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

Autor: Faakye J; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Nyúl-Tóth Á; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary., Muranyi M; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary., Gulej R; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary., Csik B; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary., Shanmugarama S; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Tarantini S; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary.; Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA., Negri S; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Prodan C; Veterans Affairs Medical Center, Oklahoma City, OK, USA.; Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Mukli P; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Yabluchanskiy A; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Conley S; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Toth P; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary., Csiszar A; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA.; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary., Ungvari Z; Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. zoltan-ungvari@ouhsc.edu.; Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. zoltan-ungvari@ouhsc.edu.; International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary. zoltan-ungvari@ouhsc.edu.; Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA. zoltan-ungvari@ouhsc.edu.; Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, USA. zoltan-ungvari@ouhsc.edu.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2024 Feb; Vol. 46 (1), pp. 21-37. Date of Electronic Publication: 2023 Dec 04.
DOI: 10.1007/s11357-023-01024-9
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to American Aging Association.)
Databáze: MEDLINE
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