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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The evolutionary theory of aging demonstrates that the force of natural selection declines with age in multicellular organisms. Two population genetic mechanisms are consistent with the evolutionary theory: mutation accumulation and antagonistic pleiotropy. These in turn account for the physiological, cellular, and molecular mechanisms associated with aging. Spaceflight provides an opportunity to examine how organisms physiologically acclimate to environmental conditions. Mitochondria and the gut microbiome are central regulators of host metabolism, redox homeostasis, immune function, and physiological resilience, and both are impacted by host adaptations and acclimations. Mitochondrial dysfunction and oxidative stress have consequently emerged as important candidate mechanisms linking biological aging and spaceflight-associated physiological change. This review examines evidence surrounding mitochondrial dysfunction, oxidative stress, and gut microbiome dysbiosis across humans, mice, and fruit flies under spaceflight and corresponding terrestrial control conditions. This review reports further on the progression of theory and recent evidence from spaceflight missions for how biomarker genes most associated with mutation accumulation and antagonistic pleiotropy appear to have a core role in natural aging and extreme physiological acclimation.<\/jats:p>","DOI":"10.3390\/ijms27177644","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:59:23Z","timestamp":1787741963000},"page":"7644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aging in Spaceflight, Oxidative Stress, and Microbiome Dysbiosis: A Comprehensive Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5036-084X","authenticated-orcid":false,"given":"Charles C.","family":"Naney","sequence":"first","affiliation":[{"name":"Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC 27411, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8446-1709","authenticated-orcid":false,"suffix":"Jr.","given":"Joseph L.","family":"Graves","sequence":"additional","affiliation":[{"name":"Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC 27411, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9577-445X","authenticated-orcid":false,"given":"Scott H.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC 27411, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e14315","DOI":"10.1111\/acel.14315","article-title":"The connection between aging, cellular senescence and gut microbiome alterations: A comprehensive review","volume":"23","author":"Jang","year":"2024","journal-title":"Aging Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e70777","DOI":"10.1096\/fj.202402989R","article-title":"Aging and altered gravity: A cellular perspective","volume":"39","year":"2025","journal-title":"FASEB J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"D1697","DOI":"10.1093\/nar\/gkae1116","article-title":"NASA open science data repository: Open Science for Life in Space","volume":"53","author":"Gebre","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eaau8650","DOI":"10.1126\/science.aau8650","article-title":"The NASA twins study: A multidimensional analysis of a year-long human spaceflight","volume":"364","author":"Darshi","year":"2019","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102361","DOI":"10.1016\/j.isci.2021.102361","article-title":"NASA GeneLab RNA-Seq consensus pipeline: Standardized processing of short-read RNA-Seq data","volume":"24","author":"Overbey","year":"2021","journal-title":"iScience"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100325","DOI":"10.1016\/j.crmeth.2022.100325","article-title":"Challenges and considerations for single-cell and spatially resolved transcriptomics sample collection during spaceflight","volume":"2","author":"Overbey","year":"2022","journal-title":"Cell Rep. Methods"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4964","DOI":"10.1038\/s41467-024-48806-z","article-title":"Collection of biospecimens from the Inspiration4 mission establishes the standards for the Space Omics and Medical Atlas (SOMA)","volume":"15","author":"Overbey","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1038\/s41586-024-07639-y","article-title":"The Space Omics and Medical Atlas (SOMA) and International Astronaut Biobank","volume":"632","author":"Overbey","year":"2024","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Guarnieri, J.W., Maghsoudi, Z., Kim, J., Bya, P., Widjaja, G.A., Barker, R., Burke, M., Cen, Z., Fazelinia, H., and Tsoy, S. (2025). Guardians of the nitochondria: Space Mitochondria 2.0 systemic analysis reveals bioenergetic dysregulation across species. SSRN.","DOI":"10.2139\/ssrn.5087025"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R1177","DOI":"10.1016\/j.cub.2017.09.015","article-title":"The origin and diversification of mitochondria","volume":"27","author":"Roger","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.jtbi.2017.04.031","article-title":"Serial endosymbiosis or singular event at the origin of eukaryotes?","volume":"434","author":"Lane","year":"2017","journal-title":"J. Theor. