Premature aging in mice activates a systemic metabolic response involving autophagy induction
Premature aging in mice activates a systemic metabolic response involving autophagy induction
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DOI：
10.1093/hmg/ddn120
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发表时间：
2008-07-15
影响因子：
3.5
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
--
作者：
Marino, Guillermo;Ugalde, Alejandro P.;Lopez-Otin, Carlos
自噬是一个高度调控的细胞内过程，参与大多数细胞成分的周转和维持细胞内的稳态。众所周知，活细胞的基本自噬活性随着年龄的增长而降低，因此有助于在衰老过程中积累受损的大分子。相反，这种分解代谢途径的活性对于延长秀丽线虫和黑腹果蝇等动物模型的寿命是必需的。在这项工作中，我们描述了一个意想不到的发现，Zmpste24缺失小鼠表现出加速衰老，并且是人类Hutchinson-Gilford早衰症的可靠模型，表现出广泛的基础自噬激活，而不是在正常衰老过程中发生的这一过程的特征下降。我们还表明，这种自噬增加与脂肪和葡萄糖代谢途径的一系列变化有关，这些变化类似于在不同情况下发生的延长寿命的情况。这些Zmpste24(-/-)小鼠的代谢变化也与循环血液参数的实质性变化有关，如瘦素、葡萄糖、胰岛素或脂联素，这反过来又导致外周LKB1-AMPK激活和mTOR抑制。在这些结果的基础上，我们认为Zmpste24(-/-)小鼠的核异常导致过早衰老，触发了涉及自噬激活的代谢反应。然而，这种分解代谢途径的慢性激活可能会将最初打算的有利于生存的策略转变为有利于衰老的机制，并可能导致在这些孕激素样小鼠中观察到的系统性退化和虚弱。
Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation of damaged macromolecules during aging. Conversely, the activity of this catabolic pathway is required for lifespan extension in animal models such as Caenorhabditis elegans and Drosophila melanogaster. In this work, we describe the unexpected finding that Zmpste24-null mice, which show accelerated aging and are a reliable model of human Hutchinson-Gilford progeria, exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. We also show that this autophagic increase is associated with a series of changes in lipid and glucose metabolic pathways, which resemble those occurring in diverse situations reported to prolong lifespan. These Zmpste24(-/-) mice metabolic alterations are also linked to substantial changes in circulating blood parameters, such as leptin, glucose, insulin or adiponectin which in turn lead to peripheral LKB1-AMPK activation and mTOR inhibition. On the basis of these results, we propose that nuclear abnormalities causing premature aging in Zmpste24(-/-) mice trigger a metabolic response involving the activation of autophagy. However, the chronic activation of this catabolic pathway may turn an originally intended pro-survival strategy into a pro-aging mechanism and could contribute to the systemic degeneration and weakening observed in these progeroid mice.