Cellular Senescence in the Absence of Galactic Cosmic-Ray Muons

Cellular senescence is a protective stress-response that halts cell proliferation to prevent the accumulation of damage. Life on Earth evolved in the presence of constant, low-dose, unavoidable genotoxic stress caused by highly penetrating muons generated by cosmic rays. However, how cosmic background radiation (CBR) shapes senescence remains unclear. We exploited the Canfranc Deep Underground Laboratory (LSC-DUL), which is located 850 meters beneath the Spanish Pyrenees, to compare senescence phenomena in near-surface versus muon-depleted deep underground environments. The LSC-DUL provides 2,450 meters of water-equivalent shielding, reducing the flux of cosmic-ray muons by five orders of magnitude. Human cancer and noncancer cells were subjected to replicative, mitotic, and oxidative insults with diverse DNA damage response (DDR) activation potencies. Muon deprivation modestly but significantly reduced progression to late, lysosome-dependent SA--gal-positive states after low-DDR replicative stressors. However, high-DDR regimens were largely insensitive to the environment. Transcriptomic signatures of senescent states and the qualitative composition of senescence-associated secretory phenotypes (SASPs) were broadly conserved. Conceptually, stressed cells enter a shallow transcriptional and SASP-positive senescent basin that is permissive across CBR conditions. However, they cross a “CBR barrier” into a deeper SA--gal+ attractor less efficiently when ambient radiogenic noise is depleted and DDR amplitude is low. The robust inertia of high DDR damage readily overrides this barrier, ensuring the immediate occupation of the SA--gal+ fate regardless of the muonic environment. Our findings identify cosmogenic muons as evolutionary radiobiological calibrators of senescence decision-making in the near-surface biosphere. They also generate testable predictions for senescence operability in habitats lacking Earth’s characteristic muon flux, such as the Moon and Mars.