Mousa Shaker A, Gallati Christine, Simone Tessa, Dier Emmy, Yalcin Murat, Dyskin Evgeny, Thangirala Sudha, Hanko Christine, Rebbaa Abdelhadi
The Pharmaceutical Research Institute at Albany, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
Aging (Albany NY). 2009 Mar 31;1(4):412-24. doi: 10.18632/aging.100035.
The organism's ability to regulate oxidative stress and metabolism is well recognized as a major determinant of longevity. While much research interest in this area is directed towards the study of genes that inhibit oxidative stress and/or improve metabolism, contribution to the aging process of genes with antagonistic effects on these two pathways is still less understood. The present study investigated the respective roles of the histone deacetylase Sirt1 and the thioredoxin binding protein TXNIP, two genes with opposite effects on oxidative stress and metabolism, in mediating the action of putative anti-aging interventions. Experiments were carried out in vitro and in vivo to determine the effect of proven, limited calorie availability, and unproven, resveratrol and dehydroepiandrosterone (DHEA), on the expression of Sirt1 and TXNIP. The results indicated that limited calorie availability consistently inhibited TXNIP in cancer and in normal cells including stem cells, however, it only slightly induced Sirt1expression in cancer cells. In contrast, resveratrol had a biphasic effect, and DHEA inhibited the expression of these two genes in a tissue specific manner, both in vitro and in vivo. Whereas all the three approaches tested inhibited TXNIP through the glycolytic pathway, DHEA acted by inhibiting G6PD and resveratrol through the activation of AMPK. In light of previous reports that Sirt1 induces AMPK-mediated signaling pathway, our findings point to the possibility of a negative relationship between Sirt1 and TXNIP that, if validated, can be exploited to improve the efficacy of putative anti-aging interventions.
生物体调节氧化应激和新陈代谢的能力被公认为是长寿的主要决定因素。虽然该领域的许多研究兴趣都集中在对抑制氧化应激和/或改善新陈代谢的基因的研究上，但对这两条途径具有拮抗作用的基因对衰老过程的贡献仍知之甚少。本研究调查了组蛋白脱乙酰酶Sirt1和硫氧还蛋白结合蛋白TXNIP这两个对氧化应激和新陈代谢具有相反作用的基因在介导假定的抗衰老干预措施作用中的各自作用。进行了体外和体内实验，以确定已证实的有限热量供应以及未证实的白藜芦醇和脱氢表雄酮（DHEA）对Sirt1和TXNIP表达的影响。结果表明，有限的热量供应在癌症细胞和包括干细胞在内的正常细胞中均持续抑制TXNIP，然而，它仅在癌细胞中轻微诱导Sirt1表达。相比之下，白藜芦醇具有双相作用，并且DHEA在体外和体内均以组织特异性方式抑制这两个基因的表达。尽管所测试的所有三种方法均通过糖酵解途径抑制TXNIP，但DHEA通过抑制G6PD起作用，而白藜芦醇则通过激活AMPK起作用。鉴于先前有报道称Sirt1诱导AMPK介导的信号通路，我们的研究结果表明Sirt1和TXNIP之间可能存在负相关关系，如果得到证实，可用于提高假定的抗衰老干预措施的疗效。
