Aging Intervention Program

卡路里限制(CR)延缓了实验动物的年龄相关疾病，一种安全地模拟其影响的小分子受到了极大的追捧。有证据表明，白藜芦醇可以在低等生物中模拟CR的作用，我们现在已经完成了衰老干预计划的第一项研究。在小鼠中，我们发现白藜芦醇在多个组织中诱导的基因表达模式与CR诱导的基因表达模式高度相似。此外，喂食白藜芦醇的老年小鼠衰老迹象明显减少。这些变化包括蛋白尿减少，血管内皮细胞炎症和细胞凋亡减少，主动脉弹性增加，运动协调性增强，白内障形成减少，骨密度保持不变。然而，当白藜芦醇在中年开始治疗时，喂食标准饮食的小鼠并没有活得更长。因此，用一种安全的口服小分子来模拟DR的转录方面并延缓功能衰退是可能的。我们的发现表明，从中年开始的白藜芦醇治疗对小鼠有一系列有益的影响，但这可能不是延长正常临时喂养动物寿命的有效策略。长期的白藜芦醇治疗模仿了体内CR的重要生理和转录方面，使接受治疗的动物能够过上更健康、更有活力的生活。除了改善高卡路里饮食小鼠的胰岛素敏感性和增加存活率外，我们还发现有证据表明，白藜芦醇可以改善心血管功能、骨密度、运动协调性，并延缓白内障，即使在非肥胖的啮齿动物中也是如此。由于心血管疾病是人类而不是老鼠与年龄相关的发病率和死亡率的主要原因，因此白藜芦醇等CR模拟物对人类健康的影响可能比对老鼠的影响更大。然而，白藜芦醇似乎并没有模仿DR的所有有益作用，因为将其引入正常一岁大的小鼠的饮食中并不能延长寿命。 当我们在非人类灵长类动物身上测试白藜芦醇时，我们能够在啮齿动物身上复制大多数发现。例如，在一篇正在审查的手稿中，我们测试了白藜芦醇治疗2年对恒河猴白色脂肪组织(WAT)中高脂肪、高糖(HFS)饮食引起的促炎和胰岛素抵抗的影响。白藜芦醇每天80 mg/d，持续12个月，然后每天480 mg/d，持续第二年，减少脂肪细胞大小，增加sirtuin 1的表达，降低核因子-kB的活性，并改善内脏Wat而不是皮下Wat的胰岛素敏感性。这些效应在3T3-L1脂肪细胞中被复制，这些细胞在添加了来自HFS+/-白藜芦醇饮食的猴子血清的培养液中培养。总而言之，长期服用白藜芦醇对饮食诱导的肥胖猴子内脏水的代谢和炎症适应是有益的。 我们测试的另一种CR模拟化合物是二甲双胍。二甲双胍，一种治疗2型糖尿病的常用处方药。我们发现，从一岁开始使用二甲双胍(饮食中0.1%的w/w)可以延长雄性小鼠的健康和寿命，而较高剂量(1%w/w)则是有毒的。二甲双胍治疗模仿了卡路里限制的一些好处，如改善体能，提高胰岛素敏感性，降低低密度脂蛋白和胆固醇水平，而不减少卡路里摄入量。在分子水平上，二甲双胍增加了AMP激活的蛋白激酶活性，增加了抗氧化保护，从而降低了氧化损伤累积和慢性炎症。我们的结果表明，这些特定的因素可能有助于二甲双胍对健康和寿命的有利影响。这些发现与目前的流行病学数据一致，并进一步支持了以二甲双胍为基础的干预措施，以促进健康老龄化。

Calorie restriction (CR) delays age-related diseases in laboratory animals, and a small molecule that safely mimics its effects has been greatly sought after. There is evidence that resveratrol can mimic effects of CR in lower organisms and we have now concluded the first study of the aging intervention program. In mice, we found that resveratrol induces gene expression patterns in multiple tissues that are highly similar to those induced by CR. Moreover, elderly resveratrol-fed mice showed a marked reduction in signs of aging. These changes included reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preservation of bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at mid-life. Thus it is possible to mimic transcriptional aspects of DR and delay functional decline with a safe, orally available small molecule. Our findings indicate that resveratrol treatment starting from mid-life has a range of beneficial effects in mice, but suggest that it may not be an effective strategy to increase the longevity of normal ad libitum-fed animals. Long-term resveratrol treatment mimicked important physiological and transcriptional aspects of CR in vivo, and allowed treated animals to live healthier, more vigorous lives. In addition to improving insulin sensitivity and increasing survival in mice fed a high calorie diet, we found evidence that resveratrol improves cardiovascular function, bone density, motor coordination, and delays cataracts, even in non-obese rodents. Since cardiovascular disease is a major cause of age-related morbidity and mortality in humans but not mice, it is possible that a CR mimetics such as resveratrol could have an even greater impact on human health than on mice. However, resveratrol does not seem to mimic all of the salutary effects of DR in that its introduction into the diet of normal one year old mice did not increase longevity. When we tested resveratrol in non-human primates we were able to replicate most of the findings in rodents. For example, in a manuscript under review, we tested the effect of a 2-year resveratrol administration on the pro-inflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Eighty mg/day of resveratrol for 12-month followed by 480 mg/day for the second year decreased adipocyte size, increased sirtuin 1 expression, decreased NF-kB activation and improved insulin sensitivity in visceral but not subcutaneous WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS +/- resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys. Another CR mimetic compound that we have tested is metformin. Metformin, a drug commonly prescribed to treat type-2 diabetes. We showed that treatment with metformin (0.1% w/w in diet) starting at one year of age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimicked some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increased AMP-activated protein kinase activity and increased antioxidant protection, resulting in lower oxidative damage accumulation and chronic inflammation. Our results indicate that these specific factors may contribute to the beneficial effects of metformin administration on healthspan and lifespan. These findings are in agreement with current epidemiological data and further support metformin-based interventions to promote healthy aging.