Mechanisms Of Neuroplasticity And Brain Degeneration: Strategies For Protection During The Aging Process Part 3

Autophagic dysfunction

Autophagy can generally be defined as a catabolic process of degradation and recycling, responsible for removing and digesting malformed or damaged cellular contents, organelles, and proteins (Wang et al., 2019). 

There is no direct link between digestive cells and memory, but our diet and physical health can have an impact on our brain health and memory.

If our body is in poor health, such as indigestion or digestive diseases such as gastritis, it may affect our body's absorption of nutrients, including vitamins and minerals that are beneficial to brain health. This can affect our brain health, leading to memory loss or other cognitive problems.

Therefore, it is very important to protect our physical health and digestive health, adopt a nutritious diet, and pay attention to physical health. Preventing or controlling physical health problems through good eating habits, daily exercise, and regular physical examinations can benefit our brain health and improve our memory.

In general, there is a certain connection between physical health and memory, so we should pay attention to physical health and reasonable eating habits, so that our body can get enough nutrition and health, thereby promoting brain health and improving our memory. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche can also regulate the balance of neurotransmitters, such as increasing the level of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche deserticola can improve blood flow and promote oxygen delivery, which can ensure that the brain obtains adequate nutrition and energy, thereby improving brain vitality and endurance.

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This mechanism is dependent on lysosomal machinery and has a high level of conservation among eukaryotes, which is easily explained since its function is essential to protect and adapt the organism in a stressful situation until the cell can return to its homeostasis state. 

In addition, basal autophagy is extremely necessary as a cleaning route under normal nutrient supply conditions, and not just under pathological conditions. Above all, to protect cells from the toxic effects of dysfunctional proteins that cannot be removed via cell division (Wang et al., 2019). 

Autophagy is also the most used pathway for the degradation of damaged intracellular organelles and aggregated or malformed proteins (Wang et al., 2019). 

Since the presence of protein aggregates is a common feature and is present in most neurodegenerative diseases, including Alzheimer's (beta-amyloid and Tau plaques), Parkinson's (alpha-synuclein), and Huntington's (huntingtin) (Frake et al., 2015), autophagy is expected to play a crucial role in removing these toxic aggregates, by decreasing harmful effects and protecting the cell (Wang et al., 2019). 

In addition, autophagy can protect against infectious diseases and promote immunity, being the main form of innate immunity against exogenous invaders (Rubinsztein et al., 2015). Both in infectious diseases and in inflammation observed in neurodegenerative disorders, it was found that stimulation of autophagy had protective effects in preclinical trials (Rubinsztein et al., 2015). 

There are studies with several animal models demonstrating that when modulating autophagy via the mTOR-dependent pathway (mammalian target of rapamycin) there is an increase in the clearance of toxic proteins (Menzies et al., 2017). 

In addition, the inhibition of autophagy was able to increase the toxicity of these proteins and lead to a considerable increase in aggregates (Frake et al., 2015). This modulation has been done in studies with the drug rapamycin and represents a promising strategy in diseases with protein accumulation (Frake et al., 2015; Menzies et al., 2017). 

There are three different mechanisms by which autophagy can process cellular structures: macroautophagy, microautophagy, and chaperone-mediated autophagy (Frake et al., 2015). 

Macroautophagy is a conserved pathway in mammals and the most recurrent process in autophagic events. It consists of transporting substrates to lysosomes through the formation of vesicles created from an isolated membrane, forming a double membrane structure called an autophagosome, which acts as an "insulating" structure of proteins and organelles. 

For the degradation of these substrates to occur, the autophagosome undergoes a fusion with the lysosome, thus forming an autolysosome, in which later this material will break down and be recycled by lysosomal hydrolases (Menzies et al., 2017). 

Autophagosome formation is highly regulated by the ordered assembly of a family of proteins called ATG (AuTophaGy-related) (Menzies et al., 2017), with the Beclin1/ Vps34 complex being the essential nucleus for the formation of the autophagosome, and may both stimulate and suppress the beginning of the autophagic process, participating in different steps, including autophagosome biosynthesis and maturation (Pickford et al., 2008).

In microautophagy, unlike macroautophagy, there is no formation of the intermediate structure of the autophagosome, consisting of a process of invagination or direct protrusion of the lysosomal membrane (Cuervo and Wong, 2014), whereby substrates are degraded by lysosomal enzymes, which can be both selective and non-selective. 

