Regulation of Lysosomal Function by the DAF-16 Forkhead Transcription Factor Couples Reproduction to Aging in Caenorhabditis elegans
Regulation of Lysosomal Function by the DAF-16 Forkhead Transcription Factor Couples Reproduction to Aging in Caenorhabditis elegans
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DOI：
10.1534/genetics.117.204222
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发表时间：
2017-09-01
期刊：
影响因子：
3.3
通讯作者：
de Carvalho, Carlos E.
中科院分区：
文献类型：
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作者：
Baxi, Kunal;Ghavidel, Ata;de Carvalho, Carlos E.
真核生物的衰老伴随着体细胞组织的广泛退化。然而，消除生殖细胞延缓了秀丽隐杆线虫的年龄依赖性体细胞衰退。在缺乏生殖细胞的成虫中，性腺中DAF-9/DAF-12类固醇信号通路的激活可以招募肠道中的DAF-16活性，从而促进长寿相关的表型。然而，这种途径对正常繁殖动物的适应性的影响尚不清楚。在这里，我们探索后代生产和体细胞衰老之间的联系，并确定溶酶体酸度的丧失-这些细胞器蛋白水解输出的关键调节因子-作为秀丽隐杆线虫衰老的新生物标志物。在老年蠕虫中，溶酶体pH值的增加不是衰老的被动结果，而是随着繁殖的停止而定时发生的，并且与成年早期蛋白质停滞的减少有关。我们的研究结果进一步暗示了类固醇信号通路和DAF-16在野生型蠕虫对生殖周期的响应中动态调节肠道溶酶体pH。在繁殖蠕虫的肠道中，DAF-16通过上调v- atp酶基因的表达来促进酸性溶酶体。这些发现支持了一个模型，在该模型中，通过对溶酶体酸化的主动调节，体细胞中的蛋白质清除与性腺中的生殖有关。
Aging in eukaryotes is accompanied by widespread deterioration of the somatic tissue. Yet, abolishing germ cells delays the age-dependent somatic decline in Caenorhabditis elegans. In adult worms lacking germ cells, the activation of the DAF-9/DAF-12 steroid signaling pathway in the gonad recruits DAF-16 activity in the intestine to promote longevity-associated phenotypes. However, the impact of this pathway on the fitness of normally reproducing animals is less clear. Here, we explore the link between progeny production and somatic aging and identify the loss of lysosomal acidity-a critical regulator of the proteolytic output of these organelles-as a novel biomarker of aging in C. elegans. The increase in lysosomal pH in older worms is not a passive consequence of aging, but instead is timed with the cessation of reproduction, and correlates with the reduction in proteostasis in early adult life. Our results further implicate the steroid signaling pathway and DAF-16 in dynamically regulating lysosomal pH in the intestine of wildtype worms in response to the reproductive cycle. In the intestine of reproducing worms, DAF-16 promotes acidic lysosomes by upregulating the expression of v-ATPase genes. These findings support a model in which protein clearance in the soma is linked to reproduction in the gonad via the active regulation of lysosomal acidification.