The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nature. 2011 Feb 17;470(7334):404-8. doi: 10.1038/nature09706.
Activating AMPK or inactivating calcineurin slows ageing in Caenorhabditis elegans and both have been implicated as therapeutic targets for age-related pathology in mammals. However, the direct targets that mediate their effects on longevity remain unclear. In mammals, CREB-regulated transcriptional coactivators (CRTCs) are a family of cofactors involved in diverse physiological processes including energy homeostasis, cancer and endoplasmic reticulum stress. Here we show that both AMPK and calcineurin modulate longevity exclusively through post-translational modification of CRTC-1, the sole C. elegans CRTC. We demonstrate that CRTC-1 is a direct AMPK target, and interacts with the CREB homologue-1 (CRH-1) transcription factor in vivo. The pro-longevity effects of activating AMPK or deactivating calcineurin decrease CRTC-1 and CRH-1 activity and induce transcriptional responses similar to those of CRH-1 null worms. Downregulation of crtc-1 increases lifespan in a crh-1-dependent manner and directly reducing crh-1 expression increases longevity, substantiating a role for CRTCs and CREB in ageing. Together, these findings indicate a novel role for CRTCs and CREB in determining lifespan downstream of AMPK and calcineurin, and illustrate the molecular mechanisms by which an evolutionarily conserved pathway responds to low energy to increase longevity.
激活 AMPK 或失活钙调神经磷酸酶可减缓秀丽隐杆线虫的衰老，并且两者都被认为是哺乳动物与年龄相关的病理学的治疗靶点。然而，介导它们对长寿影响的直接靶标仍不清楚。在哺乳动物中，CREB 调节转录共激活因子（CRTCs）是参与多种生理过程的辅因子家族，包括能量稳态、癌症和内质网应激。在这里，我们表明 AMPK 和钙调神经磷酸酶都通过秀丽隐杆线虫中唯一的 CRTC-CRTC-1 的翻译后修饰来专门调节寿命。我们证明 CRTC-1 是 AMPK 的直接靶标，并在体内与 CREB 同源物-1（CRH-1）转录因子相互作用。激活 AMPK 或失活钙调神经磷酸酶的促长寿作用降低了 CRTC-1 和 CRH-1 的活性，并诱导了与 CRH-1 缺失线虫相似的转录反应。crtc-1 的下调以依赖于 crh-1 的方式增加寿命，并且直接降低 crh-1 的表达会增加寿命，这证实了 CRTCs 和 CREB 在衰老中的作用。总之，这些发现表明 CRTCs 和 CREB 在 AMPK 和钙调神经磷酸酶下游决定寿命方面具有新的作用，并说明了进化保守途径响应低能量以增加寿命的分子机制。
