Microgravity Remodels Longevity Networks in Astronaut PBMCs: Integrated Findings of Telomere Elongation, DNA Repair Responses, and miRNA Suppression

Abstract

Microgravity provides a unique environment for elucidating the fundamental mechanisms of human aging. In the Microgravity Associated Genetics (MESSAGE) Science Mission, Turkiye\'s first human space biology experiment, we performed an integrative analysis of telomere dynamics, transcriptomic remodeling, and microRNA regulation in peripheral blood mononuclear cells (PBMCs) collected before launch (L-7day), after suborbital ascent (L+3hrs), and during days 4-10 aboard the International Space Station (ISS). Spaceflight induced a striking early elongation of telomeres, accompanied by transcriptional activation of DNA repair, oxidative stress mitigation, mitochondrial homeostasis, and immune regulatory pathways. Concurrently, microgravity triggered robust suppression of longevity-associated microRNAs, including members of the miR-17-92, miR29, and miR34 families, suggesting coordinated epigenetic reprogramming of genome stability and stress responses. Notably, the adaptor protein gene AP2A1, recently implicated in cellular rejuvenation and mechanotransductive aging processes, emerged as a consistently microgravity-responsive hub, linking cytoskeletal signaling to telomere maintenance and DNA repair networks. Together, these findings reveal that short-duration spaceflight initiates a multi-layered molecular longevity program in human immune cells, characterized by telomere extension, stabilization of genome maintenance pathways, and suppression of aging-associated miRNA regulators. This systems-level view provides foundational insight into how human biology adapts to short-term microgravity exposure and identifies AP2A1-centered networks as promising targets for enhancing astronaut health and performance and ultimately understanding terrestrial aging.