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) \(\alpha\) 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.
Results
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 \(\alpha\). For the first time in humans, we report a mutual relationship between low zinc levels, high CREM \(\alpha\) 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 \(\alpha\) overexpression, and counteract subsequent low IL-2 production rates.
Conclusions
Our ex vivo and in vivo data identify zinc deficiency-mediated CREM \(\alpha\) 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.
Graphical abstract
During the aging process, there is a progressive decrease in zinc status, which in turn leads to overexpression of the transcription factor CREM\(\mathrm{\alpha }\) 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.
WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
