Exercise-induced cellular and molecular alterations in aging and Alzheimer’s disease

The population is living longer than ever before, which in turn means that age-related diseases are now a major public health problem. Healthy aging is important not only for decreasing the risk of disease development, but also for the maintenance of the functional ability of people throughout their whole lifespan. Alzheimer’s disease (AD) is the leading cause of dementia, which affects more than 50 million people worldwide. Even though aging is one major AD risk factor, there are also environmental and lifestyle factors which exert a huge impact on the development of AD. While research into AD has contributed to our understanding of the pathological features of this devastating disease, still no cure exists. This is most likely due to our still limited understanding of the disease mechanisms. One of the most important goals to prevent age-related disease is to clarify the molecular mechanisms associated with aging and AD, and deciphering how lifestyle factors such as physical exercise affect these processes and promote healthy aging.
Therefore, this thesis explored the impact of long-term voluntary exercise in a mouse model of aging and AD. In Study I, we evaluated the effect long-term voluntary exercise on redox regulation and cellular stress upon aging in mice. We found that long-term voluntary exercise was protective against age-related oxidative and endoplasmic reticulum (ER) stress in mice. In Study II, we assessed the effect of long-term voluntary exercise on cognitive function and astrocyte state in WT and the 5xFAD mouse model of AD. We found that long-term voluntary exercise was beneficial against the cognitive impairment developing in the 5xFAD mice and was associated with astrocyte remodeling as well as a restoration of astrocytic brain derived neurotrophic factor (BDNF). In Study III, we examined the effect of long-term voluntary exercise on iron metabolism in WT and 5xFAD mice and evaluated the potential role of iron in the interplay between brain and peripheral tissues. We demonstrated that long-term voluntary exercise modulated iron homeostasis in WT and 5xFAD mice by decreasing levels of the iron regulator protein hepcidin in the brain possibly via an attenuation of the IL-6/STAT3 pathway.
In summary, our studies collectively highlight the positive impact of long-term physical exercise on aging and AD. Our results reveal new aspects of the beneficial effect of regular exercise in both the brain and skeletal muscle; for example, the potential mechanism behind the interplay between brain and periphery upon aging and AD. Regular physical exercise could be a promising preventive strategy against AD and should be further investigated as a way of promoting healthy aging.