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Michal, G., and Schomburg, D. (2013). Biochemical Pathways: An Atlas of Biochemistry and Molecular Biology, Wiley. [2nd ed.].","DOI":"10.1002\/9781118657072"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/geronj\/11.3.298","article-title":"Aging: A theory based on free radical and radiation chemistry","volume":"11","author":"Harman","year":"1956","journal-title":"J. Gerontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1172\/JCI64125","article-title":"The role of mitochondria in aging","volume":"123","author":"Bratic","year":"2013","journal-title":"J. Clin. Invest."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"757","DOI":"10.2147\/CIA.S158513","article-title":"Oxidative stress, aging, and diseases","volume":"13","author":"Liguori","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1089\/ars.2017.7105","article-title":"A tale of two concepts: Harmonizing the free Radical and Antagonistic Pleiotropy Theories of Aging","volume":"29","author":"Golubev","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"103191","DOI":"10.1016\/j.arr.2026.103191","article-title":"Aging in orbit: The Twelve Hallmarks as a Bidirectional Bridge between Spaceflight-Induced Senescence and Terrestrial Geroscience","volume":"119","author":"Minoretti","year":"2026","journal-title":"Ageing Res. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Takahashi, K., Okumura, H., Guo, R., and Naruse, K. (2017). Effect of Oxidative Stress on Cardiovascular System in Response to Gravity. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071426"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13098","DOI":"10.1038\/s41598-024-57948-5","article-title":"Aging and Putative Frailty Biomarkers Are Altered by Spaceflight","volume":"14","author":"Camera","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103398","DOI":"10.1016\/j.redox.2024.103398","article-title":"Metabolic stress in space: ROS-induced mutations in mice hint at a new path to cancer","volume":"78","author":"Stolc","year":"2024","journal-title":"Redox Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chen, Z., Xie, J., Ma, C., Zhang, P., and Lei, X. (2025). Oxidative damage under microgravity conditions: Response Mechanisms, Monitoring Methods and Countermeasures on Somatic and Germ Cells. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26104583"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"ElGindi, M., Sapudom, J., Ibrahim, I.H., Al-Sayegh, M., Chen, W., Garcia-Sabat\u00e9, A., and Teo, J.C.M. (2021). May the force be with you (or not): The immune system under microgravity. Cells, 10.","DOI":"10.3390\/cells10081941"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s40168-019-0724-4","article-title":"Reproducible changes in the gut microbiome suggest a shift in microbial and host metabolism during spaceflight","volume":"7","author":"Jiang","year":"2019","journal-title":"Microbiome"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1016\/j.csbj.2021.03.040","article-title":"Reanalysis of the Mars500 experiment reveals common gut microbiome alterations in astronauts induced by long-duration confinement","volume":"19","author":"Brereton","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Barrila, J., Yang, J., Franco Mel\u00e9ndez, K.P., Yang, S., Buss, K., Davis, T.J., Aronow, B.J., Bean, H.D., Davis, R.R., and Forsyth, R.J. (2022). Spaceflight analogue culture enhances the host-pathogen interaction between salmonella and a 3-D biomimetic intestinal co-culture model. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.705647"},{"key":"ref_28","first-page":"171","article-title":"Gut permeability among astronauts during space missions","volume":"41","author":"Akinsuyi","year":"2024","journal-title":"Life Sci. Space Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41564-021-01015-6","article-title":"A vision for spaceflight microbiology to enable human health and habitat sustainability","volume":"7","author":"Nickerson","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e00144-23","DOI":"10.1128\/mmbr.00144-23","article-title":"Microbiology of human spaceflight: Microbial responses to mechanical forces that impact health and habitat sustainability","volume":"88","author":"Nickerson","year":"2024","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"990","DOI":"10.4103\/NRR.NRR-D-23-01776","article-title":"Gut microbiota\u2013astrocyte axis: New insights into age-related cognitive decline","volume":"20","author":"Zhang","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41526-025-00490-z","article-title":"Feeding the cosmos: Tackling personalized space nutrition and the leaky gut challenge","volume":"11","author":"Rivero","year":"2025","journal-title":"npj Microgravity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3357\/ASEM.2276.2008","article-title":"immune system dysregulation following short- vs long-duration spaceflight","volume":"79","author":"Crucian","year":"2008","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1667\/RR3100.1","article-title":"Age and space irradiation modulate tumor progression: Implications for carcinogenesis risk","volume":"179","author":"Beheshti","year":"2013","journal-title":"Radiat. