The Role of Nuclear Transport Dynamics in Metformin's Geroprotective Effects

点击翻译按钮获取中文摘要

Abstract As the cell ages, the nuclear pore deteriorates, leading to dysregulated nucleocytoplasmic transport. Emerging evidence indicates that this deterioration is pathogenic in aging-related decline. Thus, targeting the nuclear pore complex (NPC), the 30+ protein, megadalton, heteromultimeric sole gateway between the nucleus and the cytoplasm, may be of therapeutic value in promoting healthy aging. We have previously shown that NPC deterioration can be halted or even reversed by metformin, a member of the biguanide class of drugs commonly prescribed in type 2 diabetes. Our previous work identified a conserved pathway that connects metformin action to the regulation of nucleocytoplasmic transport and modulation of growth and aging in the nematode, C. elegans. The central feature of this pathway is that normal mitochondrial function facilitates specific aspects of transport through the NPC. As organisms age, mitochondria facilitate nuclear leakiness, allowing cargoes to exit and enter the nucleus inappropriately, contributing to aging-related declines in cellular function. Alternatively, when cells are exposed to metformin, a modulator of mitochondrial complex I energetics, passive nuclear transport is inhibited leading to halted cell growth and increased lifespan. To fully understand how metformin exacts its effects on the cell in aging, it is important to determine its impact on nucleocytoplasmic trafficking. My hypothesis is that biguanides promote longevity by altering passive and/or facilitated transport of specific cargoes through the NPC. I will elucidate the functional mechanisms by which changes in nucleocytoplasmic transport dynamics govern aging and longevity in response to metformin. The goal of my project is twofold 1) to comprehensively define mechanisms of altered nuclear transport with metformin, and 2) to identify and functionally characterize nuclear transport cargoes that are aberrantly localized in aging and restored by metformin. As an inextricably linked consequence of conducting this work, I will obtain critical training in state-of-the-art methodologies in aging research, enabling me to do future high impact work on the fundamental biology of aging. My plan for training and mentorship at leading institutions and laboratories in aging research positions me well to achieve these goals. Ultimately, identification of aberrantly localized NPC cargoes in aging, and characterization of their role in aging and metformin-mediated lifespan extension is expected to illuminate new therapeutic targets in aging and aging-related disease.