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<p>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 <i>Caenorhabditis elegans</i>, an organism lacking both p16 and SASP. Using a conditional degradation system, we demonstrate that CDK-4 inhibition in <i>C. elegans</i> 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).</p>

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

  • 期刊论文

  • 发表日期：

    2025年5月18日

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  • Rachel Webster,
  • Maria Quintana,
  • Bin Yu,
  • Stacey Fluke,
  • Ran Kafri,
  • W. Brent Derry

摘要

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).