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1667\/RR13538.1","article-title":"Proton irradiation augments the suppression of tumor progression observed with advanced age","volume":"181","author":"Beheshti","year":"2014","journal-title":"Radiat. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1158\/0008-5472.CAN-14-1053","article-title":"host age is a systemic regulator of gene expression impacting cancer progression","volume":"75","author":"Beheshti","year":"2015","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.4137\/CIN.S34144","article-title":"The impact of age and sex in DLBCL: Systems biology analyses identify distinct molecular changes and signaling networks","volume":"14","author":"Beheshti","year":"2015","journal-title":"Cancer Inform."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35419","DOI":"10.18632\/oncotarget.6214","article-title":"Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development","volume":"6","author":"Beheshti","year":"2015","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4191","DOI":"10.1038\/s41598-018-22613-1","article-title":"Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: A systems biology GeneLab case study","volume":"8","author":"Beheshti","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1667\/RR15062.1","article-title":"NASA GeneLab project: Bridging space radiation omics with ground studies","volume":"189","author":"Beheshti","year":"2018","journal-title":"Radiat. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Beheshti, A., Ray, S., Fogle, H., Berrios, D., and Costes, S.V. (2018). A microRNA signature and TGF-\u03b21 response were identified as the key master regulators for spaceflight response. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199621"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"19195","DOI":"10.1038\/s41598-019-55869-2","article-title":"Multi-omics analysis of multiple missions to space reveal a theme of lipid dysregulation in mouse liver","volume":"9","author":"Beheshti","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Beheshti, A., McDonald, J.T., Miller, J., Grabham, P., and Costes, S.V. (2019). GeneLab database analyses suggest long-term impact of space radiation on the cardiovascular system by the activation of FYN through reactive oxygen species. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030661"},{"key":"ref_44","first-page":"58447","article-title":"Exploring the effects of spaceflight on mouse physiology using the open access NASA GeneLab platform","volume":"147","author":"Beheshti","year":"2019","journal-title":"J. Vis. Exp."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Beheshti, A., McDonald, J.T., Hada, M., Takahashi, A., Mason, C.E., and Mognato, M. (2021). genomic changes driven by radiation-induced DNA damage and microgravity in human cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910507"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9884","DOI":"10.1038\/s41598-019-49453-x","article-title":"Spaceflight influences gene expression, photoreceptor integrity, and oxidative stress-related damage in the murine retina","volume":"9","author":"Overbey","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Overbey, E.G., Paul, A.M., da Silveira, W.A., Tahimic, C.G.T., Reinsch, S.S., Szewczyk, N., Stanbouly, S., Wang, C., Galazka, J.M., and Mao, X.W. (2019). Mice exposed to combined chronic low-dose irradiation and modeled microgravity develop long-term neurological sequelae. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174094"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Li, Q., and Hoppe, T. (2023). Role of amino acid metabolism in mitochondrial homeostasis. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1127618"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/S1672-0229(08)60004-2","article-title":"Reconstruction of pathways associated with amino acid metabolism in human mitochondria","volume":"5","author":"Guda","year":"2007","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-1-4939-6824-4_2","article-title":"Isolation of functional mitochondria from cultured cells and mouse tissues","volume":"Volume 1567","author":"Mokranjac","year":"2017","journal-title":"Mitochondria"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1214012","article-title":"The costs of breathing","volume":"334","author":"Lane","year":"2011","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1152\/physrev.00018.2001","article-title":"Free radicals in the physiological control of cell function","volume":"82","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/ng1448","article-title":"Lifespan and mitochondrial control of neurodegeneration","volume":"36","author":"Wright","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1093\/brain\/awae007","article-title":"Huntington\u2019s disease affects mitochondrial network dynamics predisposing to pathogenic mitochondrial dna mutations","volume":"147","author":"Neueder","year":"2024","journal-title":"Brain"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1111\/j.1558-5646.1984.tb00370.x","article-title":"Laboratory evolution of postponed senescence in Drosophila melanogaster","volume":"38","author":"Rose","year":"1984","journal-title":"Evolution"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1111\/j.1558-5646.1984.tb00369.x","article-title":"Selection for delayed senescence in Drosophila melanogaster","volume":"38","author":"Luckinbill","year":"1984","journal-title":"Evolution"},{"key":"ref_57","first-page":"268","article-title":"Desiccation, flight, glycogen, and postponed senescence in Drosophila melanogaster","volume":"65","author":"Graves","year":"1992","journal-title":"Physiol. Biochem. Zool."