Cellular Senescence in Aging-related Metabolic Diseases

细胞衰老导致炎症、氧化应激和线粒体功能障碍，这些都与年龄相关疾病的发病机制有关。因此，衰老细胞的遗传耗尽最近被证明可以延长寿命并减轻与衰老有关的疾病。然而，衰老的细胞机制以及衰老如何促进衰老的疾病尚不清楚。我的实验室最近的研究表明，ALCAT1在细胞衰老与衰老相关疾病之间发挥了一定的作用。ALCAT1是一种在氧化应激下催化致病性心磷脂(CL)与异常脂肪酸重新合成的酶。CL是氧化磷酸化、有丝分裂和线粒体生物发生所必需的线粒体标志性磷脂。衰老与多不饱和脂肪酸(PUFA)的CL重塑有关，多不饱和脂肪酸对活性氧(ROS)的氧化损伤高度敏感。我们先前的工作揭示了ALCAT1在PUFA在肥胖、T2 DM和心血管疾病等与衰老相关的疾病中催化CL病理重塑中的关键作用。ALCAT1促进衰老障碍的发展，因为它的表达被ROS显著上调，导致氧化应激、CL氧化和线粒体功能障碍的恶性循环。我的实验室最近的其他研究也证明了ALCAT1在细胞衰老中的显著作用。我们的初步数据表明：1)复制衰老显著增加ALCAT1蛋白的表达；2)ALCAT1在细胞系和小鼠中的表达上调导致线粒体DNA(MtDNA)突变和功能障碍，导致细胞衰老；以及3)ALCAT1的靶向缺失延缓细胞衰老，防止各种与衰老相关的疾病的发生，包括T2 DM、糖尿病肾病和心肌病。根据我们以前的研究和最近的发现，我们假设ALCAT1导致的线粒体功能障碍将细胞衰老与衰老相关代谢性疾病的发病机制联系起来，这将通过三个目标进行验证。目的1将阐明ALCAT1如何促进复制衰老中的线粒体功能障碍，目的2将确定ALCAT1诱导的线粒体DNA突变是否将衰老与衰老联系在一起，目的3将确定ALCAT1在细胞衰老与饮食诱导的肥胖之间的作用。拟议研究的结果有望为将ALCAT1酶作为一种通过耗尽衰老细胞来治疗衰老相关疾病的范式转换治疗方法提供关键见解。

Cellular senescence causes inflammation, oxidative stress, and mitochondrial dysfunction, which have been implicated in the pathogenesis of age-related diseases. Accordingly, genetic depletion of senescent cells has recently been shown to extend lifespan and attenuate aging-related diseases. However, the cellular mechanisms underlying senescence and how it may promote diseases of aging are unclear. Recent work from my laboratory has implicated a role for ALCAT1 in linking cellular senescence with aging-related diseases. ALCAT1 is an enzyme that catalyzes pathogenic resynthesis of cardiolipin (CL) with aberrant fatty acids in response to oxidative stress. CL is a mitochondrial signature phospholipid required for oxidative phosphorylation, mitophagy, and mitochondrial biogenesis. Aging is associated with remodeling of CL by polyunsaturated fatty acids (PUFA) that are highly sensitive to oxidative damage by reactive oxygen species (ROS). Our prior work has revealed a key role for ALCAT1 in catalyzing the pathological remodeling of CL by PUFA in aging-related diseases, such as obesity, T2DM, and cardiovascular diseases. ALCAT1 promotes the development of the disorders of aging because its expression is significantly upregulated by ROS, leading to a vicious cycle of oxidative stress, CL oxidation, and mitochondrial dysfunction. Other recent studies from my laboratory also demonstrate a striking role for ALCAT1 in cellular senescence. Our preliminary data indicate that: 1) replicative senescence significantly increases ALCAT1 protein expression; 2) upregulated ALCAT1 expression in cell lines and mice causes mitochondrial DNA (mtDNA) mutation and dysfunction, leading to cellular senescence; and 3) targeted deletion of ALCAT1 delays cellular senescence and prevents the onset of various aging-related diseases, including T2DM, diabetic nephropathy, and cardiomyopathy. Based upon our prior studies and recent findings, we hypothesize that mitochondrial dysfunction by ALCAT1 links cellular senescence to the pathogenesis of aging-related metabolic diseases, which will be tested by three Aims. Aim 1 will elucidate how ALCAT1 promotes mitochondrial dysfunction in replicative senescence, Aim 2 will determine whether mtDNA mutations induced by ALCAT1 links senescence to aging, and Aim 3 will identify the role of ALCAT1 in linking cellular senescence to diet-induced obesity. The results from the proposed studies are expected to provide key insights on targeting ALCAT1 enzyme as a paradigm shifting treatment for aging-related diseases through depletion of senescent cells.