Transposable elements as drivers of normal and accelerated aging in Vertebrates

衰老的一个关键标志是基因组不稳定性的总体增加。越来越多的证据显示 转座因子（TE）在衰老过程中的广泛再激活跨越分类学上遥远的模型 有机体然而，这种异常的再激活和年龄相关的功能下降之间的关系在很大程度上是 在细胞、器官和生物体水平上，我们假设转座子的逐渐丢失 抑制有助于在生物体水平上广泛的与年龄相关的功能衰退。非洲 绿松石鳉（Nothobranchius furzeri），一种新兴的自然短寿命脊椎动物模式生物， 提供了一个独特的机会来调查这一联系，调查人员以前已经制定了一个 强大的基因组到表型工具包。在这项提案中，我们提议利用非洲 绿松石鳉作为一个易处理的短命模式生物，迅速询问分子和 增加的TE活性对脊椎动物体内衰老的生物影响。 为了验证我们的假设，我们提出：（i）描述基因组中的重复元素景观， 非洲绿松石鳉鱼和TE激活模式，以及（ii）探索保守的变化， TE调节衰老及与衰老相关的疾病对衰老的影响。该项目的完成将 推进对脊椎动物衰老的理解。最终，这些发现将有助于确定治疗目标 用于开发新的治疗方法，治疗经济负担沉重的与年龄相关的疾病，等等。 更重要的是，这会给病人及其家人带来极大的痛苦。

A key hallmark of aging is an overall increase in genomic instability. Accumulating evidence has revealed widespread reactivation of transposable elements (TE) during aging across taxonomically-distant model organisms. Yet, the relationship between this aberrant reactivation and age-related functional decline is largely unknown, at the cellular, organ and organism levels. We hypothesize that the progressive loss of transposon repression contributes to the widespread age-related functional decline at the organismal level. The African turquoise killifish (Nothobranchius furzeri), an emerging naturally short-lived vertebrate model organism, provides a unique opportunity to investigate this link, and the investigators have previously developed a powerful genome-to-phenotype toolkit for this species. In this proposal, we propose to leverage the African turquoise killifish as a tractable short-lived model organism to rapidly interrogate the molecular and organismal impact of increased TE activity on vertebrate aging in vivo. To test our hypothesis, we propose (i) to characterize the repetitive element landscape in the genome of the African turquoise killifish and TE activation patterns, and (ii) to explore the impact of conserved changes in TE regulation with aging and age-related disease on the aging process. The completion of this project will advance the understanding of vertebrate aging. Ultimately, these findings will help define therapeutic targets for development of new treatments for age-associated diseases that have a heavy economic burden, and more importantly, cause extreme suffering to patients and their families.