热卡限制抗心肌老化的干预时机及其作用机制研究

Calorie restriction is by far the most effective anti-aging approach. Yet it remains unclear whether its myocardial protective effects extend to all age brackets. While calorie restriction in middle and old age contributed to myocardial protection, the youth suffered deteriorating cardiac function. While glucocorticoid induced by chronic stress played an important role in the aging process, 11β-HSD1, a local stress hormone amplifier, which regulates the local glucocorticoid activity of the tissue performing a critical part in organ aging. In our previous study, the myocardial expression of 11β-HSD1 increased with aging which also increased after calorie restriction in young mice, but decreased in middle and old-aged mice. Therefore, we hypothesized that 11β-HSD1 was the marker and intervention target of cardiac aging. In this proposal, we innovatively using 11β-HSD1 knockin and knockout mice, not only to elucidate the molecular mechanism of myocardial aging induced by 11β-HSD1: 11β-HSD1 increases myocardial GC level, inhibits the transcription of AMPK, reduces autophagy, thus induces myocardial aging, but also to confirm that increased activity of 11β-HSD1 was the effective intervention target for calorie restriction to delay myocardial aging.

热卡限制是目前最经典有效的抗衰老手段，然而是否各年龄段热卡限制都有心肌保护作用尚不清楚，我们证实青年时期热卡限制恶化心功能，与中老年时期作用恰恰相反。慢性应激与机体衰老密切相关，慢性应激使应激激素糖皮质激素分泌升高促进老化，调节组织局部糖皮质激素活性的11β-HSD1是组织局部应激激素放大器，在器官老化中起关键作用。我们研究发现：11β-HSD1在衰老及青年热卡限制时升高，而在具有心脏保护作用的热卡限制后反而下降，我们假设11β-HSD1是老化标志及干预靶点，本课题开创性利用11β-HSD1基因高表达鼠、11β-HSD1基因敲除鼠，不仅阐明11β-HSD1致心肌老化的分子机制：11β-HSD1增加心肌组织GC，抑制AMPK转录、减少自噬，导致心肌老化；而且确定11β-HSD活性升高是热卡限制干预靶点、延缓心肌老化的有效干预时机，从而为临床合理进行热卡限制抗衰老奠定基础。

热卡限制是目前最经典有效的抗衰老手段，然而是否各年龄段热卡限制都有心肌保护作用尚不清楚，热卡限制抗心肌老化的具体机制也不清楚，并且由于其艰巨性也难以临床应用，因此找到热卡限制抗心肌老化的干预时机和靶点，进而开发热卡限制类似方法尤为重要。因慢性应激引起的应激激素糖皮质激素水平增加在促进老化中起重要作用，我们对调节局部组织糖皮质激素水平的关键酶——11β-羟化类固醇脱氢酶1（11β-HSD1）研究发现：11β-HSD1在衰老及青年热卡限制时（心功能恶化）升高，而在具有心脏保护作用的中老年热卡限制后反而下降，进一步利用11β-HSD1基因高表达鼠、11β-HSD1基因敲除鼠研究发现11β-HSD1增加心肌组织GC，抑制AMPK转录、减少自噬，导致心肌老化，因此11β-HSD活性升高是热卡限制抗心肌老化的干预靶点。此外，高脂饮食是老化加速器，我们通过体内外研究发现：高脂饮食可诱导大鼠心肌肥厚、心脏炎症增加及心肌纤维化，进而导致心功能下降。而11β-HSD1抑制剂BVT.2733 干预减轻高脂饮食引起的心肌老化、改善心肌细胞肥厚、炎症和纤维化，改善了高脂饮食大鼠心功能。同时通过全基因组芯片以及IPA通路分析发现cAMP和钙信号通路是11β-HSD1导致心肌细胞肥大的潜在信号通路。本课题开创性研究了热卡限制抗心肌老化的靶点及具体分子机制，开发热卡限制类似方法以便临床应用。