Alzheimer's disease is a condition that sits atop a mound of many contributing causes, layered in chains of cause and effect. Given that chronic inflammation and age-related impairment of the cellular housekeeping mechanisms of autophagy both appear to be significant, somewhere in the mix, it is perhaps to be expected that many of the usual healthy lifestyle choices have some modest impact on the progression of the condition. Exercise and calorie restriction both act to upregulate autophagy and it is thought that this accounts for a sizable fraction of the resulting benefits to health and life span. Unfortunately, the sort of stress response upregulation appears to scale down in impact on life span as species life span increases, though the effects on short term health and metabolism appear quite similar. Mice can live up to 40% longer when on a calorie restricted diet, but that is certainly not true for humans; we gain a few years at most.
Autophagy recycles damaged structures and broken proteins inside the cell. Neurodegenerative conditions such as Alzheimer's disease involve the presence of toxic molecules, such as those associated with amyloid-β and tau, but even if not directly involved in clearing away disease-associated damage, increased autophagy is generally protective of cell function. Given that this includes everything from neurons to the microglia responsible for clearing away intracellular debris and protein aggregates, we should expect increased autophagy to modestly improve just about every issue in the aging brain. Sadly, doing better than modest improvement is probably not within the scope of what might be achieved via increased rates of autophagy, even when researchers directly influence regulatory genes such as mTOR.
Autophagy as an evolutionary-conserved process can maintain normal physiological events or regulate the progression of a series of diseases through sequestering mis-folded/toxic proteins in autophagosomes, thus executing its cytoprotective role. Growing evidence demonstrates that autophagic capacity to degrade harmful proteins in cells declines with increasing age. Moreover, dysfunctional autophagy has also been linked to several aging-related neurodegenerative diseases including Alzheimer's disease (AD). Previous studies have documented the critical role of autophagy in the pathogenesis of AD, including amyloid-β (Aβ) production or deposition, Aβ precursor protein (APP) metabolism, and neuronal death. Furthermore, insufficient or reduced autophagic activity can lead to the formation of harmful protein aggregates, which results in increased reactive oxygen species (ROS), cell death, and neurodegeneration. As a result, autophagy has a crucial role in the regulation of longevity.
Mammalian target of rapamycin (mTOR) regulates a series of physiological processes. On the one hand, mTOR plays an important role in different cellular processes including cell survival, protein synthesis, mitochondrial biogenesis, proliferation, and cell death. On the other hand, the mTOR signaling pathway can execute an important role in memory reconsolidation and maintaining synaptic plasticity for memory formation, due to its regulatory function for protein synthesis in neurons. Moreover, mTOR also can interact with upstream signal components, such as growth factors, insulin, PI3K/Akt, AMPK, and GSK-3. Currently, although the molecular mechanisms responsible for AD remain unclear, more and more studies have confirmed the involvement of dysregulated mTOR signaling in AD. Activated mTOR signaling is a contributor to the progression of AD and is coordinated with both the pathological and clinical manifestations of AD. Furthermore, there is a close relationship between mTOR signaling and the presence of Aβ plaques, neurofibrillary tangles, and cognitive impairment in clinical presentation. Therefore, the development of mTOR inhibitors may be useful for the prevention and treatment of AD.
It has been reported that regular physical activity can improve brain health and provide cognitive and psychological benefits. Mechanically, regular exercise training is related to the inhibition of oxidative stress and apoptotic signaling, thus effectively executing neuroprotection. Previous studies have demonstrated that treadmill or voluntary wheel running is beneficial for the improvement of behavioral capacity, and can promote the dynamic recycling of mitochondria, thereby improving the health status of mitochondria in brain tissues. Moreover, other studies have demonstrated that regular exercise has a beneficial effect on the structure, metabolism, and function of human and rodent brains. Interestingly, our recent study has also documented that the brain aging of d-gal-induced aging rats can be noticeably attenuated by eight-week swimming training, due to the rescuing of impaired autophagy and abnormal mitochondrial dynamics in the presence of miR-34a mediation. Therefore, physical activity is regarded as an effective approach against AD.