新成果!“长寿药”谜团被破解,“接近”人类临床试验
2018/01/12
实验性药物J147是一种在研的“不老长寿药”(elixir),先前已被证明能够在小鼠中治疗阿尔茨海默症,逆转衰老。最近,来自美国Salk研究所的科学家们获得重要进展,解开了围绕J147的一个谜团,即,它是如何发挥抗衰老等作用的。


图片来源:网络

1月7日,发表在Aging Cell杂志上的这项研究中,科学家们证实,J147是与线粒体(细胞的能量工厂)中的一种蛋白质相结合,从而使衰老细胞、小鼠和果蝇看起来更年轻。

论文的通讯作者Dave Schubert教授说:“找到J147的靶点对推进临床试验至关重要。”

2011年,在筛选了具有逆转大脑中衰老细胞和分子信号能力的、来自植物的化合物后,Schubert教授的研究小组开发了J147——从咖喱香料姜黄素(curry spice curcumin)中发现的一种分子的修改版。之后的几年里,团队证明,J147能够在小鼠中逆转记忆缺陷,增强新脑细胞的产生,以及减缓或逆转阿尔茨海默症的进展。


图片来源:Aging Cell

在这项新研究中,Schubert教授等使用了多种方法来调查,究竟J147是如何起作用的,最终发现了它的分子靶标——一种叫做ATP合酶(ATP synthase)的线粒体蛋白质。

先前,该酶已经被证实能够控制线虫和果蝇的衰老,而这项新研究表明,通过操纵ATP合酶的活性,科学家们能够保护神经元细胞免受与衰老大脑相关的多重毒性的伤害。

进一步的实验显示,以J147调节ATP合酶的活性改变了多种其他分子的水平,包括ATP本身,从而使得线粒体在衰老和疾病过程中更加健康、稳定。


图片来源:Salk Institute

Schubert教授说:“J147能产生如此大的效果让我们非常惊讶。给年老小鼠服用J147后,它真的会引起根本性的变化,使这些小鼠在细胞和分子水平看起来更年轻。”

研究人员表示,这些结果不仅支持进一步探索J147作为阿尔茨海默病的治疗方法,同时也表明,J147对其他与年龄相关的疾病可能也是有用的。目前,J147已经在动物身上完成了FDA要求的毒理学测试,并正在寻求资金在人类中启动1期临床试验。

参考资料:

Researchers identify the molecular target of J147, which is nearing clinical trials to treat Alzheimer's disease

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  • The mitochondrial ATP synthase is a shared drug target for aging and dementia

    Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age-associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α-F1-ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age-associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age-associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.

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