CISD2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that plays a crucial role in cellular homeostasis and aging control 1. The protein localizes to the endoplasmic reticulum, mitochondrial outer membrane, and mitochondria-associated membranes, where it regulates cytosolic Ca2+ homeostasis, ER integrity, and mitochondrial function 1. CISD2 forms a ternary complex with IP3 receptors and anti-apoptotic BCL-2 proteins, counteracting BCL-2's inhibition of ER-mitochondrial calcium transfer by maintaining ER-mitochondrial contact sites 2. Functionally, CISD2 expression decreases with age in various tissues, and this decline correlates with mitochondrial breakdown and aging phenotypes 31. Genetic studies demonstrate that CISD2 deficiency shortens lifespan and accelerates aging in mice, while persistently high CISD2 levels promote longevity 1. CISD2 can be pharmaceutically activated by compounds like hesperetin, which enhances mitochondrial function and protects against oxidative stress in aged cells 4. Mutations in CISD2 cause Wolfram syndrome 2, an autosomal recessive disorder with metabolic and neurodegenerative manifestations 5. The gene has also been implicated in ADHD through Mendelian randomization studies 6, highlighting its broader neurological significance.