Centro Andaluz de Biología del Desarrollo (CABD)-Universidad Pablo de Olavide (UPO), Departamento de Biología Molecular e Ingeniería Bioquímica, UPO/ CSIC/JA, Sevilla, Spain.
Instituto de la Grasa (CSIC), Campus Universitario Pablo de Olavide (UPO), Sevilla, Spain.
Nat Commun. 2021 Jan 4;12(1):49. doi: 10.1038/s41467-020-20269-y.
Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer's disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.
衰老和生育是两个相互关联的过程。从无脊椎动物到哺乳动物，生殖系的缺失都会延长寿命。在这里，我们表明，秀丽隐杆线虫类固醇硫酸酯酶（STS）sul-2 的功能丧失会增加硫酸化甾体激素的池，从而延长寿命并改善蛋白质聚集疾病。这种寿命的延长需要涉及生殖系介导的寿命的因素（daf-16、daf-12、kri-1、tcer-1 和 daf-36 基因），尽管 sul-2 突变不会影响生育能力。有趣的是，sul-2 仅在感觉神经元中表达，这表明环境线索对硫酸化激素状态的调节。用特异性 STS 抑制剂 STX64 以及来源于睾丸激素的硫酸化激素处理可再现 sul-2 突变体的长寿表型。值得注意的是，这些处理可改善秀丽隐杆线虫中的蛋白质聚集疾病，并且 STX64 还可改善哺乳动物模型中的阿尔茨海默病。这些结果为重新分配类固醇硫酸酯酶抑制剂或衍生物以治疗衰老和与衰老相关的疾病提供了可能性。
