Calcium and ROS crosstalk: a key to extending healthspan?

Mounting evidence shows an important role for calcium and ROS interplay in fine-tuning cellular signalling and physiological responses, thereby regulating aging and age-related disorders.

Calcium (Ca2+) and reactive oxygen species (ROS) are essential biological messengers that regulate a plethora of cellular signalling cascades and physiological responses. Given their critical role in cellular and organismal homeostasis, it is not surprising that disruptions to Ca2+ and ROS balance have been implicated in various human diseases.

Longevity.Technology: More recently, Ca2+ and ROS imbalances have been linked to aging, suggesting that Ca2+– and ROS-modulating agents may represent a valuable approach to treat age-related disorders, including cancer, neurodegenerative conditions, diabetes, and cardiovascular diseases [1].

Intracellular Ca2+ levels are important determinants of the activation status of numerous cellular proteins, including calcineurin (CaN) and calmodulin (CaM). Additionally, Ca2+ regulates membrane potential and production of adenosine triphosphate (ATP) and other key metabolic molecules. Importantly, elevated Ca2+ levels within mitochondria induce cell death. Therefore, intracellular Ca2+ levels are tightly regulated by channels that transport Ca2+ ions between cytosol, cellular compartments, and the extracellular space [1].

In contrast to Ca2+ that is shuffled between different cellular compartments, ROS are generated continuously during intracellular metabolic reactions – especially in mitochondria, the “energy-producing engine of the cells”. As they are unstable and highly reactive, ROS interact with and damage various cellular components, including proteins, lipids, and DNA. Hence, sophisticated cellular mechanisms and detoxifying enzymes exist to maintain intracellular ROS levels under control and prevent oxidative stress and ROS-mediated cell damage [1].

Mounting evidence from animal models and isolated human cells suggests a close interplay between Ca2+ and ROS signalling during aging, and that this interplay plays a critical role in the development and progression of numerous age-related disorders.

Specifically, ROS modulate the activity of Ca2+ signalling pathway components (e.g., Ca2+ transporters), which in turn, regulate ROS production systems (e.g., mitochondrial respiration and NADPH oxidases) [1, 2]; this crosstalk creates a complex feedback loop, wherein the intracellular levels of Ca2+ regulate ROS homeostasis and vice versa.

A representative example of the importance of Ca2+-ROS crosstalk in age-related diseases is the study by Togashi et al. [3] showing that hydrogen peroxide-induced Ca2+ influx promotes insulin secretion in pancreatic β cells, linking Ca2+/ROS signalling to type 2 diabetes. Furthermore, Cali et al. [4] reported that ROS-mediated oxidative stress disrupts Ca2+ homeostasis, affecting neuronal function and potentially causing age-related neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease.

Cancer is another disease strongly associated with aging. Holzmann et al. [5] have shown that ROS-mediated alterations in Ca2+ signalling promoted cell survival in prostate cancer cells. Interestingly, Tosatto et al. [6] uncovered a link between Ca2+, ROS, and HIF-1α, which was key to breast cancer progression. Notably, decreased expression of the mitochondrial Ca2+ uniporter (MCU) impaired ROS production, reducing HIF-1α levels and thereby inhibiting tumour growth and cancer cell migration.

The overwhelming evidence of the essential role of the extensive crosstalk between Ca2+ and ROS homeostasis during aging calls for further comprehensive studies of the role of Ca2+/ROS signalling in cellular senescence and organismal aging, which will facilitate the development of novel Ca2+– and ROS-modulating strategies to combat age-related disorders and extend healthspan.

Image by Cheska Poon from Pixabay