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S0959-437X(96)80016-5","article-title":"Genetic analysis of mechanisms of aging","volume":"6","author":"Rose","year":"1996","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_59","unstructured":"Dani, S.U., Hori, A., and Walter, G.F. (1997). General Theories of Aging: Unification and Synthesis. Principles of Neural Aging, Elsevier."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/s43587-021-00051-5","article-title":"Common genetic associations between age-related diseases","volume":"1","author":"Fabian","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_61","first-page":"346","article-title":"Can Ageing Be Slowed?: Hormetic and redox perspectives","volume":"4","author":"Gaman","year":"2011","journal-title":"J. Med. Life"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrm3801","article-title":"Cellular mechanisms and physiological consequences of redox-dependent signalling","volume":"15","author":"Finkel","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kagan, V.E., and Quinn, P.J. (2001). Coenzyme Q: Molecular Mechanisms in Health and Disease, CRC Press.","DOI":"10.1201\/9781420036701"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41392-024-02095-6","article-title":"Redox regulation: Mechanisms, biology and therapeutic targets in diseases","volume":"10","author":"Li","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.freeradbiomed.2025.06.033","article-title":"A chance insight into phosgene toxicity","volume":"238","author":"Daplan","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_66","first-page":"63","article-title":"The Great Evolutionary Divide: Two Genomic Systems Biologies of Aging","volume":"Volume 40","author":"Yashin","year":"2015","journal-title":"Interdisciplinary Topics in Gerontology and Geriatrics"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"20313","DOI":"10.1074\/jbc.272.33.20313","article-title":"Protein oxidation in aging, disease, and oxidative stress","volume":"272","author":"Berlett","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_68","unstructured":"Lane, N. (2003). Oxygen: The Molecule That Made the World, Oxford University Press. Popular Science Series."},{"key":"ref_69","unstructured":"Lane, N. (2005). Power, Sex, Suicide: Mitochondria and the Meaning of Life, Oxford University Press. Oxford Landmark Science Series."},{"key":"ref_70","unstructured":"Lane, N. (2016). The Vital Question: Energy, Evolution, and the Origins of Complex Life, W.W. Norton and Company."},{"key":"ref_71","unstructured":"Lane, N. (2022). Transformer, W.W. Norton & Company."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s40168-022-01279-y","article-title":"Metabolic modeling of the international space station microbiome reveals key microbial interactions","volume":"10","author":"Kumar","year":"2022","journal-title":"Microbiome"},{"key":"ref_73","first-page":"5","article-title":"Current status of the prebiotic synthesis of small molecules","volume":"26B","author":"Miller","year":"1986","journal-title":"Chem. Scr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/421583a","article-title":"Chemiosmotic coupling: The cost of living","volume":"421","author":"Rich","year":"2003","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1042\/BIO03705047","article-title":"Classic Papers on the Quantification of Respiratory Proton Ejection","volume":"37","author":"West","year":"2015","journal-title":"Biochemist"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.cell.2015.10.001","article-title":"Mitochondrial ROS signaling in organismal homeostasis","volume":"163","author":"Shadel","year":"2015","journal-title":"Cell"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Strollo, F., Gentile, S., Strollo, G., Mambro, A., and Vernikos, J. (2018). Recent progress in space physiology and aging. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.01551"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Sun, Y., Wang, X., Li, L., Zhong, C., Zhang, Y., Yang, X., Li, M., and Yang, C. (2024). The role of gut microbiota in intestinal disease: From an oxidative stress perspective. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1328324"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.molcel.2012.09.025","article-title":"Physiological roles of mitochondrial reactive oxygen species","volume":"48","author":"Sena","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Pavlakou, P., Dounousi, E., Roumeliotis, S., Eleftheriadis, T., and Liakopoulos, V. (2018). Oxidative stress and the kidney in the space environment. