Spindler Stephen R, Mote Patricia L, Flegal James M
Department of Biochemistry, University of California at Riverside, Riverside, CA, 92521, USA.
Department of Statistics, University of California at Riverside, Riverside, CA, 92521, USA.
Age (Dordr). 2016 Dec;38(5-6):379-391. doi: 10.1007/s11357-016-9948-4. Epub 2016 Sep 2.
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.
他汀类药物，如辛伐他汀，以及血管紧张素转换酶抑制剂（ACEIs），如雷米普利，是预防和治疗心血管疾病的标准疗法。这类药物通常联合使用。最近，血管紧张素II 1型受体（AT1R）拮抗剂，如坎地沙坦酯（坎地沙坦），已被用于替代ACEIs或与ACEIs联合使用。在此，我们研究了辛伐他汀和雷米普利单药及联合治疗，以及坎地沙坦治疗对等量热量喂养的长寿B6C3F1小鼠寿命的影响。选用雄性小鼠是因为其内分泌相对简单，且可减少动物使用量。药物通过食物每日给药。辛伐他汀和雷米普利联合治疗使平均寿命和中位寿命显著延长了9%。相比之下，辛伐他汀、雷米普利或坎地沙坦单药治疗均无效。所有组消耗的卡路里数量相同。辛伐他汀单独使用或与雷米普利联合使用时，在不改变热量消耗的情况下降低了体重，这表明它可能改变了小鼠的能量利用。联合治疗提高了血清甘油三酯和葡萄糖水平，这与能量稳态改变一致。在各治疗组之间，与死亡相关的病理学方面几乎没有发现显著或一致的差异。辛伐他汀治疗并未降低这些小鼠的正常血清胆固醇或脂质水平，这表明其延长寿命的作用可能源于他汀类药物的多效性、非胆固醇相关的作用。总之，结果表明他汀类药物和ACEIs联合使用可能会延长小鼠寿命。他汀类药物和血管紧张素转换酶抑制剂通常耐受性良好，并且联合使用已被证明可延长血压正常、胆固醇正常的人的寿命。
