Cellular senescence is an irreversible growth arrest that occurs as a result of damaging stimuli, including DNA damage and/or telomere shortening. Here, we investigate histone variant H2A.J as a new biomarker to detect senescent cells during human skin aging. Skin biopsies from healthy volunteers of different ages (18–90 years) were analyzed for H2A.J expression and other parameters involved in triggering and/or maintaining cellular senescence. In the epidermis, the proportions of H2A.J-expressing keratinocytes increased from ≈20% in young to ≈60% in aged skin. Inverse correlations between Ki67- and H2A.J staining in germinative layers may reflect that H2A.J-expressing cells having lost their capacity to divide. As cellular senescence is triggered by DNA-damage signals, persistent 53BP1-foci, telomere lengths, and telomere-associated damage foci were analyzed in epidermal keratinocytes. Only slight age-related telomere attrition and few persistent nuclear 53BP1-foci, occasionally colocalizing with telomeres, suggest that unprotected telomeres are not a significant cause of senescence during skin aging. Quantification of integrin-α6+ basal cells suggests that the number and function of stem/progenitor cells decreased during aging and their altered proliferation capacities resulted in diminished tissue renewal with epidermal thinning. Collectively, our findings suggest that H2A.J is a sensitive marker of epidermal aging in human skin.

细胞衰老是不可逆的生长停滞，是由于破坏性刺激（包括DNA损伤和/或端粒缩短）而发生的。在这里，我们调查组蛋白变体H2A.J作为一种新的生物标记，以检测人类皮肤衰老过程中的衰老细胞。分析了来自不同年龄（18-90岁）健康志愿者的皮肤活检组织中的H2A.J表达及其他触发和/或维持细胞衰老的参数。在表皮中，表达H2A.J的角质形成细胞的比例从年轻人的约20％增加到老年皮肤的约60％。萌发层中Ki67和H2A.J染色之间的负相关关系可能反映了表达H2A.J的细胞已经失去了分裂能力。由于细胞衰老是由DNA损伤信号，持续的53BP1病灶，端粒长度，并在表皮角质形成细胞中分析了端粒相关的损伤灶。仅轻微的与年龄相关的端粒磨损和很少的持久性核53BP1病灶（偶有与端粒共定位）提示未保护的端粒不是皮肤衰老过程中衰老的重要原因。整联蛋白-α6+基底细胞的定量表明干/祖细胞的数量和功能在衰老过程中减少，并且它们改变的增殖能力导致表皮变薄的组织更新减少。总的来说，我们的发现表明H2A.J是人类皮肤表皮衰老的敏感标志。提示未保护的端粒不是皮肤衰老过程中衰老的重要原因。整联蛋白-α6+基底细胞的定量表明，干细胞/祖细胞的数量和功能在衰老过程中会降低，它们改变的增殖能力会导致表皮变薄的组织更新减少。总的来说，我们的发现表明H2A.J是人类皮肤表皮衰老的敏感标志。提示未保护的端粒不是皮肤衰老过程中衰老的重要原因。整联蛋白-α6+基底细胞的定量表明，干细胞/祖细胞的数量和功能在衰老过程中会降低，它们改变的增殖能力会导致表皮变薄的组织更新减少。总的来说，我们的发现表明H2A.J是人类皮肤表皮衰老的敏感标志。