BPS2026 – Revealing cellular functional fluctuations through nonequilibrium physics

Living cells have a remarkable ability to sense environmental changes and adapt their internal structure, morphology, and motility with high accuracy. However, at the microscopic scale, all cellular components, molecules, structures and even entire cells, are continuously exposed to stochastic fluctuations. Although the molecular pathways and signaling mechanisms underlying adaptive responses have been extensively studied, how cells preserve such sophisticated adaptability in a noise-dominated environment remains poorly understood. Here, we propose a quantitative framework based on nonequilibrium physics to distinguish intrinsic cellular fluctuations from thermal noise, thereby revealing functional fluctuations actively regulated by cells. By integrating fluorescence correlation spectroscopy with theoretical analyses of nonequilibrium dynamics, we identified nonthermal fluctuations that reflect active regulation within living cells. Our results reveal that, surprisingly, intracellular fluctuations are not predominantly governed by microtubule-based motors such as kinesin or dynein, but are instead influenced by actomyosin activity. Furthermore, we demonstrate that cellular senescence reshapes the fluctuation landscape, with increased magnitude while decreased diversity of fluctuations. This reduction in fluctuation heterogeneity suggests a decline in regulatory flexibility and provides a mechanistic link between intracellular fluctuations and the reduced adaptive capacity observed in senescent cells. Together, these findings suggest intracellular fluctuations as a functional readout of cellular adaptability and highlight their active regulation as a key determinant of the physiological state of cells. Our work elucidates the physical basis of how cells maintain adaptability among pervasive fluctuations and introduces fluctuation dynamics as a means to explore cellular senescence.