CDK-4 regulates nucleolar size and metabolism at the cost of late-life fitness in C. elegans.

Abstract

Studies on aging have centered on two molecular pathways: CDK4/6 and insulin/mTORC1. These pathways are thought to influence aging through distinct mechanisms: mTORC1 by reprogramming systemic metabolism, and CDK4 through p16-mediated senescence and inflammatory signaling (SASP). Here, we investigate the connection between aging and CDK4 in Caenorhabditis elegans, an organism lacking both p16 and SASP. Using a conditional degradation system, we demonstrate that CDK-4 inhibition in C. elegans phenocopies its aging-related functions observed in mammals. Worms with depleted CDK-4 exhibited accelerated aging phenotypes, including reduced lifespan, decreased motility, increased yolk accumulation, and earlier onset of senescence. At the physiological level, CDK4-inhibited worms show substantial metabolic shifts; including enhanced protein synthesis, elevated ATP production, and increased fat accumulation. These metabo-aging phenotypes occur independently of mTORC1, instead operating through the canonical CDK-4 effectors LIN-35 (Rb) and EFL-1 (E2F).