<b><i>Aims</i></b>: Mg<sup>2+</sup> is fundamental for life and its shortage severely impairs vital functions. However, whether excessive Mg<sup>2+</sup> has beneficial or adverse effects has remained unknown. To clarify this issue, we analyzed the effect of suppressing the functions of Cyclin M (CNNM) Mg<sup>2+</sup> efflux transporters in various experimental systems. <b><i>Results</i></b>: Investigation of short-lived <i>Caenorhabditis elegans</i> worms mutated for CNNM genes revealed reactive oxygen species (ROS) augmentation in intestinal cells, coincidently with high levels of Mg<sup>2+</sup>. Knockdown of <i>
gtl-1</i>, encoding Mg<sup>2+</sup>-incorporating channel into intestinal cells, reduced ROS levels and restored lifespan, confirming the causative role of excessive Mg<sup>2+</sup>. Also, inactivation of orthologous CNNM in human cultured cells and mice by RNA interference, expression of CNNM-inhibiting protein, phosphatase of regenerating liver (PRL) 3, or gene knockout resulted in ROS overproduction. Moreover, biochemical analyses revealed that excessive Mg<sup>2+</sup> stimulates ATP overproduction and accelerates mitochondrial electron transport, whose suppression shut down ROS generation. <b><i>Innovation and Conclusion</i></b>: These results provide definitive evidence that excessive Mg<sup>2+</sup> drives overproduction of ROS by affecting energy metabolism, implying the crucial importance of the tight regulation of intracellular Mg<sup>2+</sup> levels.