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

总体进展概述：在上一个资助期，我们发现细胞中的DNA损伤或 组织驱动代谢改变，NF- B、FOXO 3a和UPRmit的活化，活性氧增加 物种与衰老这清楚地表明了细胞自主机制响应内源性 DNA损伤。这项工作严重依赖于报告基因小鼠品系。此外，使用组织特异性突变体 在小鼠中，我们发现在某些但不是所有情况下，内源性DNA损伤增加的细胞或组织， 可导致组织稳态的丧失和其他未受损组织的老化。我们的初步工作表明 受损的免疫细胞是通过细胞非自主机制驱动衰老的最有力的因素。 相当大的努力和资源致力于开发这些独特的转基因小鼠，使我们能够 深入挖掘，发现在哪里，何时以及如何自发的时间依赖性的随机积累， 损伤导致老化。在上一个资助期间，我们开发了85种独特的转基因小鼠 其中DNA修复复合物ERCC 1-XPF被系统性地或组织特异性地+/-缺失或敲除 多种报告构建体，以测量衰老标志物、自噬或应激反应活化+/- 寿命/健康寿命的关键调节因子的突变（例如，mTOR、过氧化氢酶、NRF 2、NF- B、ATM、p53、p21 Cip 1或 p16 Ink4a）。

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).