IPMK-1 governs C. elegans physiology through ceTOR but lifespan via a distinct IP3-dependent pathway.

Inositol-polyphosphate multikinase (IPMK) is a pleiotropic enzyme essential for metabolic homeostasis, cancer, neural function, and development. While mammalian IPMK is well-characterized, the systemic integration of its signaling outputs - ranging from metabolism to longevity - remains poorly understood. Here, we show that the Caenorhabditis elegans homolog, IPMK-1, regulates the rhythmic defecation, postembryonic development, lipid metabolism, and reproduction by maintaining endoplasmic reticulum (ER) calcium homeostasis. Loss of ipmk-1 causes excessive ER calcium retention, leading to compromised mitochondrial bioenergetic capacity and reduced activity of the C. elegans target of rapamycin (ceTOR) pathway. Interestingly, while IPMK-1 is required for normal lifespan, its role in longevity operates through a distinct inositol 1,4,5-trisphosphate (IP₃)-dependent mechanism that may partially independent of the ER-mitochondria-ceTOR signaling axis controlling rhythmic, development, lipid metabolism, and reproduction. Furthermore, IPMK-1 may also regulate lifespan beyond IP3 pathway, function in parallel or as a partial component of multiple longevity pathways, such as canonical insulin/IGF-1, dietary restriction, mitochondria respiration, and germline signaling pathways. This multiple-pathway architecture underscores the evolutionary conservation of IPMK as a nexus that integrates nutrient sensing and processing, calcium signaling, and organismal aging. Further research on these functions and their underlying mechanisms of IPMK could help to understand IPMK mediated human metabolic and age-related disorders.