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103176"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Buchheim, J.-I., Matzel, S., Rykova, M., Vassilieva, G., Ponomarev, S., Nichiporuk, I., H\u00f6rl, M., Moser, D., Biere, K., and Feuerecker, M. (2019). Stress related shift toward inflammaging in cosmonauts after long-duration space flight. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00085"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Pantha, N., Ramasubramanian, M., Gurung, I., Maskey, M., Sanders, L.M., Casaletto, J., and Costes, S.V. (2024). Feature selection in high-dimensional space with applications to gene expression data. Proceedings of the SoutheastCon 2024, IEEE.","DOI":"10.1109\/SoutheastCon52093.2024.10500057"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/s12602-021-09903-3","article-title":"Emerging interrelationship between the gut microbiome and cellular senescence in the context of aging and disease: Perspectives and therapeutic opportunities","volume":"14","author":"Sharma","year":"2022","journal-title":"Probiotics Antimicrob. Proteins"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41526-021-00136-w","article-title":"Evaluating the effect of spaceflight on the host\u2013pathogen interaction between human intestinal epithelial cells and Salmonella Typhimurium","volume":"7","author":"Barrila","year":"2021","journal-title":"npj Microgravity"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/j.cub.2016.04.016","article-title":"Gut microbiota and extreme longevity","volume":"26","author":"Biagi","year":"2016","journal-title":"Curr. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/nature25973","article-title":"Environment dominates over host genetics in shaping human gut microbiota","volume":"555","author":"Rothschild","year":"2018","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Krishnamurthy, H.K., Pereira, M., Bosco, J., George, J., Jayaraman, V., Krishna, K., Wang, T., Bei, K., and Rajasekaran, J.J. (2023). Gut commensals and their metabolites in health and disease. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1244293"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e00585-24","DOI":"10.1128\/msystems.00585-24","article-title":"Impact of urbanization on gut microbiome mosaics across geographic and dietary contexts","volume":"9","author":"Vinogradova","year":"2024","journal-title":"mSystems"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1096\/fj.11-197921","article-title":"Intestinal microbiota determine severity of myocardial infarction in rats","volume":"26","author":"Lam","year":"2012","journal-title":"FASEB J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1053\/j.gastro.2009.08.042","article-title":"High-fat diet determines the composition of the murine gut microbiome independently of obesity","volume":"137","author":"Hildebrandt","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1038\/s41598-020-58898-4","article-title":"Validation of a new rodent experimental system to investigate consequences of long duration space habitation","volume":"10","author":"Choi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"100148","DOI":"10.1016\/j.patter.2020.100148","article-title":"A new era for space life science: International standards for space omics processing","volume":"1","author":"Rutter","year":"2020","journal-title":"Patterns"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"111982","DOI":"10.1016\/j.celrep.2022.111982","article-title":"Defining the age-dependent and tissue-specific circadian transcriptome in male mice","volume":"42","author":"Wolff","year":"2023","journal-title":"Cell Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2359677","DOI":"10.1080\/19490976.2024.2359677","article-title":"The human gut microbiome and aging","volume":"16","author":"Bradley","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41522-025-00657-2","article-title":"Molecules-mediated bidirectional interactions between microbes and human cells","volume":"11","author":"Wu","year":"2025","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Lian, W.-S., Wu, R.-W., Lin, Y.-H., Chen, Y.-S., Jahr, H., and Wang, F.-S. (2024). Tricarboxylic acid cycle regulation of metabolic program, redox system, and epigenetic remodeling for bone health and disease. Antioxidants, 13.","DOI":"10.3390\/antiox13040470"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41526-025-00492-x","article-title":"Space-Driven ROS in Cells: A hidden danger to astronaut health and food safety","volume":"11","author":"Mokhtari","year":"2025","journal-title":"npj Microgravity"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Turroni, S., Magnani, M., Kc, P., Lesnik, P., Vidal, H., and Heer, M. (2020). Gut microbiome and space travelers\u2019 health: State of the art and possible pro\/prebiotic strategies for long-term space missions. