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。