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. 2025 May 18.
doi: 10.1038/s41437-025-00769-7. Online ahead of print.

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

Rachel Webster  1   2   3 , Maria Quintana  2 , Bin Yu  2 , Stacey Fluke  2 , Ran Kafri  4   5   6 , W Brent Derry  7   8
Affiliations

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

Rachel Webster et al. Heredity (Edinb). .

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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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics: No ethics approvals are required for research using Caenorhabditis elegans in Canada. All experiments were performed in accordance with the relevant guidelines and regulations.

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