Physical mechanisms underlying cellular senescence and rejuvenation

• Applicant: Professor Dr. Christoph Weber
• Subject Area: Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics ; Biophysics
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572511795

Cellular senescence – a state in which cells permanently stop dividing – is a key hallmark of aging and occurs across all cell types and organisms. While the phenotype of cellular senescence is well characterized, the physical mechanisms driving it, as well as the processes behind cellular rejuvenation, remain incompletely understood. At the molecular level, senescent cells were reported to display the accumulation of β-sheet-rich proteins within the nucleolus. These proteins initially assemble in dynamic, liquid-like condensates that transit to more rigid, aggregate-like structures over time – a process known as aberrant phase transitions. These transitions are the key to understanding the mechanisms underlying the emergence of senescence. In this project, we investigate the aggregation of β-sheet folded proteins in the nucleolus of human prostate epithelial cells undergoing drug-induced senescence and, conversely, counter-drug-induced rejuvenation. Using label-free Raman scattering (coherent anti-Stokes Raman scattering: CARS) microscopy, we monitor changes in protein folding states and nucleolar viscosity in real time, providing a window into the cell’s physical state from molecular to mesoscopic length scales. We aim to address two central questions: (WP1) How do condensate-like aggregates nucleate and grow within the nucleolus during drug-induced senescence? (WP2) How does the transition from liquid-like to solid-like condensates correlate with the onset of senescence, and to what extent can this process be reversed (rejuvenation)? By integrating experimental data with biophysical models – combining non-dilute protein aggregation kinetics with time-dependent rheological properties of phase-separated condensates – we seek to draw a direct link between protein condensation, cellular biophysics, and the senescence phenotype. Ultimately, this work aims to deepen our understanding of the physical underpinnings of senescence and lay the groundwork for future therapeutic strategies to modulate senescence and rejuvenation at the cellular level.

• DFG Programme: Research Grants
• International Connection: Japan
• Partner Organisation: Japan Society for the Promotion of Science (JSPS)
• Cooperation Partner: Ryo Suzuki, Ph.D.