p16INK4A is a robust in vivo biomarker of cellular aging in human skin
p16INK4A is a robust in vivo biomarker of cellular aging in human skin
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DOI：
10.1111/j.1474-9726.2006.00231.x
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发表时间：
2006-10-01
期刊：
影响因子：
7.8
通讯作者：
Wlaschek, Meinhard
中科院分区：
文献类型：
--
作者：
Ressler, Sigrun;Bartkova, Jirina;Wlaschek, Meinhard
细胞周期调节基因p16(INK4A)编码细胞周期蛋白依赖性激酶4和6的一种抑制剂，被认为在细胞衰老和过早衰老中起重要作用。尽管在体外人成纤维细胞衰老过程中p16(INK4A)的表达随年龄增长而增加，但关于体内p16(INK4A)的年龄依赖性尚无数据。为了确定人皮肤中p16(INK4A)的表达是否与供体年龄相关，通过免疫组织化学以及p16(INK4A)抑制因子BMI1的表达分析了p16(INK4A)的表达。从健康人皮肤库中选取了0 - 20岁、21 - 70岁和71 - 95岁年龄组的样本。我们发现老年个体中p16(INK4A)阳性细胞的数量明显高于较年轻的年龄组。在表皮和真皮（具有截然不同增殖活性的区域）中都发现p16(INK4A)阳性细胞数量增加。BMI1基因表达随着供体年龄的增加显著下调，而Ki67未观察到明显的年龄差异。在免疫荧光共表达研究中，Ki67阳性细胞p16(INK4A)为阴性，BMI1表达细胞Ki67也呈阴性。总之，我们首次提供证据表明体内人皮肤中p16(INK4A)的表达与年龄增长直接相关。因此，p16(INK4A)是体内人类衰老的一个生物标志物。这里报道的数据提出了一个驱动人皮肤衰老的调节基因表达变化的模型。
The cell-cycle regulating gene, p16(INK4A), encoding an inhibitor of cyclin-dependent kinases 4 and 6, is considered to play an important role in cellular aging and in premature senescence. Although there is an age-dependent increase of p16(INK4A) expression in human fibroblast senescence in vitro, no data are available regarding the age dependency of p16(INK4A) in vivo. To determine whether p16(INK4A) expression in human skin correlates with donor age, p16(INK4A) expression was analyzed by immunohistochemistry as well as the expression of the p16(INK4A) repressor BMI1. Samples from the age groups 0-20, 21-70, and 71-95 years were selected from a bank of healthy human skin. We show that the number of p16(INK4A) positive cells is significantly higher in elderly individuals compared to the younger age groups. The number of p16(INK4A) positive cells was found to be increased in both epidermis and dermis, compartments with strictly different proliferative activities. BMI1 gene expression was significantly down-regulated with increasing donor age, whereas no striking age differences were observed for Ki67. In immunofluorescence co-expression studies, Ki67-positive cells were negative for p16(INK4A) and BMI1-expressing cells also stained negatively for Ki67. In conclusion, we provide for the first time evidence that p16(INK4A) expression directly correlates with chronological aging of human skin in vivo. p16(INK4A) therefore is a biomarker for human aging in vivo. The data reported here suggest a model for changes in regulatory gene expression that drive aging in human skin.