Influence of Mutation Burden on Cellular Aging

描述（由申请人提供）：随着年龄的增长，由于突变的积累，我们的细胞遭受遗传信息的进行性和永久性损失。不断增加的遗传缺陷可能会限制细胞功能或导致细胞死亡，从而导致衰老期间发生的组织稳态丧失。该建议旨在测试突变负荷对二倍体酵母老化的影响。我们有证据表明，过度的突变率可以导致单倍体酵母的灭绝，由于随机失活的必要基因。在目标1中，我们将定义二倍体突变负荷的上限。在目标2中，我们将暂时提高突变率，然后测量复制寿命，时间老化，以及在存在和不存在氧化损伤和热量限制的情况下的竞争适应性。在目标3中，我们将监测细胞中蛋白质稳态的改变，这可能是突变负荷的结果。通过这些研究，我们希望确定随机突变负荷是否有助于细胞衰老，并获得足够的初步数据，以申请R01将我们的研究扩展到动物。

DESCRIPTION (provided by applicant): As we age, our cells suffer a progressive and permanent loss of genetic information due to the accumulation of mutations. The mounting genetic deficits may limit cellular function or lead to cell death, thereby contributing to the loss of tissue homeostasis that occurs during aging. This proposal seeks to test the influence of mutation burden on aging of diploid yeast. We have evidence that excessive mutation rates can cause extinction of haploid yeast, due to random inactivation of essential genes. In Aim 1 we will define the upper limits of mutation burden for diploids. In Aim 2 we will transiently elevate mutation rates and then measure replicative lifespan, chronological aging, and competitive fitness in the presence and absence of oxidative damage and caloric restriction. In Aim 3, we will monitor cells for altered protein homeostasis as a possible consequence of mutation load. By these studies we hope to establish whether random mutation burden contributes to cellular aging and gain sufficient preliminary data to apply for an R01 to extend our studies into animals.