Nature:不用限制饮食也能实现长寿
科技日报 · 2014/05/18
英国《自然》杂志5月15日在线发表了一篇关于衰老的研究报告,科学家们宣布在秀丽隐杆线虫的饮食中添加α-酮戊二酸,可以延长它们的寿命50%左右。而α-酮戊二酸,这种能量代谢的中间产物,似乎能够起到和限制饮食类似的延缓衰老的作用。


延缓甚至抵抗衰老是一个梦吗?如果能把目前对实验室线虫进行的生命科学研究应用到人类身上,或许大有可为。英国《自然》杂志5月15日在线发表了一篇关于衰老的研究报告,科学家们宣布在秀丽隐杆线虫(Caenorhabditis elegans)的饮食中添加α-酮戊二酸,可以延长它们的寿命50%左右。而α-酮戊二酸,这种能量代谢的中间产物,似乎能够起到和限制饮食类似的延缓衰老的作用。新的发现对于衰老和年龄相关的疾病来说,会带来预防和治疗的新策略。

在既往的研究中,人类已发现饮食限制与衰老之间存在一定的关系——在一系列生物中,限制热量或者限制进食可以延长寿命,并推迟与衰老相关疾病的发生;同样的,通过基因或药物干扰营养或者能量代谢也可以获得延长寿命的好处。目前,尽管有好几个调控衰老过程的代谢产物已经被发现了,但还不清楚它们具体的调控方法。

此次的实验对象为秀丽隐杆线虫,其是一种无毒无害、可以独立生存的线虫,也是第一种完整遗传密码被科学家绘制成图的动物。由于具有固定的细胞渊源的优点,科学家很早就开始利用这种线虫来研究细胞凋亡遗传调控的机制,使它成为分子生物学和发育生物学研究领域的一种模式生物。2013年,美国研究人员就曾通过稍微调整秀丽隐杆线虫的两个基因通路,使这种动物的寿命显著增加。

美国加州大学洛杉矶分校的黄晶(音译)和她的研究团队此次针对秀丽隐杆线虫的饮食进行了实验,从而发现代谢产物α-酮戊二酸能够延缓秀丽隐杆线虫的衰老。他们同时还确认了这种物质产生如此影响的机制。

研究表明,这种代谢产物作用于三磷酸腺苷合酶(涉及能量生产的一种酶)来产生类似限制饮食的状态。因此他们推断,给秀丽隐杆线虫提供的α-酮戊二酸,可以通过调节能量代谢来达成延长寿命的作用。研究人员同时提出,这一机制可能为治疗干预提供了目标,但要将相关成果应用于延长人类生命,还需要多年研究才行。
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  • The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR

    Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms1, 2. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits3, 4. Recently, several metabolites have been identified that modulate ageing5, 6; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS)7. The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution8, 9. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan10, 11, 12, 13. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

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