Chronic stress increases transcriptomic indicators of biological aging in mouse bone marrow leukocytes.
Chronic stress increases transcriptomic indicators of biological aging in mouse bone marrow leukocytes.
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DOI：
10.1016/j.bbih.2022.100461
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发表时间：
2022-07
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对动物和人类的研究表明，慢性压力暴露会影响关键的生物衰老途径，如炎症和DNA损伤，这表明压力可能会增加年龄相关疾病的风险。然而，目前尚不清楚这些影响是否延伸到衰老过程的其他标志，如细胞衰老。雄性SCID小鼠暴露于14天的束缚应激，给予（n = 6）或不给予（n = 10）普萘洛尔，或非应激对照条件（n = 10）。正常的股骨骨髓白细胞是从移植的白血病细胞中分离出来的，这些白血病细胞是在应激源之前注射的，因为小鼠也处于癌症攻击之下。我们进行了全基因组转录谱分析，以评估生物老化的指标：细胞应激，DNA损伤修复，细胞衰老标记物p16 INK 4a和p21，以及促炎性衰老相关分泌表型（SASP）。根据肿瘤负荷调整的ANCOVA和Fisher成对比较显示，与对照小鼠相比，应激小鼠的p16 INK 4a（p = .02）和p21（p = .004）增强，DNA损伤修复降低（p < .001），SASP（p = .03）基因表达升高。与对照小鼠相比，应激小鼠还显示出上调的β-肾上腺素能（CREB）和炎性（NF-κ B，AP-1）转录因子活性以及下调的细胞应激（Nrf 2）转录因子活性（ps <0.01）。普萘洛尔逆转CREB和Nrf 2活性（ps < .03）。研究结果表明，慢性应激暴露可以影响骨髓白细胞内的几个关键生物衰老途径，这些影响可能部分由交感神经β-肾上腺素能受体激活介导。
Research with animals and humans has demonstrated that chronic stress exposure can impact key biological aging pathways such as inflammation and DNA damage, suggesting a mechanism through which stress may increase risk for age-related disease. However, it is less clear whether these effects extend to other hallmarks of the aging process, such as cellular senescence. Male SCID mice were exposed to 14 days of restraint stress, with (n = 6) or without (n = 10) propranolol administration, or a non-stress control condition (n = 10). Normal femoral bone marrow leukocytes were isolated from engrafted leukemia cells that had been injected prior to the stressor, as the mice were also under a cancer challenge. We performed whole genome transcriptional profiling to assess indicators of biological aging: cell stress, DNA damage repair, cellular senescence markers p16INK4a and p21, and the pro-inflammatory senescence-associated secretory phenotype (SASP). ANCOVAs that adjusted for tumor load and Fisher's pairwise comparisons revealed that stressed mice had enhanced p16INK4a (p = .02) and p21 (p = .004), lower DNA damage repair (p < .001), and higher SASP (p = .03) gene expression than control mice. Stressed mice also showed up-regulated beta-adrenergic (CREB) and inflammatory (NF-кB, AP-1) and down-regulated cell stress (Nrf2) transcription factor activity relative to control mice (ps < .01). Propranolol reversed CREB and Nrf2 activity (ps < .03). Findings suggest that chronic stress exposure can impact several key biological aging pathways within bone marrow leukocytes and these effects may be partially mediated by sympathetic beta-adrenergic receptor activation.