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.553929"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1080\/09637486.2019.1580682","article-title":"The Human-microbiome superorganism and its modulation to restore health","volume":"70","author":"Salvucci","year":"2019","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"9911","DOI":"10.1038\/s41598-019-46303-8","article-title":"Study of the impact of long-duration space missions at the international space station on the astronaut microbiome","volume":"9","author":"Voorhies","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00394-017-1445-8","article-title":"Gut microbiota functions: Metabolism of nutrients and other food components","volume":"57","author":"Rowland","year":"2018","journal-title":"Eur. J. Nutr."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1007\/s10875-012-9824-7","article-title":"Immune system dysregulation occurs during short duration spaceflight on board the space shuttle","volume":"33","author":"Crucian","year":"2013","journal-title":"J. Clin. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"15013","DOI":"10.1038\/npjmgrav.2015.13","article-title":"Alterations in adaptive immunity persist during long-duration spaceflight","volume":"1","author":"Crucian","year":"2015","journal-title":"npj Microgravity"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41522-024-00545-1","article-title":"Spaceflight alters host-gut microbiota interactions","volume":"10","author":"Gonzalez","year":"2024","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e13700","DOI":"10.1111\/acel.13700","article-title":"A Gut-centric view of aging: Do intestinal epithelial cells contribute to age-associated microbiota changes, inflammaging, and immunosenescence?","volume":"21","author":"Hohman","year":"2022","journal-title":"Aging Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41593-022-01027-3","article-title":"Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine","volume":"25","author":"Mossad","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/nm.4185","article-title":"Signals from the gut microbiota to distant organs in physiology and disease","volume":"22","author":"Schroeder","year":"2016","journal-title":"Nat. Med."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Tian, Y., Ma, X., Yang, C., Su, P., Yin, C., and Qian, A.-R. (2017). The impact of oxidative stress on the bone system in response to the space special environment. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102132"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"105213","DOI":"10.1016\/j.isci.2022.105213","article-title":"Muscle atrophy phenotype gene expression during spaceflight is linked to a metabolic crosstalk in both the liver and the muscle in mice","volume":"25","author":"Vitry","year":"2022","journal-title":"iScience"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41584-022-00905-1","article-title":"Inflammation and DNA damage: Cause, effect or both","volume":"19","author":"Pezone","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Pinte\u00f1o, A., Pilla, R., Manteca, X., Suchodolski, J., Torre, C., and Salas-Mani, A. (2023). Age-associated changes in intestinal health biomarkers in dogs. Front. Vet. Sci., 10.","DOI":"10.3389\/fvets.2023.1213287"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Blaber, E., Pecaut, M., and Jonscher, K. (2017). Spaceflight activates autophagy programs and the proteasome in mouse liver. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102062"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1091\/mbc.E18-07-0434","article-title":"Dysfunctional peroxisomes compromise gut structure and host defense by increased cell death and tor-dependent autophagy","volume":"29","author":"Simmonds","year":"2018","journal-title":"Mol. Biol. Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1089\/ars.2009.2637","article-title":"Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases","volume":"11","author":"Leto","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1159\/000252852","article-title":"Space, gravity and the physiology of aging: Parallel or convergent disciplines? A nini-review","volume":"56","author":"Vernikos","year":"2010","journal-title":"Gerontology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1038\/s41564-024-01635-8","article-title":"Longitudinal multi-omics analysis of host microbiome architecture and immune responses during short-term spaceflight","volume":"9","author":"Tierney","year":"2024","journal-title":"Nat. Microbiol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1532-5415.1972.tb00787.x","article-title":"The biologic clock: The mitochondria?","volume":"20","author":"Harman","year":"1972","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1093\/gerona\/glx042","article-title":"Biological aging and the human gut microbiota","volume":"72","author":"Maffei","year":"2017","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"881","DOI":"10.3390\/metabo3040881","article-title":"Transcriptomics and metabonomics identify essential metabolic signatures in calorie restriction (CR) regulation across multiple mouse strains","volume":"3","author":"Collino","year":"2013","journal-title":"Metabolites"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Ball, H.C., levari-Shariati, S., Cooper, L.N., and Aliani, M. (2018). Comparative metabolomics of aging in a long-lived bat: Insights into the physiology of extreme longevity. