Abstract
Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility.
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Acknowledgements
We sincerely thank the Division of Comparative Medicine team at the University of Oklahoma Health Sciences Center for their invaluable support in supervising animal care and sharing their extensive expertise. Special recognition is extended to Dr. Shawn Lane, DVM, for his invaluable guidance and expertise in surgical and postsurgical care. We are grateful to Dr. Wendy Williams, DVM, for her instrumental role in designing appropriate pre- and postsurgical treatments. We also acknowledge Ms. Carlye Yancey, BS, for her exceptional animal husbandry knowledge and contributions to parabiosis housing. Furthermore, we wish to express our gratitude to Mr. Chad Cunningham, Electronic & Instrument Shop Supervisor Building Manager of the University of Oklahoma’s Department of Physics and Engineering, for his essential assistance in fabricating the parabiont-adjusted components of the stereotactic frame, which was instrumental in facilitating simultaneous measurements of neurovascular coupling in parabionts. The 4.0 version of ChatGPT, developed by OpenAI, was used as a language tool to refine our writing, enhancing the clarity of our work.
Funding
This work was supported by grants from the American Heart Association (RG: 916225, ANT: AHA834339, and ST: AHA CDA941290), the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging (RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614, K01AG073613, R03AG070479), the National Institute of Neurological Disorders and Stroke (R01NS100782), the National Cancer Institute (R01CA255840), the Oklahoma Shared Clinical and Translational Resources (U54GM104938) with an Institutional Development Award (IDeA) from NIGMS, the Presbyterian Health Foundation, the Reynolds Foundation, the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (P20GM125528), the NCI Cancer Center Support Grant (P30 CA225520), and the Oklahoma Tobacco Settlement Endowment Trust. DMH is supported by P30AG038072. ANT was supported by TKP2021-NKTA-47, implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-NKTA funding scheme, and by funding through the National Cardiovascular Laboratory Program (RRF-2.3.1-21-2022-00003) provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund; Project no. 135784 implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the K20 funding scheme and the European University for Well-Being (EUniWell) program (grant agreement number: 101004093/ EUniWell/EAC-A02-2019 / EAC-A02-2019-1). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
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The study’s conception, design, and data interpretation involved contributions from all authors. Parabiosis surgeries were executed by RG and BC, while the post-surgical monitoring of animals was carried out by RG, BC, BP, JF, and SS. The assessment of blood-brain barrier permeability and microvascular density and subsequent data analysis were undertaken by RG, ANT, SN, and RP The initial draft of the manuscript was jointly composed by RG, ANT, ST, and ZU. Subsequent revisions to the manuscript were conducted by all authors, who also collectively reviewed and provided their approval for the final version of the manuscript.
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Dr. Anna Csiszar serves as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience. Dr. Stefano Tarantini, Dr. Adam Nyul-Toth, Dr. Shannon Conley, Dr. Peter Mukli, Dr. Derek M. Huffman, and Dr. Andriy Yabluchanskiy serve as Associate Editors for GeroScience.
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Gulej, R., Nyúl-Tóth, Á., Csik, B. et al. Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain. GeroScience (2024). https://doi.org/10.1007/s11357-024-01154-8
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DOI: https://doi.org/10.1007/s11357-024-01154-8