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

An outstanding question in biology concerns mechanisms of size control in organs, cells, and organelles. Size impacts metabolic efficiency, surface area-to-volume ratio, and environmental adaptation, which are all required for optimal function. Cyclin-dependent kinase 4 (CDK4), traditionally recognized for its role in cell cycle progression, has gained increasing support for cell cycle-independent roles. Previously, we described a mechanism of cell size control involving a CDK4 and p38 MAPK circuitry that dictates target cell size. In this study, we target the CDK4/6 ortholog CDK-4 in the nematode worm Caenorhabditis elegans to describe functional consequences of changing biological size in vivo. Our data suggest that CDK-4 regulates nucleolar size and anabolic metabolism independent from cell cycle progression. When size and metabolism are increased, we report enhanced thermotolerance early in life but accelerated aging and reduced longevity late in life, suggesting a novel function of CDK-4 in somatic maintenance and organism health.