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

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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.