This process and its mechanisms in pathologies are still poorly understood, in part due to the difficulty of analysis. Chaperone-mediated autophagy, on the other hand, consists of a highly specific pathway (Cuervo and Wong, 2014). 

The substrates to be degraded by this route are marked by the motif containing the pentapeptide KFERQ (Lys-Phe-GluArg-Gln), which is recognized by a complex formed with the cytosolic heat shock protein (HSPA8/HSC70), which transports the substrate to the lysosome membrane where it unfolds and binds to monomers of the LAMP2A receptor (protein associated with the lysosome membrane) (Cuervo and Wong, 2014). 

Beclin1 (also known as Atg6) is an autophagic protein that is part of the PI3K kinase complex and plays an essential role in the formation of autophagosomes. 

A reduction in this protein was observed in the brains of patients with Alzheimer's disease (Furuya et al., 2005). Pickford et al. (2008) showed the essential role of Beclin1 in autophagy since the knockout of the Beclin1 gene in PDAPP mice dramatically compromised the process. 

There was an increase in the accumulation of intraneuronal beta-amyloid, decreased neuronal autophagy, neurodegeneration, lysosomal rupture, and microglial alterations, indicating neuronal injury. It was also found in that same study that Beclin1 overexpression reduced levels of both intracellular and extracellular amyloid-β. 

According to Menzies et al. (2017), although there is growing evidence of the physiological importance of autophagy in normal neuronal physiology, the clinical pathological manifestation of most neurodegenerative diseases is late, so it is possible that small changes in the autophagic machinery and consequent recycling of the aggregates have cumulative effects that will manifest themselves only later in life. 

In addition, autophagy consists of an extremely dynamic and highly regulated process, making the identification of the complex occurrence in initial steps with less biological repercussion. 

Taking all of these studies into account, the present set of findings suggests that the decrease in autophagic events or their impairment may contribute to Alzheimer's pathology. 

It is essential that the entire autophagic pathway, from the induction stage to the subsequent stages of maturation and purification, are highly regulated. It is suggested that the pathology characterized by beta-amyloid accumulation occurs partly through impaired autophagy, an essential pathway for the degradation of cytotoxic protein aggregates (Menzies et al., 2017). 

Based on the data found in these studies, an attempt has been made to understand the relationship between the autophagy process and the mechanisms by which this phenomenon occurs in the context of neuroprotection against neurodegenerative diseases. Autophagy may be a relevant therapeutic target for these disorders.

Cell senescence, neurodegeneration and neuroprotection

Cell senescence is a fundamental, multi-faceted aging mechanism defined by irreversible cell cycle arrest determined by several mechanisms, such as telomere shortening, activation of oncogenes, oxidative stress, and cell-to-cell fusion (Biran et al., 2017; Childs et al., 2017). 

In this situation, cells produce SASPs that include proinflammatory agents like cytokines and chemokines, growth factors, and proteases. The release of these factors leads to the formation of irregular nuclei and pleomorphic mitochondria, a reduction in endoplasmic reticulum, and distortion of the Golgi apparatus leading to dysfunction of many cell types (Wang et al., 2019). 

Secretion of SASPs produces potent effects in neighboring cells changing the local tissue. The main reported beneficial effect of SASPs (chemokines and cytokines) that are secreted by senescent cells is the ability to recruit natural killers for the clearance of tumor cells. 

At the same time, the main detrimental effects promoted by SASPs are the interruption of the structure and function of normal tissues, the induction of transitions between normal epithelial cells and premalignant cells, and the stimulation of pre-malignant but nonaggressive cancer cells to move around and go inside the basal membrane (Chinta et al., 2015). Some stressors are classically linked to cell senescence. 

Although not fully understood, these stressors trigger all the mechanisms described above and create a suitable neuroinflammatory environment for cancers and neurodegeneration. The phosphorylation of tau protein, for instance, has been linked to the release of SASPs and the promotion of toxicity in central nervous system cells (Mendelsohn and Larrick, 2018). 

Amyloid-β plaques, a neuropathological marker of Alzheimer's disease, are also related to cell senescence in the brain, causing oligodendrocyte progenitor cells to release SASPs and create a destructive environment (Zhang et al., 2019). In agreement with this, some environmental agents like pesticides (paraquat) can also induce cell senescence and trigger α- synuclein phosphorylation, increasing the probability of Parkinson's disease (Chinta et al., 2018). 

