Administrative Supplement to: Cell Autonomous and Non-Autonomous Mechanisms of Aging

进展总体总结：在前一个资助期，我们发现细胞或 组织驱动新陈代谢改变，激活核因子-B、FOXO3a和UPRmit，增加活性氧 物种和衰老。这清楚地表明了细胞自主机制对内源激素的反应 DNA损伤。这项工作在很大程度上依赖于报告老鼠的品系。此外，使用组织特异性突变体 我们发现，在某些情况下，但不是所有情况下，内源性DNA损伤增加的细胞或组织 会导致组织动态平衡的丧失和其他未受损组织的衰老。我们的初步工作表明 受损的免疫细胞通过细胞非自主机制最有效地推动衰老。 人们投入了大量的精力和资源来开发这些独特的转基因小鼠，使我们能够 向下钻取并发现随机性在哪里、何时以及如何自发地随时间积累 损坏会导致衰老。在之前的资助期间，我们开发了85种独特的转基因小鼠 其中DNA修复复合体ERCC1-XPF被系统或组织特异性地耗尽或敲除/- 用来测量衰老标记物、自噬或应激反应激活的各种报告结构 寿命/健康的关键调控因子(如mTOR、过氧化氢酶、NRF2、核因子-B、ATM、p53、p21Cip1或 P16INK4a)。

Overall Summary of Progress: In the previous funding period, we found that DNA damage in cells or tissues drives altered metabolism, activation of NF- B, FOXO3a, and UPRmit, an increase in reactive oxygen species and senescence. This clearly demonstrates cell autonomous mechanisms in response to endogenous DNA damage. This work relied heavily on reporter mouse strains. In addition, using tissue-specific mutant mice, we discovered that in some but not all cases, cells or tissues with increased endogenous DNA damage can drive loss of tissue homeostasis and aging in other non-damaged tissues. Our preliminary work indicates that damaged immune cells are the most potent in driving aging via cell non-autonomous mechanisms. Considerable effort and resources were dedicated to developing these unique transgenic mice that enable us to drill down and discover where, when and how spontaneous time-dependent accumulation of stochastic damage drives aging. During the previous funding period, we developed 85 unique strains of transgenic mice in which the DNA repair complex ERCC1-XPF is depleted or knocked-out systemically or tissue-specifically +/- a variety of reporter constructs to measure senescence markers, autophagy, or stress response activation +/- mutation of key regulators of lifespan/healthspan (e.g., mTOR, catalase, NRF2, NF- B, ATM, p53, p21Cip1 or p16Ink4a).