Aging in orbit: The twelve hallmarks as a bidirectional bridge between spaceflight-induced senescence and terrestrial...

Human spaceflight exposes crew members to a combination of environmental stressors - including microgravity, galactic cosmic radiation, circadian disruption, and prolonged confinement - that together induce multisystem physiological changes resembling terrestrial aging. In this narrative review, we examine how short- and medium-term spaceflight affects all twelve recognized hallmarks of aging. Integrated multi-omics analyses in astronauts and rodent models identified mitochondrial dysfunction as a central node of spaceflight biology, with oxidative damage propagating genomic instability, cellular senescence, and chronic inflammation. At the chromosomal level, telomere dynamics were characterized by a paradoxical elongation-shortening cycle that may compress years of terrestrial attrition into months. In parallel, epigenetic clock analyses showed a ∼1.9-year biological age acceleration in astronauts after a 9-day orbital mission, with hierarchical post-flight recovery (reversible transcriptomic and epigenomic shifts versus persistent chromosomal inversions and clonal hematopoiesis mutations). This partial reversibility distinguishes the spaceflight paradigm from the largely unidirectional trajectory of chronological aging. We conclude that the relationship between spaceflight biology and terrestrial geroscience is bidirectional. Aging research on Earth provides the interpretive framework that renders astronaut molecular data biologically meaningful, and spaceflight offers geroscience a compressed, partially reversible aging-like phenotype in healthy young subjects that has no direct terrestrial counterpart. The observation that space radiation induces qualitatively distinct senescent phenotypes amenable to senolytic clearance supports a translational framework in which geroprotective strategies may simultaneously serve astronaut health and promote healthy longevity in the broader aging population.