Endoplasmic reticulum (ER) stress has been linked to various metabolic pathologies, neurodegeneration and aging. Although various mechanistic aspects of the resulting unfolded protein response (UPR) have been elucidated, its regulation in genetically diverse populations remains elusive. In the present study we evaluated the expression of chaperones BiP/GRP78, GRP94 and calnexin (CANX) in the lungs, liver and brain of 7 months old and 2–3 years old outbred deer mice P. maniculatus and P. leucopus. Chaperones' expression was highly variable between species, tissues and ages suggesting that levels of expression of individual chaperones do not change consistently during aging. Despite this variation, a high degree of coordination was maintained between chaperones' expression indicating the tight regulation of the UPR which is consistent with its adaptive activity to maintain homeostasis. In the brain though of older P. maniculatus, at which neurodegenerative changes were detected, loss of coordination was revealed, especially between BiP and either of GRP94 or calnexin which indicates that de-coordination rather than aberrant expression is linked to deregulation of the UPR in aging. These findings underscore the involvement of UPR in the onset of aging-related pathologies and suggest that beyond levels of expression, concerted activation may be of significance to attain homeostasis. These findings emphasize the value of genetically diverse models and suggest that beyond levels of expression of individual targets the coordination of transcriptional networks should be considered when links to pathology are explored.

内质网（ER）应激与各种代谢病理，神经退行性变和衰老有关。尽管已阐明了最终的蛋白反应（UPR）的各种机制，但在遗传多样性人群中其调控仍然难以捉摸。在本研究中，我们评估了伴侣BiP / GRP78，GRP94和钙粘蛋白（CANX）在7个月大和2-3岁大的杂种鹿P. maniculatus和P. leucopus的肺，肝和脑中的表达。。分子伴侣的表达在物种，组织和年龄之间是高度可变的，这表明各个分子伴侣的表达水平在衰老过程中不会持续变化。尽管有这种变化，但在伴侣的表达之间维持了高度的协调性，表明UPR的严格调节，这与其维持体内稳态的适应性活动相一致。在大脑中，尽管是老P. maniculatus，在检测到神经退行性改变时，发现失去协调，特别是在BiP与GRP94或钙连接蛋白之间，这表明去协调而非异常表达与衰老过程中UPR的失调有关。这些发现强调了UPR参与了与衰老相关的疾病的发作，并表明，在表达水平之外，协同激活对于实现体内平衡可能具有重要意义。这些发现强调了遗传多样性模型的价值，并表明，在探索与病理学的联系时，除了单个靶标的表达水平外，还应考虑转录网络的协调性。