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全面增加。越来越多的证据表明 在分类学上遥远的模型中，在老化过程中转座元件(TE)的广泛重新激活 有机体。然而，这种异常的重新激活与年龄相关的功能衰退之间的关系在很大程度上是 未知，在细胞、器官和有机体水平上。我们假设转座子的渐进性丢失 在生物体水平上，压抑是普遍存在的与年龄相关的功能衰退的原因。非洲人 绿松石鱼(Nothobranchius Furzeri)是一种新兴的自然短暂的脊椎动物模式生物， 为调查这一联系提供了一个独特的机会，调查人员此前已经制定了一项 为这个物种提供了强大的基因组到表型工具包。在这项提案中，我们建议利用非洲 绿松石龙鱼作为一种易驯化的短寿命模式生物，快速询问分子和 在活体内TE活动增加对脊椎动物衰老的生物影响。 为了验证我们的假设，我们建议(I)描述在人类基因组中的重复元素景观。 非洲绿松石龙鱼和TE的激活模式，以及(Ii)探索保守变化对 TE与衰老和衰老相关疾病对衰老过程的调节。这项工程的竣工将 增进对脊椎动物衰老的认识。最终，这些发现将有助于确定治疗目标。 用于开发具有沉重经济负担的与年龄相关的疾病的新疗法，以及更多 重要的是，这会给患者及其家人带来极度痛苦。

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.