidic diets [99]. Ramipril (ACEi) in combination (but not alone) with Simvastatin extended lifespan of long-lived, B6C3F1 male mice [100].…”

“…Although, many studies found life-extending benefits of ACEi but not ARB, some studies showed equal benefits of ACEi and ARB [117]. Animal studies showed consistent life extension from ACEi alone [97][98][99] or in combination with statins [100]. Disruption of the Angiotensin II type 1 receptor increases median and maximum lifespan in mice by 26% [118].…”

The goal of geroscience is life extension

“…Enalapril treatment increased lifespan in Wistar rats on standard and palatable hyper lipidic diets [ 99 ]. Ramipril (ACEi) in combination (but not alone) with Simvastatin extended lifespan of long-lived, B6C3F1 male mice [ 100 ].…”

“…Although, many studies found life-extending benefits of ACEi but not ARB, some studies showed equal benefits of ACEi and ARB [ 117 ]. Animal studies showed consistent life extension from ACEi alone [ 97 – 99 ] or in combination with statins [ 100 ]. Disruption of the Angiotensin II type 1 receptor increases median and maximum lifespan in mice by 26% [ 118 ].…”