Preventing spontaneous cerebral microhemorrhages in aging mice: a novel approach targeting cellular senescence with ABT263/navitoclax.
Janet FaakyeÁdám Nyúl-TóthMihaly MuranyiRafal GulejBoglarka CsikSantny ShanmugaramaStefano TarantiniSharon NegriCalin ProdanPeter MukliAndriy YabluchanskiyShannon ConleyPeter TothAnna CsiszarZoltan I UngvariPublished in: GeroScience (2023)
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.
Keyphrases
- cerebral ischemia
- subarachnoid hemorrhage
- angiotensin ii
- cognitive impairment
- induced apoptosis
- brain injury
- blood brain barrier
- blood pressure
- endothelial cells
- dna damage
- white matter
- resting state
- cell cycle arrest
- high fat diet induced
- healthcare
- public health
- stress induced
- angiotensin converting enzyme
- multiple sclerosis
- cell death
- oxidative stress
- physical activity
- cerebral blood flow
- type diabetes
- drug delivery
- endoplasmic reticulum stress
- stem cells
- cancer therapy
- adipose tissue
- bone marrow
- cell therapy
- mesenchymal stem cells
- replacement therapy
- pi k akt
- social media