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Rejuvenation of cerebromicrovascular function in aged mice through heterochronic parabiosis: insights into neurovascular coupling and the impact of young blood factors

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Abstract

Age-related impairment of neurovascular coupling (NVC; “functional hyperemia”) is a critical factor in the development of vascular cognitive impairment (VCI). Recent geroscience research indicates that cell-autonomous mechanisms alone cannot explain all aspects of neurovascular aging. Circulating factors derived from other organs, including pro-geronic factors (increased with age and detrimental to vascular homeostasis) and anti-geronic factors (preventing cellular aging phenotypes and declining with age), are thought to orchestrate cellular aging processes. This study aimed to investigate the influence of age-related changes in circulating factors on neurovascular aging. Heterochronic parabiosis was utilized to assess how exposure to young or old systemic environments could modulate neurovascular aging. Results demonstrated a significant decline in NVC responses in aged mice subjected to isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis) when compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, exposure to young blood from parabionts significantly improved NVC in aged heterochronic parabionts [A-(Y)]. Conversely, young mice exposed to old blood from aged parabionts exhibited impaired NVC responses [Y-(A)]. In conclusion, even a brief exposure to a youthful humoral environment can mitigate neurovascular aging phenotypes, rejuvenating NVC responses. Conversely, short-term exposure to an aged humoral milieu in young mice accelerates the acquisition of neurovascular aging traits. These findings highlight the plasticity of neurovascular aging and suggest the presence of circulating anti-geronic factors capable of rejuvenating the aging cerebral microcirculation. Further research is needed to explore whether young blood factors can extend their rejuvenating effects to address other age-related cerebromicrovascular pathologies, such as blood–brain barrier integrity.

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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.

Funding

This work was supported by grants from the American Heart Association (R.G.: 916225, ANT: AHA834339, and S.T.: 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), and the Cellular and Molecular GeroScience CoBRE (P20GM125528), the NCI Cancer Center Support Grant (P30 CA225520) and the Oklahoma Tobacco Settlement Endowment Trust. ANT was supported by Project no. DMH is supported by P30AG038072. 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; 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 K_20 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the American Heart Association, or the Presbyterian Health Foundation. The 3.5 version of ChatGPT, developed by OpenAI, was used as a language tool to refine our writing, enhancing the clarity of our work.

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Author notes

  1. Rafal Gulej and Ádám Nyúl-Tóth equal contribution.

Authors and Affiliations

  1. Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Rafal Gulej, Ádám Nyúl-Tóth, Boglarka Csik, Benjamin Petersen, Janet Faakye, Sharon Negri, Siva Sai Chandragiri, Peter Mukli, Andriy Yabluchanskiy, Anna Csiszar, Stefano Tarantini & Zoltan Ungvari

  2. Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Rafal Gulej, Ádám Nyúl-Tóth, Boglarka Csik, Benjamin Petersen, Janet Faakye, Sharon Negri, Siva Sai Chandragiri, Peter Mukli, Andriy Yabluchanskiy, Shannon Conley, Anna Csiszar, Stefano Tarantini & Zoltan Ungvari

  3. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Ádám Nyúl-Tóth, Boglarka Csik, Peter Mukli, Andriy Yabluchanskiy, Stefano Tarantini & Zoltan Ungvari

  4. Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA

    Andriy Yabluchanskiy, Anna Csiszar, Stefano Tarantini & Zoltan Ungvari

  5. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Shannon Conley

  6. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    Derek M. Huffman

  7. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    Derek M. Huffman

  8. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary

    Anna Csiszar

Authors
  1. Rafal Gulej
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  2. Ádám Nyúl-Tóth
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  3. Boglarka Csik
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  4. Benjamin Petersen
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  14. Zoltan Ungvari
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Contributions

The study’s conception, design, and data interpretation involved contributions from all authors. Parabiosis surgeries were executed by R.G. and B.Cs., while the post-surgical monitoring of animals was carried out by R.G., B.C., B.P., J.F., and S.S. The assessment of neurovascular coupling responses and subsequent data analysis were undertaken by R.G., ANT, S.N., and P.T. The initial draft of the manuscript was jointly composed by R.G., ANT, S.T., and Z.U. 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.

Corresponding author

Correspondence to Zoltan Ungvari.

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Competing interests

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. 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. Rejuvenation of cerebromicrovascular function in aged mice through heterochronic parabiosis: insights into neurovascular coupling and the impact of young blood factors. GeroScience 46, 327–347 (2024). https://doi.org/10.1007/s11357-023-01039-2

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