Establishment of biotechnology-derived recombinant mice expressing accelerated aging -a sensitive model for drug-induced epigenetic damages

大约180年前，冈珀茨在他的开创性研究中发现，在人类衰老的过程中，年死亡率呈线性单对数增长的规律。gompertzan表达规律表明，活体动物的长寿似乎是一种获得性表型（acquired phenotype），可能是一个基因对另一个基因对各种相关基因（如诱变抑制、抗氧化应激、DNA损伤修复机制等）的遗传，从大约一亿年前的活体动物诞生进化而来。衰老可以被认为是一种多层次、多维度的现象，即从亚细胞细胞器的分子周转，细胞老化，包括从体内组织中移除的细胞，每个物种的个体寿命，直至种群衰老。另一方面，氧化应激等环境负面因素使Gompertzean表达曲线变陡，从而导致衰老加速。综上所述，总结出以下三点：klotho小鼠造血干细胞的特征表现为细胞周期减慢和细胞凋亡抑制，这似乎潜在地诱导了突出的基因组不稳定性。由于上述干细胞区室的改变，甲基亚硝基源化学暴露后微核试验的频率增加。由于p53和klotho同时缺乏表明了基因组不稳定性的协同增加，因此在杂合双缺陷中检测了可能增加的致癌性：双缺陷中mnu诱导的生存期显示寿命减少50%；但在致瘤谱上无显著差异。下一步应进一步阐明潜在的背景机制。

Gompertz discovered, about 180 years ago by his pioneer study, the rule of linear single logarithmic increase in yearly death-rate along the course of human senescence. The rule of Gompertzean expression implies that the longevity of life span in living animals seem to be an acquired phenotype, which is obtained, presumably, one gene to the other for various genes related to, such as, mutagenic suppression, anti-oxidative stresses, repairing mechanism for DNA damages, etc., since the birth of living animals evolved about a hundred million years ago. The senescence may be recognized as multi-layered, multi-dimensional phenomena, i.e. from a molecular turnover of subcellular organelles, a cellular aging including cells removed from an in vivo tissue, an individual life span of each species, up to populational aging. On the other hand, environmental negative factors including oxidative stresses make the curve of Gompertzean expression steeper, which consequently induces an accelerated aging.Based on the above, following three items are concluded:1.Characteristics of hemopoietic stem cells in klotho mice showed a decelerated slower cell cycle and a suppression of apoptosis, which seem potentially to induce a prominent genomic instability.2.Because of above-mentioned alteration in the stem cell compartment, an increased frequency of micronucleus test was observed after chemical exposure with methyl nitrosourea.3.Since synergistic increase of genomic instability was suggested by simultaneous deficiency of p53 and klotho, a possible increase of carcinogenicity was examined in the heterozygous double deficiencies : MNU-induced survival in the double deficiency showed a 50% decrease in lifespan ; however, with no significant differences in tumorigenic spectrum.Further underlying background mechanism should be elucidated in the next step.