Baarz Bastian Robinson, Laurentius Thea, Wolf Jana, Wessels Inga, Bollheimer Leo Cornelius, Rink Lothar
Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
Department of Geriatric Medicine, Faculty of Medicine, RWTH Aachen University Hospital, Morillenhang 27, 52074, Aachen, Germany.
Immun Ageing. 2022 Aug 30;19(1):40. doi: 10.1186/s12979-022-00295-8.
Aging is accompanied by a dramatic decline in the interleukin (IL)-2 production capacity of human immune cells, thus making seniors more susceptible to a variety of age-related diseases. A common cause of impaired cytokine production in advanced age is a deficiency of the essential micronutrient zinc. Nevertheless, the molecular mechanisms underlying a zinc deficiency-induced decrease in IL-2 production have not yet been satisfactorily elucidated. Recent animal and in vitro data suggested that the transcription factor cAMP-responsive element modulator (CREM) [Formula: see text] plays a critical role in T cells´ disturbed IL-2 production in suboptimal zinc conditions. However, its role in the human aging process and the possibility of influencing this detrimental process by short-term zinc supplementation have not yet been evaluated.
Comparing peripheral lymphocytes of 23 young and 31 elderly subjects with either high, intermediate, or deficient zinc status, we observed zinc-dependent regulation of the IL-2 production mediated by the transcription factor CREM [Formula: see text]. For the first time in humans, we report a mutual relationship between low zinc levels, high CREM [Formula: see text] expression, subsequent impaired IL-2 production, and vice versa. Remarkably, an average of only 6 days of in vivo zinc supplementation to zinc-deficient seniors was sufficient to rapidly improve zinc status, reverse CREM [Formula: see text] overexpression, and counteract subsequent low IL-2 production rates.
Our ex vivo and in vivo data identify zinc deficiency-mediated CREM [Formula: see text] overexpression as a key cellular mechanism underlying impaired IL-2 production in the elderly and point toward the use of zinc as a rapidly immune-enhancing add-on nutraceutical in geriatric therapy. During the aging process, there is a progressive decrease in zinc status, which in turn leads to overexpression of the transcription factor CREM[Formula: see text] in peripheral lymphocytes. CREMα is a negative regulator of the IL-2 gene, the overexpression of which dramatically limits adequate IL-2 production. This deleterious mechanism can be counteracted by short-term oral zinc administration, which can adjust IL-2 production in old, zinc-deficient individuals to a level similar to that of young adults.
衰老伴随着人类免疫细胞白细胞介素（IL）-2产生能力的显著下降，从而使老年人更容易患上各种与年龄相关的疾病。老年人细胞因子产生受损的一个常见原因是必需的微量营养素锌缺乏。然而，锌缺乏导致IL-2产生减少的分子机制尚未得到令人满意的阐明。最近的动物和体外数据表明，转录因子环磷酸腺苷反应元件调节剂（CREM）[公式：见正文]在锌条件欠佳时T细胞IL-2产生紊乱中起关键作用。然而，其在人类衰老过程中的作用以及通过短期补充锌来影响这一有害过程的可能性尚未得到评估。
比较23名年轻受试者和31名老年受试者外周淋巴细胞的锌状态，分别为高、中或低锌状态，我们观察到转录因子CREM[公式：见正文]介导的IL-2产生的锌依赖性调节。在人类中，我们首次报告了低锌水平、高CREM[公式：见正文]表达、随后IL-2产生受损之间的相互关系，反之亦然。值得注意的是，给缺锌的老年人平均仅进行6天的体内锌补充就足以迅速改善锌状态，逆转CREM[公式：见正文]的过表达，并抵消随后较低的IL-2产生率。
我们的体外和体内数据确定锌缺乏介导的CREM[公式：见正文]过表达是老年人IL-2产生受损的关键细胞机制，并表明在老年治疗中使用锌作为一种能迅速增强免疫力的营养补充剂。在衰老过程中，锌状态逐渐下降，这反过来导致外周淋巴细胞中转录因子CREM[公式：见正文]的过表达。CREMα是IL-2基因的负调节因子，其过表达显著限制了足够的IL-2产生。这种有害机制可以通过短期口服锌来抵消，短期口服锌可以将老年缺锌个体的IL-2产生调整到与年轻人相似的水平。
