Involvement of Na/Dicarboxylate Cotransporter in Aging

本研究的重点是哺乳动物Na+/二羧酸盐共转运蛋白NaDC-1，它在小肠和肾近端小管上皮细胞的顶膜上表达。NaDC-1转运克雷布斯循环的代谢中间体，包括柠檬酸盐和琥珀酸盐。这种转运体是与决定寿命有关的果蝇Indy基因产物的哺乳动物同源物。导致Indy部分失活的突变会增加寿命，类似于哺乳动物热量限制的效果。结果表明，通过失活或减少其底物来降低NaDC-1的活性可能会产生导致寿命延长的代谢变化。本研究的长期目标是确定使用NaDC-1作为靶蛋白来模拟热量限制效果的可行性。我们的团队对NaDC-1相关的转运体有着长期的兴趣，我们已经克隆了人、兔和小鼠的NaDC-1同源物。本提案中的研究将使用编码小鼠和人类NaDC-1的cdna在两个方面产生初步数据：首先，将NaDC-1的活性与衰老和热量限制联系起来，其次，确定调节NaDC-1活性的因素。

The focus of the current proposal is the mammalian Na+/dicarboxylate co-transporter, NaDC-1, which is expressed on the apical membranes of the epithelial cells of the small intestine and kidney proximal tubule. NaDC-1 transports the metabolic intermediates of the Krebs cycle, including citrate and succinate. This transporter is the mammalian homolog of the Drosophila Indy gene product that has been implicated in determining lifespan. Mutations that lead to a partial inactivation of Indy produce an increase in lifespan, similar to the effects of caloric restriction in mammals. The results suggest that a reduction in the activity of NaDC-1 by inactivation or by reducing its substrates may produce the metabolic changes that lead to increased longevity. The long-term objective of this research is to determine the feasibility of using NaDC-1 as a target protein to mimic the effects of caloric restriction. Our group has a longstanding interest in the transporters related to NaDC-1 and we have cloned the NaDC-1 orthologs form human, rabbit and mouse. The studies in this proposal will use the cDNAs coding for the mouse and human NaDC-1 to produce preliminary data in two areas: first, relating the activity of NaDC-1 in aging and caloric restriction, and second, identifying factors that regulate the activity of NaDC-1.