RAPGEF3 and metabolic disease: Previous experiments have shown that in ageing-related metabolic diseases, rolipram could inhibit PDE4 and increase intracellular cAMP levels, leading to the activation of exchange protein activated by cAMP-1 (EPAC1) and its effector protein, which increases intracellular Ca2+ levels and ultimately activates the AMPK pathway and increases the activities of NAD+ and SIRT142.