Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation.
Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation.
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DOI：
10.7554/elife.02077
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发表时间：
2014-04-29
期刊：
影响因子：
7.7
通讯作者：
Gladyshev VN
中科院分区：
文献类型：
--
作者：
Avanesov AS;Ma S;Pierce KA;Yim SH;Lee BC;Clish CB;Gladyshev VN
衰老被认为与增加的分子损伤有关，但代表性的标记物在不同的条件和生物体之间存在差异，因此难以评估整个寿命期间累积损伤的特性。我们使用非靶向代谢物分析来跟踪果蝇中> 15，000种代谢物的年龄相关轨迹，这些代谢物接受对照和延长寿命的饮食。我们发现衰老与代谢物多样性增加和低丰度分子有关，这表明它们包括累积损伤。值得注意的是，检测到的化合物数量在晚年趋于稳定，这种模式与生存率有关。14%的代谢物显示出与年龄相关的变化，在晚年和长寿的果蝇中减速。与此相反，已知的代谢物在丰度上的变化与非靶向代谢物和转录物相似，但多样性没有增加。有针对性的分析也揭示了较慢的代谢和寿命限制分子的积累。因此，衰老的特征在于逐渐的代谢组重塑，并且这种重塑的状况和晚期年龄相关减速与死亡率和分子损伤有关。http://dx.doi.org/10.7554/eLife.02077.001在许多不同的物种中都观察到了衰老的迹象，但对潜在的机制仍然知之甚少。人们认为衰老受新陈代谢的影响。例如，科学家发现新陈代谢会导致副产品的积累，这可能会对细胞造成损害。此外，随着生物体的衰老，这些副产品的多样性会增加。然而，事实证明很难衡量这种累积损害。Avanesov等人现在尝试了一种不同的方法，并研究了细胞代谢，寿命和累积损伤之间的关系。雄性果蝇被饲养在两种饮食中的一种标准饮食，或延长寿命的限制性饮食，然后使用一种称为代谢物分析的技术来监测两组果蝇中超过15，000种代谢物。Avanesov等人发现代谢物的数量随着时间的推移而增加，这表明分子合成中的损伤或错误随着年龄的增长而增加。但在最老的果蝇中，代谢物的数量达到了一个平台，即使是那些寿命被人为延长的果蝇。这可能是由于细胞变得不那么活跃，因为他们变得非常老。Avanesov等人还发现，代谢产物的特征变化方式与基因转录模式的变化方式相似。这表明转录是细胞中产生蛋白质过程的第一步可能与新陈代谢和衰老有关。DOI：http://dx.doi.org/10.7554/eLife.02077.002网站
Aging is thought to be associated with increased molecular damage, but representative markers vary across conditions and organisms, making it difficult to assess properties of cumulative damage throughout lifespan. We used nontargeted metabolite profiling to follow age-associated trajectories of >15,000 metabolites in Drosophila subjected to control and lifespan-extending diets. We find that aging is associated with increased metabolite diversity and low-abundance molecules, suggesting they include cumulative damage. Remarkably, the number of detected compounds leveled-off in late-life, and this pattern associated with survivorship. Fourteen percent of metabolites showed age-associated changes, which decelerated in late-life and long-lived flies. In contrast, known metabolites changed in abundance similarly to nontargeted metabolites and transcripts, but did not increase in diversity. Targeted profiling also revealed slower metabolism and accumulation of lifespan-limiting molecules. Thus, aging is characterized by gradual metabolome remodeling, and condition- and advanced age-associated deceleration of this remodeling is linked to mortality and molecular damage. DOI: http://dx.doi.org/10.7554/eLife.02077.001 Signs of aging have been observed in many different species, but the underlying mechanisms are still poorly understood. It is thought that aging is influenced by metabolism. For example, scientists have found that metabolism can lead to the accumulation of byproducts, which may cause damage to cells. Moreover, as organisms get older, the diversity of these byproducts can increase. However, it has proven difficult to measure this cumulative damage. Avanesov et al. have now tried a different approach and examined the relationship between cellular metabolism, lifespan, and cumulative damage. Male fruit flies were raised on one of two diets—a standard diet, or a restrictive diet that extends their lifespan—and a technique called metabolite profiling was then used to monitor more than 15,000 metabolites in both sets of flies. Avanesov et al. found that the number of metabolites increased over time, suggesting that damage or mistakes in molecular synthesis increased with age. But the number of metabolites reached a plateau in the oldest flies, even in those whose lifespans were artificially extended. This could be due to cells becoming less active as they get very old. Avanesov et al. also found that the profile of the metabolites changed in a way that was similar to the way that patterns of gene transcription changed. This suggests that there may be a link between transcription—which is the first step in the process that produces proteins in cells—and metabolism and aging. DOI: http://dx.doi.org/10.7554/eLife.02077.002