Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal function with potential implications for cognitive health, including involvement in adult neurogenesis. A decline in BDNF levels is associated with mild impairments in learning and memory. The hippocampus, known for its involvement in learning and memory processes, serves as a focal point for investigation in the brain due to its responsiveness to environmental stimuli, including exercise. There is an existing knowledge gap concerning whether running promotes an increase in BDNF levels within the hippocampus at very old ages, despite BDNF's importance in neuronal function and its potential implications for cognitive health. This study was designed to investigate whether physical exercise influences BDNF levels in the hippocampus of aged mice. Aged C57BL/6 mice were allowed access to running wheels, or locked running wheels, for three days, after which their brains were collected, post-euthanasia for neuropathology assessment. Immunohistochemistry (IHC) was performed with an anti-BDNF antibody by measuring BDNF presence, since lack of BDNF levels signifies lost neurons. QuPath digital imaging techniques were employed to provide a quantitative measure of the potential impact of running on hippocampal BDNF expression. Both the average and the variance of total distance run during voluntary wheel running decreased with age. Elevated BDNF levels were observed in the hippocampus of running mice compared to sedentary counterparts. The study provides insight into the potential impact of exercise on neurotrophic support in the aging brain. Such findings suggest a beneficial effect of exercise on neurotrophic support in the aging brain, and indicates the need for further investigations into lifestyle stratergies for promoting resilience to brain aging and cognitive decline in older adults.

Mild cognitive decline with increasing age commonly affects millions of people beginning as early as middle age. It can progress to more severe levels of cognitive impairment including dementia associated with Alzheimer’s disease and irreversible brain damage with eventual death. Therefore, treatment before the onset of dementia would be the most effective way to prevent the devastating loss of normal daily living and death as an outcome. However, few drugs have been shown to be successful in preventing the progression of mild cognitive decline to more severe cognitive dysfunction. One candidate drug we are testing is the naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), which is known to have regenerative and anti-inflammatory properties in the brain. In order to test this peptide, we treated middle-aged male and female C57BL/6 mice with GHK as a copper complex (GHK-Cu) or saline using a novel intranasal atomizer daily for two months. We then conducted behavioral tests to assess learning and memory, and then mice were euthanized to collect brain samples for special stains for biomarkers of brain aging including the presence of non-neuronal microglia, brain-derived neurotrophic factor, and synapse integrity. Our preliminary observations from behavioral tests show that mice treated with intranasal GHK-Cu performed better in learning and memory tests than mice treated with intranasal saline. The brain aging biomarker tests I completed show that the neuropathology markers associated with aging are less severe in mice treated with intranasal GHK-Cu. Such a positive outcome provides the rationale to do further preclinical testing as a way to move toward clinical studies designed to treat mild cognitive decline and prevent the devastating progression of irreversible neurodegeneration.