长皱纹、掉发?Nature子刊证实:逆转皮肤衰老的关键在线粒体
2018/07/31
长皱纹、脱发是很多人衰老的典型现象。这一表征是否可以逆转?现在,科学家们在小鼠身上验证了这一可能。他们发现,当线粒体功能受损,小鼠会在几周内皮肤起皱、大面积掉毛发。更意外的是,关闭引发功能障碍的突变可以让小鼠“重返年轻”——衰老症状得到缓解。


图片来源:Pixabay

7月20日,《Cell Death & Disease》期刊发表了这一篇题为“Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function”的文章。由阿拉巴马大学伯明翰分校(UAB)医学院的遗传学教授Keshav Singh带领的团队发现,引发这一奇妙“现象”的突变发生在核基因中,关联着线粒体功能。


线粒体功能障碍引发衰老

线粒体是维持细胞能量供给、有氧呼吸的主要场所。伴随着衰老,线粒体功能也会逐渐衰退。更要命的是,线粒体功能障碍容易引发一系列年龄相关性疾病,例如心血管疾病、糖尿病、年龄相关性神经疾病和癌症等。

在这项研究中,Keshav Singh以小鼠为模型,利用抗生素强力霉素(doxycycline)诱导与线粒体功能障碍有关的突变,引发线粒体DNA缺失。

结果发现,当食用添加有强力霉素的食物或者饮用水4周内,这些小鼠的头发会变白、掉发、行动迟缓、无精打采,这些变化类似于自然衰老。4-8周内,小鼠的皮肤开始起皱,而且雌鼠比雄鼠更严重。

突变被诱导后,其他器官的变化很少。这意味着,与其他组织相比,线粒体在皮肤中的作用更为重要。


中间小鼠:在线粒体DNA缺失几周内,小鼠皮肤会起皱,以及大面积的毛发脱落;右图小鼠:当关闭这一突变基因恢复线粒体功能之后,衰老小鼠会“重返年轻”——重获光滑的皮肤和厚厚的皮毛,且与同龄的健康小鼠没有区别;左图小鼠:正常对照。图片来源:UAB

逆转衰老

戏剧性的是,这种脱发、长皱纹现象可以通过关闭突变进行逆转!在停止使用强力霉素一个月后,这些已有衰老症状的小鼠会“重返年轻”,丢失的线粒体DNA会恢复。

突变小鼠的皮肤会出现大量的皮肤细胞,且外层异常增厚、毛囊功能障碍以及炎症增加。这些病理变化类似于人类皮肤的外在老化(extrinsic aging,通常由日晒、长期吸烟等外因导致)。

同时,线粒体DNA缺失也会导致突变小鼠体内4种与衰老相关标记物的表达水平发生改变,类似于内在衰老(intrinsic aging,自然的衰老过程)。

小结

皮肤为什么会变皱?研究表明,皮肤中的基质金属蛋白酶(matrix metalloproteinase enzymes)和组织特异性抑制剂之间的平衡被破坏——这两者平衡对于保持皮肤中的胶原纤维、防止起皱是必要的。

由抗生素诱导的这一突变会降低线粒体DNA水平,改变线粒体基因表达,并让线粒体中参与氧化磷酸化的复合体不稳定。

同时,逆转突变可以恢复线粒体功能,进而恢复皮肤、毛发。这表明,线粒体是皮肤衰老和脱发的可逆性调节因子。

责编:风铃

参考资料:

Scientists reverse aging-associated skin wrinkles and hair loss in a mouse model

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  • Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function

    Mitochondrial DNA (mtDNA) depletion is involved in mtDNA depletion syndromes, mitochondrial diseases, aging and aging-associated chronic diseases, and other human pathologies. To evaluate the consequences of depletion of mtDNA in the whole animal, we created an inducible mtDNA-depleter mouse expressing, in the polymerase domain of POLG1, a dominant-negative mutation to induce depletion of mtDNA in various tissues. These mice showed reduced mtDNA content, reduced mitochondrial gene expression, and instability of supercomplexes involved in oxidative phosphorylation (OXPHOS) resulting in reduced OXPHOS enzymatic activities. We demonstrate that ubiquitous depletion of mtDNA in mice leads to predominant and profound effects on the skin resulting in wrinkles and visual hair loss with an increased number of dysfunctional hair follicles and inflammatory responses. Development of skin wrinkle was associated with the significant epidermal hyperplasia, hyperkeratosis, increased expression of matrix metalloproteinases, and decreased expression of matrix metalloproteinase inhibitor TIMP1. We also discovered markedly increased skin inflammation that appears to be a contributing factor in skin pathology. Histopathologic analyses revealed dysfunctional hair follicles. mtDNA-depleter mice also show changes in expression of aging-associated markers including IGF1R, KLOTHO, VEGF, and MRPS5. mtDNA-repleter mice showed that, by turning off the mutant POLG1 transgene expression, mitochondrial function, as well as the skin and hair pathology, is reversed to wild-type level. To our knowledge that restoration of mitochondrial functions can reverse the skin and hair pathology is unprecedented.

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