Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure. Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden. Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight. Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.

Impaired Cognitive Performance in Mice Exposed to Prolonged Hyperoxia.

Supplementation of oxygen at concentrations significantly above environmental level for prolonged periods may lead to hyperoxia and tissue toxicity. The mammalian brain undergoes structural and functional changes during adaptation to hypoxia and hyperoxia. In this study we investigated the effect of prolonged hyperoxic exposure on cognitive and motor performance in mice. Two-month-old male mice were placed in either hyperoxic (50% O2) or normoxic conditions for 3 weeks. Cognitive function was measured using the Y-maze test. High alteration rate between the three arms of the maze is indicative of sustained memory and cognitive function. Motor function was measured using the grip strength and rotarod tests. In the rotarod test high speed and long latency are indicative of coordination and resistance. After 3 weeks of exposure, hematocrit levels were significantly decreased in the hyperoxia group compared to normoxic control littermates (%, mean ± SD, 37.8 ± 1.3, n = 15 vs. 49.9 ± 5.1, n = 15, p < 0.05). In the Y-maze test, chronic hyperoxic exposure resulted in a statistically significant decrease in alteration rate compared to normoxic control (%, mean ± SD, 53.4 ± 9.9, n = 30 vs. 61.2 ± 9.5, n = 15, p < 0.05). The rotarod and grip strength tests did not show statistically significant changes between the two groups. Our data suggest that chronic hyperoxia may lead to decreased cognitive performance in adult mice, which may be secondary to structural and functional changes in the brain.

Pan-cancer analysis reveals molecular patterns associated with age.

Older age is a strong risk factor for several diseases, including cancer. The etiology and biology of age-associated differences among cancers are poorly understood. To address this knowledge gap, we aim to delineate differences in tumor molecular characteristics between younger and older patients across a variety of tumor types from The Cancer Genome Atlas. We show that these groups exhibit widespread molecular differences in select tumor types. Our work shows that tumors in younger individuals exhibit a dysregulated molecular aging phenotype and are associated with hallmarks of premature senescence. Additionally, we find that these tumors are enriched for driver gene mutations, resulting in homologous recombination defects. Lastly, we observe a trend toward decreased immune infiltration and function in older patients and find that, immunologically, young tumor tissue resembles aged healthy tissue. Taken together, we find that tumors from young individuals possess unique characteristics that may be leveraged for therapy.