Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

Abstract

The aging process is characterized by a series of molecular and cellular changes over the years that could culminate in the deterioration of physiological parameters important to keeping an organism alive and healthy. Physical exercise, defined as planned, structured and repetitive physical activity, has been an important force to alter physiology and brain development during the process of human beings' evolution. Among several aspects of aging, the aim of this review is to discuss the balance between two vital cellular processes such as autophagy and apoptosis, based on the fact that physical exercise as a non-pharmacological strategy seems to rescue the imbalance between autophagy and apoptosis during aging. Therefore, the effects of different types or modalities of physical exercise in humans and animals, and the benefits of each of them on aging, will be discussed as a possible preventive strategy against neuronal death.

Keywords: aging; apoptosis; autophagy; brain; exercise.

Figure 1

Cellular proteostasis and apoptotic cell death. Proteostasis network is the protein pool quality control system that integrates the pathways related to protein synthesis since translation, protein folding, protein unfolding, secretion, trafficking and degradation or elimination. To succeed in protein folding, unfolding, refolding and trafficking, chaperone proteins (heat shock proteins—Hsp) are of fundamental importance. In the elimination phase that usually happens when misfolded proteins turn into toxic aggregates, degradation of damaged proteins occurs through proteolytic systems: autophagy and ubiquitin-proteasome. The activity of both systems avoids cell death. However, when the proteostatic network cannot avoid protein aggregates accumulation, the cell undergoes apoptosis. Thus, degradation system and apoptosis are both important mechanisms for organism homeostasis due to the elimination of damaged proteins and damaged cells, respectively.

Figure 2

Summary of the review. During aging (red box) an increase in proteostasis impairment is observed in the Central Nervous System, which may lead to increased levels of misfolded proteins, in part due to decreased autophagic process. The balance between apoptosis and autophagy is lost and an increase in programmed cell death is observed. Otherwise, physical exercise in aging (green box) can partially revert the disbalance observed in aging, decreasing proteostasis impairment and improving autophagic process, as well as decreasing levels of misfolded proteins and toxic protein aggregates, which lead to less apoptosis activation.

Figure 3

Autophageal mechanism and stages. (A) Pro-autophagic signaling induces ULK1 activation and Beclin-1 complex, activating the ATG machinery, thereby initiating the autophagy stages consisting of initiation, elongation, closure and autophagosome formation, autophagosome fusion with lysosome and degradation. (B) Physical exercise causes a decrease in the ATP/AMP ratio by activating AMPK. AMPK inhibits the mTOR pathway, so ULK Ser⁷⁵⁷ phosphorylation will be decreased and it may interact with AMPK and be activated by phosphorylation on Ser³¹⁷. AMPK phosphorylated ULK1 becomes active and may initiate autophagy. PI3K activation occurs culminating in increased expression of autophagy-related proteins (Atg12, Atg5, Atg16). AMPK also promotes signaling of autophagy-related transcription factors (FOXOs), thereby increasing the expression of autophagy-related proteins (Atg12, Atg5, Atg16, LC3-II). Atg, autophagy-related protein; ATP/AMP, adenosine triphosphate/adenosine monophosphate; AMPK, AMP-activated protein kinase; Beclin-1, autophagy-related protein; FOXO, Forkhead box O; LC3II, microtubule-associated protein 1 light chain 3–form II; mTOR, mammalian target of rapamycin; PI3K, Phosphatidylinositol 3-kinase; UKL1, Unc-51-like kinase 1.

Figure 4

Physical exercise actions against aging brain and the apoptotic process. In the central boxes: Apoptosis can be divided into extrinsic and intrinsic signaling pathways. The extrinsic pathway illustrated in the upper central box is induced by death receptors such as FASL, and their ligands, FAS. On the other hand, the intrinsic pathway illustrated in the central inferior box is induced by signs that cause changes in the mitochondrial membrane, called mitochondrial outer membrane permeabilization (MOMP). This process generates macropores on the mitochondrial surface and a release of Cytochrome C, which once released by mitochondria binds to and induces APAF-1 and pro-caspase 9, forming the Apoptosome complex, which activates caspase 9 causing cell death. This pathway is mediated by anti-apoptotic proteins such as BCL-2 and BCL-XL, and pro-apoptotic proteins such as BAX and BAK. In the left box, brain aging is illustrated, and a decrease of neurotrophic factors such as nerve growth factor (NGF) is observed, and brain-derived neurotrophic factor (BDNF), especially in dentate gyrus located on hippocampus, may be related to decreased cell proliferation and increased apoptosis. In addition, TNF-alpha, a pro-inflammatory cytokine, can increase the apoptosis process by intrinsic and extrinsic pathways and lead to the emergence of neurodegenerative diseases. Physical exercise effects, illustrated in the right box, act in reverse, increasing the amount of NGF and BDNF, increasing cell survival and culminating in decreased apoptosis. In addition, physical exercise inhibits the production of pro-inflammatory cytokine TNF-alpha which, in low quantities, decreases the extrinsic apoptosis process.