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0196154"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Florian, J.P., Baisch, F.J., Heer, M., and Pawelczyk, J.A. (2015). Caloric restriction decreases orthostatic tolerance independently from 6\u00b0 head-down bedrest. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118812"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.1210\/en.2005-0378","article-title":"Minireview: The role of oxidative stress in relation to caloric restriction and longevity","volume":"146","author":"Gredilla","year":"2005","journal-title":"Endocrinology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1038\/s42255-025-01297-8","article-title":"Cysteine depletion triggers adipose tissue thermogenesis and weight-loss","volume":"7","author":"Lee","year":"2025","journal-title":"Nat. Metab."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF02071591","article-title":"A qualitative analysis of some life-history correlates of longevity in Drosophila melanogaster","volume":"2","author":"Luckinbill","year":"1988","journal-title":"Evol. Ecol."},{"key":"ref_125","unstructured":"Rose, M.R. (2005). The Long Tomorrow: How Advances in Evolutionary Biology Can Help Us Postpone Aging, Oxford University Press."},{"key":"ref_126","unstructured":"Kirkwood, T. (2001). Time of Our Lives: The Science of Human Aging, Oxford University Press."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1086\/367983","article-title":"The naturalist in a world of genomics","volume":"161","author":"Stearns","year":"2003","journal-title":"Am. Nat."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s43587-025-01016-8","article-title":"Organ-specific proteomic aging clocks predict disease and longevity across diverse populations","volume":"6","author":"Wang","year":"2026","journal-title":"Nat. Aging"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1016\/j.cell.2020.11.002","article-title":"Comprehensive multi-omics analysis reveals mitochondrial stress as a central biological hub for spaceflight impact","volume":"183","author":"Fazelinia","year":"2020","journal-title":"Cell"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1098\/rstb.1991.0028","article-title":"Evolution of senescence: Late survival sacrificed for reproduction","volume":"332","author":"Kirkwood","year":"1991","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Arnold, K.R., and Rose, M.R. (2023). Conceptual Breakthroughs in the Evolutionary Biology of Aging, Academic Press.","DOI":"10.1016\/B978-0-12-821545-6.00040-6"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0167-4943(93)90023-B","article-title":"Prospective and retrospective tests of evolutionary theories of senescence","volume":"16","author":"Luckinbill","year":"1993","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Rose, M.R., Passananti, H.B., and Matos, M. (2004). Methuselah Flies: A Case Study in the Evolution of Aging, World Scientific.","DOI":"10.1142\/9789812567222"},{"key":"ref_134","first-page":"54","article-title":"Genomics of parallel experimental evolution in Drosophila","volume":"34","author":"Graves","year":"2017","journal-title":"Mol. Biol. Evol."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Rose, M.R., Lenski, R., Matos, M., and Graves, J.L. (2026). A Primer for Experimental Evolution, World Scientific.","DOI":"10.1142\/14651"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"20250026","DOI":"10.1098\/rsfs.2025.0026","article-title":"Evolution in space: Experimental pathways to understanding life\u2019s adaptability beyond earth","volume":"15","author":"Sadier","year":"2025","journal-title":"Interface Focus"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41526-022-00205-8","article-title":"Adaptation to simulated microgravity in Streptococcus mutans","volume":"8","author":"Fernander","year":"2022","journal-title":"npj Microgravity"},{"key":"ref_138","unstructured":"de Grey, A.D.N.J. (1999). The Mitochondrial Free Radical Theory of Aging, R.G. Landes. Molecular biology intelligence unit."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1080\/14728222.2024.2330425","article-title":"Combining rejuvenation interventions in rodents: A milestone in biomedical gerontology whose time has come","volume":"28","author":"Lewis","year":"2024","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Crucian, B.E., Chouk\u00e8r, A., Simpson, R.J., Mehta, S., Marshall, G., Smith, S.M., Zwart, S.R., Heer, M., Ponomarev, S., and Whitmire, A. (2018). immune system dysregulation during spaceflight: Potential countermeasures for deep space exploration missions. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01437"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7644\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T11:00:56Z","timestamp":1787742056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":140,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177644"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177644","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]}}}