Moment-to-moment adjustment of regional cerebral blood flow to neuronal activity via
neurovascular coupling (NVC or "functional hyperemia") has a critical role in maintenance
of healthy cognitive function. Aging-induced impairment of NVC responses importantly
contributes to age-related cognitive decline. Advanced aging is associated with increased
prevalence of senescent cells in the cerebral microcirculation, but their role in
impaired NVC responses remains unexplored. The present study was designed to test
the hypothesis that a validated senolytic treatment can improve NVC responses and
cognitive performance in aged mice. To achieve this goal, aged (24-month-old) C57BL/6
mice were treated with ABT263/Navitoclax, a potent senolytic agent known to eliminate
senescent cells in the aged mouse brain. Mice were behaviorally evaluated (radial
arms water maze) and NVC was assessed by measuring CBF responses (laser speckle contrast
imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker
stimulation. We found that NVC responses were significantly impaired in aged mice.
ABT263/Navitoclax treatment improved NVC response, which was associated with significantly
improved hippocampal-encoded functions of learning and memory. ABT263/Navitoclax treatment
did not significantly affect endothelium-dependent acetylcholine-induced relaxation
of aorta rings. Thus, increased presence of senescent cells in the aged brain likely
contributes to age-related neurovascular uncoupling, exacerbating cognitive decline.
The neurovascular protective effects of ABT263/Navitoclax treatment highlight the
preventive and therapeutic potential of senolytic treatments (as monotherapy or as
part of combination treatment regimens) as effective interventions in patients at
risk for vascular cognitive impairment (VCI).
