Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics, University of Basel, CH-4012 Basel, Switzerland.
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7218-23. doi: 10.1073/pnas.1008882108. Epub 2011 Apr 11.
Human aging is accompanied by dramatic changes in daily sleep-wake behavior: Activity shifts to an earlier phase, and the consolidation of sleep and wake is disturbed. Although this daily circadian rhythm is brain-controlled, its mechanism is encoded by cell-autonomous circadian clocks functioning in nearly every cell of the body. In fact, human clock properties measured in peripheral cells such as fibroblasts closely mimic those measured physiologically and behaviorally in the same subjects. To understand better the molecular mechanisms by which human aging affects circadian clocks, we characterized the clock properties of fibroblasts cultivated from dermal biopsies of young and older subjects. Fibroblast period length, amplitude, and phase were identical in the two groups even though behavior was not, thereby suggesting that basic clock properties of peripheral cells do not change during aging. Interestingly, measurement of the same cells in the presence of human serum from older donors shortened period length and advanced the phase of cellular circadian rhythms compared with treatment with serum from young subjects, indicating that a circulating factor might alter human chronotype. Further experiments demonstrated that this effect is caused by a thermolabile factor present in serum of older individuals. Thus, even though the molecular machinery of peripheral circadian clocks does not change with age, some age-related circadian dysfunction observed in vivo might be of hormonal origin and therefore might be pharmacologically remediable.
人类衰老伴随着日常睡眠-觉醒行为的巨大变化：活动转移到更早的阶段，睡眠和觉醒的巩固受到干扰。尽管这种日常的昼夜节律是由大脑控制的，但它的机制是由身体几乎每个细胞中自主运行的生物钟编码的。事实上，在成纤维细胞等外周细胞中测量的人类生物钟特性与在同一受试者中生理和行为上测量的特性非常相似。为了更好地理解人类衰老影响生物钟的分子机制，我们对来自年轻和年长受试者皮肤活检的成纤维细胞的生物钟特性进行了表征。尽管行为不同，但两组细胞的成纤维细胞周期长度、振幅和相位完全相同，这表明外周细胞的基本生物钟特性在衰老过程中不会发生变化。有趣的是，与用年轻供体的血清处理相比，用老年供体的血清处理相同的细胞会缩短周期长度并提前细胞生物钟的相位，这表明一种循环因子可能会改变人类的生物钟类型。进一步的实验表明，这种效应是由老年个体血清中存在的一种热敏因子引起的。因此，尽管外周昼夜节律钟的分子机制不会随年龄而变化，但体内观察到的一些与年龄相关的昼夜节律功能障碍可能与激素有关，因此可能具有药物治疗效果。