With all this information, it is natural to think about the development of senolytic drugs and strategies to prevent or treat cell senescence and decrease the increasing incidence of related devastating neurodegenerative diseases. Several fundamental studies are, therefore, being conducted to better understand the mechanisms of cell senescence and advance senolytic treatments. 

Hydrogen peroxide (H2O2) is one example of a stressor that induces the release of ROS and triggers cell senescence by oxidative stress induction. Depending on the stressor concentration, cells can present significant damage leading to necrosis, or cumulative damage that brings the beginning of apoptotic mechanisms or cell senescence and the development of diseases (de Magalhaes and Passos, 2018). 

Even the presence of a few senescent cells may lead to cellular and organ dysfunction, impairment of tissue renewal, and the development of an aging phenotype (de Magalhaes and Passos, 2018). However, in some species (spiny mice and rabbits, for instance), there are mechanisms of cell protection that are linked to regeneration that are not found in other species (like other mice and rats). 

In these species, there is an increase in the resistance limit for mitochondria in response to H2O2 stress that increases regenerative ability (Saxena et al., 2019). This mechanism may have implications for healing and overcoming cell senescence and for similar mechanisms that could be explored to increase neuroprotection. 

There is increasing evidence for protective products that are being considered as potential senolytic agents. These include the well-known substances quercetin, piperlongumine, and curcumin which are already commonly taken as antioxidants and neuroprotective, and are now being taken as natural analytics that can extend healthspan (Liang et al., 2019). 

Many studies have addressed in vitro cell senescence caused by stressors and the effects of senolytics, but the in vivo evidence comes only from animal studies with limited translational correlation to human beings, mainly because of the differences between rodent and human biology (Kirkland and Tchkonia, 2017). 

The long-term effects of these products, therefore, still need to be investigated, as not all senescent cells are bad and need to be eliminated (wound healing, for instance, involves the activation of senescent cells). 

Strategies that eliminate senescent cell inductors in a balanced way may be the key to healthy aging and the "super agers" phenomenon (people aged over 85, with no cognitive dysfunction, cancer, or cardiopulmonary disease), beyond the general genetic heritage that supports the hypothesis to explain the extended healthspan in this population (Halaschek-Wiener et al., 2018).

Strategies to maintain resistance or resilience of neurons and astrocytes

Several pharmacological and non-pharmacological strategies are currently being developed to increase neuroplasticity and promote neuroprotection or even neurogenesis. In the last five years, our research team has shown that particular lifestyles are neuroprotective, and adopting these can change the course of the aging process. 

It has been shown that chronic treatment with microdose lithium carbonate (Li2CO3) can reduce neuronal loss in the hippocampus and increase neuronal density in the pre-frontal cortex of transgenic mice for Alzheimer's disease, as well as increase the density of BDNF in the same area (Nunes et al., 2015). Also, in organotypic hippocampal tissue from old senescence-accelerated mouse prone 8 (SAMP-8) a significant reduction in nuclear factor-kappa B activation and release of proinflammatory cytokines was observed after microdose Li2CO3 treatment, together with an increase in the density of the anti-inflammatory cytokine IL-10. 

As a proof-of-principle, many short clinical studies were done, suggesting the beneficial effects of microdose lithium in patients with mild cognitive impairment (MCI) or diagnosed with Alzheimer's disease (Rybakowski, 2018). In a study with 61 older adults with MCI, for example, treatment with low concentrations of Li2CO3 for 24 consecutive months promoted a better performance in memory and attention tasks, when compared to placebo-treated age-matched individuals (Forlenza et al., 2019). 

Also, considering that Alzheimer's disease can be an early source of morbidity for individuals with Down syndrome, a recent medical hypothesis points to a real possibility of the benefits of microdose lithium to prevent early dementia in this population (Priebe and Kanzawa, 2020). Still focusing on the suppression of neuroinflammation and oxidative stress, studies with humans and rodents show that polyphenols can be used to avoid inflammation and cellular apoptosis (Spagnuolo et al., 2016). 

One example is, pomegranate, a fruit with high levels of polyphenols in the pulp and in the peel (Yang et al., 2016). Our group showed that mice submitted to a neurodegenerative model with the infusion of amyloid-beta peptide (1–42) and then treated with pomegranate peel extract presented increases in BDNF levels in the hippocampus and a reduction in senile plaque density, which contributed to improved spatial memory (Morzelle et al., 2016). It is believed that the neuroprotective effect of pomegranate is related to the production of the metabolite urolithin, as it has already been shown that this compound can inhibit the formation of senile plaques and prevent neurotoxicity (Yuan et al., 2016). 

