Brejning Jeanette, Nørgaard Steffen, Schøler Lone, Morthorst Tine H, Jakobsen Helle, Lithgow Gordon J, Jensen Louise T, Olsen Anders
Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, Aarhus, 8000-DK, Denmark.
Aging Cell. 2014 Feb;13(1):156-64. doi: 10.1111/acel.12165. Epub 2013 Nov 28.
NDG-4 is a predicted transmembrane acyltransferase protein that acts in the distribution of lipophilic factors. Consequently, ndg-4 mutants lay eggs with a pale appearance due to lack of yolk, and they are resistant to sterility caused by dietary supplementation with the long-chain omega-6 polyunsaturated fatty acid dihommogamma-linolenic acid (DGLA). Two other proteins, NRF-5 and NRF-6, a homolog of a mammalian secreted lipid binding protein and a NDG-4 homolog, respectively, have previously been shown to function in the same lipid transport pathway. Here, we report that mutation of the NDG-4 protein results in increased organismal stress resistance and lifespan. When NDG-4 function and insulin/IGF-1 signaling are reduced simultaneously, maximum lifespan is increased almost fivefold. Thus, longevity conferred by mutation of ndg-4 is partially overlapping with insulin signaling. The nuclear hormone receptor NHR-80 (HNF4 homolog) is required for longevity in germline less animals. We find that NHR-80 is also required for longevity of ndg-4 mutants. Moreover, we find that nrf-5 and nrf-6 mutants also have extended lifespan and increased stress resistance, suggesting that altered lipid transport and metabolism play key roles in determining lifespan.
NDG-4是一种预测的跨膜酰基转移酶蛋白，在亲脂性因子的分布中起作用。因此，ndg-4突变体产下的卵由于缺乏卵黄而外观苍白，并且它们对因饮食中添加长链ω-6多不饱和脂肪酸二高γ-亚麻酸（DGLA）导致的不育具有抗性。另外两种蛋白质，NRF-5和NRF-6，分别是哺乳动物分泌的脂质结合蛋白的同源物和NDG-4的同源物，先前已被证明在相同的脂质运输途径中发挥作用。在此，我们报告NDG-4蛋白的突变导致生物体抗逆性和寿命增加。当NDG-4功能和胰岛素/IGF-1信号同时降低时，最大寿命几乎增加了五倍。因此，ndg-4突变赋予的长寿与胰岛素信号部分重叠。核激素受体NHR-80（HNF4同源物）是生殖系缺失动物长寿所必需的。我们发现NHR-80也是ndg-4突变体长寿所必需的。此外，我们发现nrf-5和nrf-6突变体也具有延长的寿命和增加的抗逆性，这表明脂质运输和代谢的改变在决定寿命中起关键作用。
