Elucidating Cellular Aging and Quality Control Pathways through Meiotic Differentiation

项目总结 包括癌症和神经退行性疾病在内的流行疾病的主要风险因素是衰老。在手机上 水平，衰老表现为保守的生理缺陷的积累，这些缺陷最终导致功能性 衰退、疾病和自然死亡。尽管有一系列与年龄相关的功能障碍，但我们有一个 对衰老如何成为主要疾病决定因素的理解有限。这一领域的传统方法是 在衰老过程显现之前，在模型生物体中诱导基因修改，并 随后确定这些变化如何影响寿命。虽然这些研究在 识别影响寿命和健康寿命的因素，他们缺乏时间分辨率来区分 基因产品直接抵消那些对寿命有间接影响的与年龄相关的损害， 仅仅通过延缓细胞周期进程、生长和/或发育。关键的挑战是 开发一种有效的系统，以便能够识别衰老和 以受控的方式操纵已确定的因素。我的实验室发现配子发生， 产生生殖细胞的分化程序，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核的能力 与年龄有关的病理学。因此，对这个节目的机械剖析提供了独一无二的 对衰老生物学的洞察，以及与年龄相关疾病的潜在治疗途径。 这项提议试图提供对分子和细胞事件的全面理解 它们与减数分裂的恢复有关。目标1中提出的实验将决定配子如何 能够排除并随后消除随年龄积累的核和细胞质缺陷。这个 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 能够延长营养酵母细胞寿命的减数分裂基因的补充，类似于后生动物 体细胞。进一步将这些研究扩展到线虫将识别保守的减数分裂基因，这些基因可以 对抗细胞器损伤，并将决定激活配子发生特异性返老还童的效果 关于特定组织和组织健康范围的途径。本文件中描述的研究的组合 该提议将揭示对减数分裂复壮如何在分子水平上发生的机械论理解， 确定哪些基因改善了减数分裂外的健康和寿命，并揭示了 可以利用来延长健康寿命。

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.