Elucidating Cellular Aging and Quality Control Pathways through Meiotic Differentiation

项目摘要 包括癌症和神经变性在内的流行疾病的主要风险因素是衰老。在细胞 水平，衰老表现为保守的生理缺陷的积累，最终导致功能性疾病。 衰退、疾病和有机体死亡。尽管与年龄相关的功能障碍有很多， 对衰老如何成为主要疾病决定因素的理解有限。该领域的传统方法是 在衰老过程表现出来之前诱导模型生物体的遗传修饰， 随后确定这些改变如何影响寿命。虽然这些研究有助于 识别影响寿命和健康的因素，他们缺乏时间分辨率来区分 基因产物直接抵消那些间接影响寿命的与年龄相关的损害， 仅仅通过延迟细胞周期进程、生长和/或发育。关键的挑战是 开发一个有效的系统，可以识别衰老的潜在机制， 以可控的方式操纵已识别的因素。我的实验室发现配子发生， 分化程序产生生殖细胞，包含内源性再生途径。 这些生理途径具有排除和消除细胞质和细胞核的能力 与年龄相关的病理学。因此，机械解剖这个程序提供了独特的 深入了解衰老的生物学以及与年龄相关的疾病的潜在治疗途径。 该建议旨在提供对分子和细胞事件的全面理解， 与减数分裂返老还童有关目标1中提出的实验将确定配子如何 能够排除并随后消除随着年龄积累的细胞核和细胞质缺陷。的 目标2中提出的实验将采用正交方法来识别和表征完整的 减数分裂基因的补充，能够延长营养酵母细胞的寿命，类似于后生动物 体细胞将这些研究进一步推广到C.线虫将鉴定出保守的减数分裂基因， 抵消细胞器损伤，并将确定激活配子发生特异性复壮的效果 途径对组织特异性以及有机体的健康跨度。本文中描述的研究组合 该提案将揭示在分子水平上如何进行减数分裂复壮的机械理解， 确定哪些基因在减数分裂之外提高健康和寿命，并揭示保守的途径， 可以用来延长健康寿命。

PROJECT SUMMARY The primary risk factor for prevalent diseases including cancer and neurodegeneration is aging. At the cellular level, aging manifests as an accumulation of conserved physiological defects that eventually cause functional decline, disease, and organismal death. Despite an extensive list of age-associated dysfunctions, we have a limited understanding of how aging becomes a major disease determinant. The traditional method in the field is to induce genetic modifications in a model organism before the aging process manifests itself, and to subsequently determine how these alterations affect lifespan. While these studies have been instrumental in identifying factors that impact longevity and healthspan, they lack the temporal resolution to distinguish the gene products that directly counteract age-associated damage from those that have indirect effects on lifespan, merely through delaying cell cycle progression, growth and/or development. The key challenge is the development of an effective system that allows identification of the underlying mechanisms of aging and manipulation of identified factors in a controlled manner. My lab has discovered that gametogenesis, the differentiation program that gives rise to reproductive cells, contains endogenous rejuvenation pathways. These physiological pathways have the ability to exclude and eliminate both cytoplasmic and nuclear pathologies that are associated with age. Therefore, mechanistic dissection of this program offers unique insights into the biology of aging as well as potential therapeutic avenues for age-associated diseases. This proposal seeks to provide a comprehensive understanding of the molecular and cellular events that are associated with meiotic rejuvenation. The experiments proposed in Aim 1 will determine how gametes are able to exclude and subsequently eliminate nuclear and cytoplasmic defects that accumulate with age. The experiments proposed in Aim 2 will take an orthogonal approach to identify and characterize the complete complement of meiotic genes that are capable of extending lifespan in vegetative yeast cells, akin to metazoan somatic cells. Further extension of these studies to C. elegans will identify conserved meiotic genes that can counteract organellar damage and will determine the effects of activating gametogenesis-specific rejuvenation pathways on tissue-specific as well as organismal healthspan. The combination of studies described in this proposal will reveal a mechanistic understanding of how meiotic rejuvenation occurs at the molecular level, determine which genes improve fitness and lifespan outside of meiosis, and reveal conserved pathways that can be leveraged to extend healthspan.