Another potent polyphenol that has a reported neuroprotective action is resveratrol. In a controlled trial with 60 people (60–79 years old), treatment with this compound promoted the preservation of verbal memory and improvements in memory related to the recognition of patterns (Huhn et al., 2018). As discussed above, an increased BDNF level is a sign of neuroprotection, as the activation of tropomyosin receptor kinase B receptors leads to the activation of the PI3K/ Akt neuroprotective antiapoptotic pathway (Kowianski et al., 2018). 

Physical exercise is a well-known strategy that increases BDNF and other hormones like irisin, leading to significant improvements in cognitive function, both in animals and humans (de Meireles et al., 2019; Chen and Gan, 2019). Moderate physical activity for 11 weeks, for instance, improved the cognitive ability of less-responsive rats to a memory task (in an active avoidance apparatus) (Albuquerque et al., 2016). 

In addition to improving cognitive ability, moderate physical activity promoted neurogenesis, prevented neuronal death, and induced neuronal differentiation, unlike intense physical activity that did not produce similar effects (So et al., 2017). 

Another benefit of moderate physical activity is the release of irisin, a hormone released into the bloodstream through activation of the Fndc5 gene by the PGC-1α gene transcription co-activator (Ruth, 2012). 

Irisin also promoted synaptic function improvement and prevented cognitive decline in transgenic Alzheimer's disease-like mice (Lourenco et al., 2019). Similar effects have also been observed in animals with ischemic stroke and increased activation of the PI3K/Akt and ERK 1/2 signaling pathways after administration of irisin (Li et al., 2017). 

Both physical activity and environmental enrichment have been seen as means of improving memory and learning as well as increasing hippocampal neurogenesis (Sakalem et al., 2017), leading to the construction of a cognitive reserve. 

In a study recently published by our group, we demonstrated that an enriched environment promoted memory retention in a transgenic mice model of Alzheimer's disease (Balthazar et al., 2018). In addition, it has already been shown that environmental improvement can promote a reduction in the pro-inflammatory cytokine IL-1β and an increase in astrocytes (Goncalves et al., 2018). 

In humans, it seems that physical exercise has benefits when undertaken over a long period. Exercises for 12 or 16 weeks, for example, did not significantly change the parameters related to improvements in cognition like increased cerebral blood flow or growth factors (as BDNF) (van der Kleij et al., 2018; Marston et al., 2019). 

However, individuals who have greater activity for a longer period (1 year) have been shown to have a higher hippocampal volume (Clemenson et al., 2015). These data demonstrate that improvements in cognitive performance and neurogenesis can be related to a more active stimulating life. 

These studies clearly show that lifestyle, and not only pharmacological treatments, is important in the promotion of neuroprotection and neurogenesis. Therefore, studies that analyze both pharmacological and non-pharmacological strategies are extremely important in the production of reliable results.

Conclusion

During the aging process, neuroplasticity and memory are subjected to environmental conditions that influence individuals' genetic profiles and may lead to the development of a cognitive reserve as well as better all-round health in older adults. 

Neurodegeneration can be modulated by alterations in cell senescence, which can decrease neuronal and glial cell populations, leading to dysfunction of the central nervous system. 

However, a healthy lifestyle can help to maintain the neuroprotective mechanisms that work against the cell death processes involved in neurodegenerative diseases. 

More studies are needed, particularly in vivo studies and studies focused on human cells, to clarify the role of cell senescence in neuroprotection during aging, to facilitate the development of senolytic drugs, as well as to provide further scientific evidence on the role of physical exercise, better nutrition and environmental enrichment in improving quality of life and increasing healthspan.

Author contributions: MT, AARP, GSA, HNM, JM, and TAV wrote the text. HSB and TAV revised the text. All authors approved the final version. Conflicts of interest: The authors declare no conflicts of interest.

Financial support: MT received a studentship from the Sao Paulo Research Foundation (2017/21655-6). HSB was a Brazilian National Council for Scientific and Technological Development researcher (425838/2016-1, 307252/2017-5). This work was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 and FAPESP (2016/07115-6).

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check: Checked twice by iThenticate. Peer review: Externally peer-reviewed. Open access statement: This is an open-access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 

License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under identical terms. 

Open peer reviewer: Gabriele Siciliano, University of Pisa, Italy. Additional file: Open peer review report 1.

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