Cell Autonomous and Non-Autonomous Mechanisms of Aging

描述（由申请人提供）：本项目资助的目标是“细胞自主和非自主衰老机制”，旨在研究自发、随机损伤驱动衰老的机制。该项目旨在挑战目前的观念，即随机细胞损伤，特别是DNA损伤，通过主要的细胞自主机制，通过触发程序性细胞死亡或衰老来促进衰老。虽然已经证实，在高剂量的基因毒性应激下，细胞可以分泌与衰老相关的因子，这些因子对邻近细胞有旁分泌作用，但还没有人确定非细胞自主事件在体内对内源性DNA损伤的生理水平作出反应，从而驱动衰老。提出的实验将解决衰老模型，其中年龄依赖性随机损伤的积累，包括DNA损伤，通过细胞自主和非自主途径驱动衰老。本项目由三个高度整合的项目组成。项目1 （Laura Niedernhofer）将检查DNA损伤的细胞自主和非自主效应，测量DNA氧化损伤、细胞衰老、ROS水平和衰老相关病理。项目2 （Paul Robbins）将研究NF-KB的细胞自主和非自主作用，NF-KB是一种响应细胞损伤和应激而激活的转录因子，在衰老过程中驱动衰老、ROS和氧化DNA损伤。最后，项目3 （Johnny Huard）将分析与年龄相关的干细胞功能丧失有关的细胞自主和非自主途径，并确定功能性成体干细胞分泌的延长寿命和健康寿命的因素。所有项目都将使用自然衰老小鼠和加速衰老小鼠模型的组织和细胞，包括ERCC1被删除的小鼠组织——专门影响DNA一次损伤一个组织的速度。这些项目将得到四个核心的支持：A)行政（保罗·罗宾斯）；B)小鼠模型（Laura Niedernhofer）；C)成像（西蒙·沃特金斯）和D)蛋白质组学（内森·耶茨）。

DESCRIPTION (provided by applicant): The goal of this Program Project Grant, entitled "Cell Autonomous and Non-autonomous Mechanisms of Aging" is to examine the mechanisms by which spontaneous, stochastic damage drives aging. This Program seeks to challenge the current notion that stochastic cellular damage, in particular, DNA damage promotes aging through a predominantly cell-autonomous mechanism by triggering programmed cell death or senescence. Although it is well-established that in response to high doses of genotoxic stress cells can secrete senescence-associated factors, which have a paracrine effect on neighboring cells, no one has established that non-cell autonomous events drive aging in response to physiological levels of endogenous DNA damage in vivo. The proposed experiments will address a model of aging where age-dependent accumulation of stochastic damage, including DNA damage, drives aging through both cell autonomous and non-autonomous pathways. This Program Project is comprised of three highly integrated projects. Project 1 (Laura Niedernhofer) will examine the cell autonomous and non-autonomous effects of DNA damage, measuring oxidative DNA damage, cellular senescence, ROS levels and aging-related pathology. Project 2 (Paul Robbins) will examine the cell autonomous and non-autonomous roles of NF-KB, a transcription factor activated in response to cellular damage and stress, in driving senescence, ROS and oxidative DNA damage with aging. Finally, Project 3 (Johnny Huard) will analyze the cell autonomous and non-autonomous pathways involved in age-related loss of stem cell function, as well as identify the factors secreted by functional adult stem cells that extend lifespan and healthspan. All projects will use tissues and cells from naturally aged mice and mouse models of accelerated aging, including mice in which ERCC1 is deleted tissue-specifically to affect the rate of DNA damage one tissue at a time. The projects will be supported by four cores, A) Administrative (Paul Robbins); B) Mouse Models (Laura Niedernhofer); C) Imaging (Simon Watkins) and D) Proteomics (Nathan Yates).