Chronic stress increases transcriptomic indicators of biological aging in mouse bone marrow leukocytes

衰老 奶油 DNA损伤 骨髓 转录组 生物 炎症 内分泌学 内科学 DNA修复 癌症研究 医学 免疫学 转录因子 基因表达 基因 细胞生物学 遗传学 DNA
作者
Kelly E. Rentscher,Judith E. Carroll,Lilian R. Polsky,Donald M. Lamkin
标识
DOI:10.1016/j.bbih.2022.100461
摘要

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.
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