Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans.
Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans.
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DOI：
10.1016/j.bbi.2015.08.024
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Irwin MR
中科院分区：
文献类型：
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作者：
Carroll JE;Cole SW;Seeman TE;Breen EC;Witarama T;Arevalo JMG;Ma J;Irwin MR
与年龄相关的疾病风险与睡眠时间短和睡眠障碍有关;然而，将睡眠不足与衰老疾病联系起来的具体分子途径却定义不清。随着年龄的增长，被认为是导致疾病的关键细胞事件可能对睡眠不足特别敏感。我们测试了一个晚上的部分睡眠剥夺（PSD）是否会增加白细胞基因表达的DNA损伤反应（DDR），衰老相关的分泌表型（SASP）和衰老指标p16 INK 4a在老年人，谁是在增加细胞衰老的风险。年龄在61-86岁之间的社区居住老年人（n=29; 48%男性）经历了4个晚上的实验性部分睡眠剥夺（PSD）协议，包括适应，不间断的睡眠，部分睡眠剥夺（睡眠限制在凌晨3点至7点），以及随后的整晚睡眠。每天早晨获得血液样品以使用Illumina HT-12阵列评估外周血单核细胞（PBMC）基因表达。微阵列结果分析显示SASP（p <0.05）和DDR（p = 0.08）基因表达从基线到PSD夜晚升高。在NFKB 2、NBS 1和CHK 2中也观察到从基线到PSD的基因表达变化（所有p <0.05）。衰老标志物p16 INK 4a（CDKN 2A）在PSD后一天与基线相比增加（p <0.01），然而验证性RT-PCR没有复制该发现。一个晚上的部分睡眠剥夺激活PBMC基因表达模式与生物老化在这个老年人样本一致。PSD增强了SASP，并增加了损伤的积累，从而启动细胞周期停滞并促进细胞衰老。这些发现将睡眠剥夺与生物衰老相关的分子过程联系起来。
Age-related disease risk has been linked to short sleep duration and sleep disturbances; however, the specific molecular pathways linking sleep loss with diseases of aging are poorly defined. Key cellular events seen with aging, which are thought to contribute to disease, may be particularly sensitive to sleep loss. We tested whether one night of partial sleep deprivation (PSD) would increase leukocyte gene expression indicative of DNA damage responses (DDR), the senescence-associated secretory phenotype (SASP), and senescence indicator p16INK4a in older adult humans, who are at increased risk for cellular senescence. Community-dwelling older adults aged 61-86 years (n=29; 48% male) underwent an experimental partial sleep deprivation (PSD) protocol over 4 nights, including adaptation, an uninterrupted night of sleep, partial sleep deprivation (sleep restricted 3 AM to 7 AM), and a subsequent full night of sleep. Blood samples were obtained each morning to assess peripheral blood mononuclear cell (PBMC) gene expression using Illumina HT-12 arrays. Analyses of microarray results revealed that SASP (p < .05) and DDR (p = .08) gene expression were elevated from baseline to PSD nights. Gene expression changes were also observed from baseline to PSD in NFKB2, NBS1 and CHK2 (all p's < .05). The senescence marker p16INK4a (CDKN2A) was increased one day after PSD compared to baseline (p < .01), however confirmatory RT-PCR did not replicate this finding. One night of partial sleep deprivation activates PBMC gene expression patterns consistent with biological aging in this older adult sample. PSD enhanced the SASP and increased the accumulation of damage that initiates cell cycle arrest and promotes cellular senescence. These findings causally link sleep deprivation to the molecular processes associated with biological aging.