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Preventing spontaneous cerebral microhemorrhages in aging mice: a novel approach targeting cellular senescence with ABT263/navitoclax

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Abstract

Emerging evidence from both clinical and preclinical studies underscores the role of aging in potentiating the detrimental effects of hypertension on cerebral microhemorrhages (CMHs, or cerebral microbleeds). CMHs progressively impair neuronal function and contribute to the development of vascular cognitive impairment and dementia. There is growing evidence showing accumulation of senescent cells within the cerebral microvasculature during aging, which detrimentally affects cerebromicrovascular function and overall brain health. We postulated that this build-up of senescent cells renders the aged cerebral microvasculature more vulnerable, and consequently, more susceptible to CMHs. To investigate the role of cellular senescence in CMHs’ pathogenesis, we subjected aged mice, both with and without pre-treatment with the senolytic agent ABT263/Navitoclax, and young control mice to hypertension via angiotensin-II and L-NAME administration. The aged cohort exhibited a markedly earlier onset, heightened incidence, and exacerbated neurological consequences of CMHs compared to their younger counterparts. This was evidenced through neurological examinations, gait analysis, and histological assessments of CMHs in brain sections. Notably, the senolytic pre-treatment wielded considerable cerebromicrovascular protection, effectively delaying the onset, mitigating the incidence, and diminishing the severity of CMHs. These findings hint at the potential of senolytic interventions as a viable therapeutic avenue to preempt or alleviate the consequences of CMHs linked to aging, by counteracting the deleterious effects of senescence on brain microvasculature.

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Funding

This work was supported by grants from the American Heart Association (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), and the Cellular and Molecular GeroScience CoBRE (P20GM125528), the NCI Cancer Center Support Grant (P30 CA225520) and the Oklahoma Tobacco Settlement Endowment Trust. ZS was supported by Project no. 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).

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Author notes

  1. Janet Faakye and Ádám Nyúl-Tóth have 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

    Janet Faakye, Ádám Nyúl-Tóth, Rafal Gulej, Boglarka Csik, Santny Shanmugarama, Stefano Tarantini, Sharon Negri, Peter Mukli, Andriy Yabluchanskiy, Peter Toth, Anna Csiszar & Zoltan Ungvari

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

    Janet Faakye, Ádám Nyúl-Tóth, Rafal Gulej, Boglarka Csik, Santny Shanmugarama, Stefano Tarantini, Sharon Negri, Peter Mukli, Andriy Yabluchanskiy, Shannon Conley, Peter Toth, 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

    Ádám Nyúl-Tóth, Mihaly Muranyi, Rafal Gulej, Boglarka Csik, Stefano Tarantini & Zoltan Ungvari

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

    Stefano Tarantini, Anna Csiszar & Zoltan Ungvari

  5. Veterans Affairs Medical Center, Oklahoma City, OK, USA

    Calin Prodan

  6. Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Calin Prodan

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

    Shannon Conley

  8. Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary

    Peter Toth

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

    Anna Csiszar

  10. Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, USA

    Zoltan Ungvari

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  1. Janet Faakye
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  2. Ádám Nyúl-Tóth
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  15. Zoltan Ungvari
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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. Shannon Conley, Dr. Peter Mukli, Dr. Peter Toth and Dr. Andriy Yabluchanskiy serve as Associate Editors for GeroScience.

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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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Faakye, J., Nyúl-Tóth, Á., Muranyi, M. et al. Preventing spontaneous cerebral microhemorrhages in aging mice: a novel approach targeting cellular senescence with ABT263/navitoclax. GeroScience 46, 21–37 (2024). https://doi.org/10.1007/s11357-023-01024-9

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