Aging is a fundamental biological process accompanied by a general decline in tissue function and increased risk for many diseases. Indeed, decline in fine motor control, gait and balance is among the most important health problems in the elderly. Although the mechanism underlying cerebellar dysfunction is unclear, compelling evidence indicate that when the cerebellum ages, it starts to shrink in volume as a whole in the mid-fifties of humans. Looking particularly at the lobules as a whole, the anterior lobules (vermis) that control bodily posture and locomotion are most significantly affected by aging, but not the lateral portions of the cerebellum. It is well-known that aging-related structural and functional disturbances in the macro- or microcirculation of the brain lead to brain degeneration and dysfunction. However, whether aging impairs vascular structure and function of cerebellum is largely unknown. Our preliminary study showed that the number and volume of blood vessels were selectively reduced in vermis of cerebellum in aged mice, along with increased glutathione redox state, but the hippocampus was not affected. Thus, our central hypothesis is that: aging selectively impairs the vascular structure and function in vermis of cerebellum, which, in turn, increase oxidative damage in these regions, leading to neuronal dysfunction or loss and motor deficits.
Our SPECIFIC AIM i s to (1) determine whether aging selectively impairs vascular structure and function in the vermis of cerebellum, compared to other cerebellar and cerebral regions. (2) Determine whether aging increases oxidative stress and neurodegeneration in the vermis of cerebellum, compared to other cerebellar and cerebral regions. (3) Explore whether improved cerebral blood flow via increase of endothelial NAD+-SIRT1 activity reduces oxidative stress and attenuates neurodegeneration in the vermis of cerebellum and improve age-related cerebellar motor dysfunction. The rationale for the proposed research is that successful completion of the proposed experiments will provide missing, fundamental knowledge regarding the impact of the aging on vessel structure and function, and potential mechanisms underlying motor dysfunction in elderly.
Decline in fine motor control, gait and balance is among the most important health problems in the elderly. The proposed experiments are to determine whether the effect of aging on dysfunction of vascular structure and function of cerebellum contributes cerebellar cell death and motor deficits, and find a way to ameliorate the motor deficits caused by aging.
