Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
Nat Commun. 2013;4:2626. doi: 10.1038/ncomms3626.
Insufficient cell proliferation has been suggested as a potential cause of age-related tissue dysgenesis in mammals. However, genetic manipulation of cell cycle regulators in the germ lines of mice results in changes in animal size but not progeroid phenotypes. Here we increase levels of the cyclin-dependent kinase inhibitor Cdkn1b (p27kip1) in adult mice through doxycycline-inducible expression and show this results in reduced cell proliferation in multiple tissues. The mice undergo changes resembling ageing even in the absence of an elevated DNA damage response or evidence of senescent cells, suggesting an altered balance between genetic and tissue ageing. In contrast, suppressing cell proliferation by doxycycline treatment of neonates retards growth, but the onset of degenerative changes is delayed during the period of reduced body mass. These results support the hypothesis that many of the most recognizable features of mammalian ageing can result from an imbalance between cell production and the mass of tissue that must be maintained.
细胞增殖不足被认为是哺乳动物与年龄相关的组织发育不良的潜在原因。然而，通过对小鼠生殖系中的细胞周期调节剂进行基因操作，只会导致动物体型发生变化，而不会出现早衰表型。在这里，我们通过诱导型表达的方法增加成年小鼠中环细胞依赖性激酶抑制剂 Cdkn1b（p27kip1）的水平，结果表明这会导致多种组织中的细胞增殖减少。即使没有升高的 DNA 损伤反应或衰老细胞的证据，这些小鼠也会发生类似于衰老的变化，表明遗传和组织衰老之间的平衡发生了改变。相比之下，通过对新生小鼠进行多西环素处理来抑制细胞增殖会减缓生长，但在体重减轻期间，退行性变化的发生会延迟。这些结果支持这样一种假设，即哺乳动物衰老的许多最明显特征可能是由于细胞产生与必须维持的组织质量之间的不平衡所致。
