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).
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Acknowledgements
This work was supported by a Canadian Institutes of Health Research Project grant to WBD. (PJT 165837). WBD is the Canada Research Chair in Animal Models of Human Disease.
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Conceptualization: RW, WBD, RK. Methodology: RW, WBD, RK. Investigation: RW. Visualization: RW. Funding acquisition: WBD. Supervision: WBD, RK. Writing – original draft: RW. Writing – review & editing: RW, WBD, RK.
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Webster, R., Quintana, M., Yu, B. et al. CDK-4 regulates nucleolar size and metabolism at the cost of late-life fitness in C. elegans. Heredity (2025). https://doi.org/10.1038/s41437-025-00769-7
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DOI: https://doi.org/10.1038/s41437-025-00769-7
