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

大约180年前，贡珀茨通过他的先驱研究发现，随着人类衰老，年死亡率呈线性单对数增长规律。Gompertzean的表达规律表明，活体动物的寿命似乎是一种获得性表型，这可能是自约1亿年前活体动物诞生以来，与突变抑制、抗氧化应激、DNA损伤修复机制等相关的各种基因的一个基因对另一个基因的获得。衰老可以被认为是多层次、多维度的现象，即亚细胞细胞器的分子更替，包括从体内组织中移除的细胞的细胞老化，每个物种的个体寿命，直到种群老化。另一方面，包括氧化应激在内的环境负面因素使Gompertzean的表达曲线变得陡峭，从而导致加速衰老。在此基础上，得出以下三点结论：1.Klotho小鼠造血干细胞的特点是细胞周期减慢，细胞凋亡受到抑制，这可能导致显著的基因组不稳定性。2.由于上述干细胞室的上述变化，化学暴露于甲基亚硝酸盐后，微核试验的频率增加。3.由于p53和Klotho的同时缺乏，提示基因组不稳定性的协同增加。在杂合子双缺乏中检测到可能的致癌性增加：MNU在双缺乏中诱导的存活显示寿命减少50%；然而，在致瘤谱上没有明显的差异。下一步还需要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.