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Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood

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Abstract

Aging-induced functional and phenotypic alterations of the vasculature (e.g., endothelial dysfunction, oxidative stress) have a central role in morbidity and mortality of older adults. It has become apparent in recent years that cell autonomous mechanisms alone are inadequate to explain all aspects of vascular aging. The present study was designed to test the hypothesis that age-related changes in circulating anti-geronic factors contribute to the regulation of vascular aging processes in a non-cell autonomous manner. To test this hypothesis, through heterochronic parabiosis we determined the extent, if any, to which endothelial function, vascular production of ROS, and shifts in the vascular transcriptome (RNA-seq) are modulated by the systemic environment. We found that in aortas isolated from isochronic parabiont aged (20-month-old) C57BL/6 mice [A-(A); parabiosis for 8 weeks] acetylcholine-induced endothelium-dependent relaxation was impaired and ROS production (dihydroethidium fluorescence) was increased as compared with those in aortas from young isochronic parabiont (6-month-old) mice [Y-(Y)]. The presence of young blood derived from young parabionts significantly improved endothelium-dependent vasorelaxation and attenuated ROS production in vessels of heterochronic parabiont aged [A-(Y)] mice. In aortas derived from heterochronic parabiont young [Y-(A)] mice, acetylcholine-induced relaxation and ROS production were comparable with those in aortas derived from Y-(Y) mice. Using RNA-seq we assessed transcriptomic changes in the aortic arch associated with aging and heterochronic parabiosis. We identified 347 differentially expressed genes in A-(A) animals compared with Y-(Y) controls. We have identified 212 discordant genes, whose expression levels differed in the aged phenotype, but have shifted back toward the young phenotype by the presence of young blood in aged A-(Y) animals. Pathway analysis shows that vascular protective effects mediated by young blood–regulated genes include mitochondrial rejuvenation. In conclusion, a relatively short-term exposure to young blood can rescue vascular aging phenotypes, including attenuation of oxidative stress, mitochondrial rejuvenation, and improved endothelial function. Our findings provide additional evidence supporting the significant plasticity of vascular aging and evidence for the existence of anti-geronic factors capable of exerting rejuvenating effects on the aging vasculature.

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Funding

This work was supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938, to AY and JW), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). DMH is supported by R21AG055026, the American Federation for Aging Research (AFAR) and the Einstein Nathan Shock Center (P30AG038072). 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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Author notes

  1. Tamas Kiss, Stefano Tarantini, Tamas Csipo, Priya Balasubramanian and Ádám Nyúl-Tóth contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Tamas Kiss, Stefano Tarantini, Tamas Csipo, Priya Balasubramanian, Ádám Nyúl-Tóth, Andriy Yabluchanskiy, Jonathan D. Wren, Anna Csiszar & Zoltan Ungvari

  2. International Training Program in Geroscience, Theoretical Medicine Doctoral School/Departments of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Tamas Kiss, Anna Csiszar & Zoltan Ungvari

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

    Stefano Tarantini, Tamas Csipo & Zoltan Ungvari

  4. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Stefano Tarantini & Zoltan Ungvari

  5. International Training Program in Geroscience, Department of Cardiology, Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Tamas Csipo

  6. International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Szeged, Hungary

    Ádám Nyúl-Tóth

  7. Oklahoma Medical Research Foundation, Genes & Human Disease Research Program, Oklahoma City, OK, USA

    Jonathan D. Wren & Lori Garman

  8. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Derek M. Huffman

  9. Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA

    Derek M. Huffman

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

    Derek M. Huffman

  11. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Anna Csiszar & Zoltan Ungvari

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  1. Tamas Kiss
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Correspondence to Zoltan Ungvari.

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Kiss, T., Tarantini, S., Csipo, T. et al. Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood. GeroScience 42, 727–748 (2020). https://doi.org/10.1007/s11357-020-00180-6

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