From mitochondria to inflammation: mechanisms of brain aging

Highlights:

• Aging carries about structural and functional changes in the brain, leading to reduced cognitive capacity
• Hormones, genetics, neurotransmitters, and environmental factors play a role in the brain aging process
• Mechanisms related to brain aging include, among others, mitochondrial dysfunction, oxidative stress, lysosomal dysregulation, inflammation, defective stress response
• Diet and physical activity can slow down the brain aging process

Introduction

As with bodily processes, the brain's functional capacity progressively declines as individuals age. The literature highlights that cognitive functioning in older adults decreases across multiple domains, manifested as a reduction in learning, memory, attention, decision making, and sensory and motor capabilities. This is the reason why older adults have difficulty comprehending rapid speech and complex sentences coupled with impaired capacity to retrieve words. This process notably accelerates beyond 50 years, as individuals in their sixties, seventies, and eighties are more prone to develop neurodegenerative disorders. Oxidative damage, impaired DNA repair, and disrupted neuronal activity are among the mechanisms leading to brain aging.
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Factors influencing brain aging

Many factors play a role in brain aging, namely genetics, hormones, neurotransmitters, and environmental factors, leading to a reduction in both the grey matter of the brain. (1, 2). The grey matter represents neuronal cell bodies that make up the outermost brain layer, while the white matter is mainly composed of myelinated axons and is responsible for communication, where it facilitates the process between grey matter areas. According to research, the degradation of grey matter begins in early adulthood and almost follows a linear pattern. Conversely, the volume of white matter increases until approximately the fifth decade of life, after which it starts to decrease (3). Taken together, the rate of brain atrophy can be used to predict the chance of developing dementia and cognitive impairment.

According to the literature, certain factors exposure during early and midlife can influence the risk of functional brain deterioration and neurodegenerative diseases development at later stages of life. For example, Blennow et al. suggest that traumatic brain injury and early-life emotional trauma could increase the risk of Parkinson’s disease and Alzheimer’s disease development at later stages of life (2, 3). In addition to the previous, stress has been shown to accelerate and propagate multiple factors like inflammation and oxidative stress that contribute to the brain aging process (5-7).

Other factors that have been found to play a role in brain aging across life are diet and physical activity. Research has highlighted that excessive caloric intake and obesity contribute to accelerated hippocampal (a complex brain structure that plays a role in learning and memory) atrophy (8).

Neurotransmitters like dopamine and serotonin have also been found to play a role in brain aging. Research highlights that dopamine levels decline with age at a rate of 10% per decade from early adulthood onwards (1). The effect of aging on the dopaminergic pathway in the brain could be attributed to a decline in neurotransmitter levels, reduced receptor-binding capacity, or synapse activity. Similarly, serotonin levels have also been found to be inversely related to the aging process (1).
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Mitochondrial dysfunction as a cause of brain aging

Mitochondria (organelles involved in energy production in the form of adenosine triphosphate, calcium homeostasis, and other critical functions) are distributed in the dendrites (a neural extension that receives electrochemical communication from other cells) and axons (projection from the neuron that sends impulses away from the neuron body to the next nerve cell) of neurons (5,6). 

To better understand the impact of aging on mitochondria in brain cells, researchers analyzed mitochondrial genes and specific proteins, among other things (7). They found that aging influences brain-tissue mitochondria in several ways, like increased oxidative damage to the mitochondrial DNA, impaired calcium handling, and defects in the electron transport chain (ECT) (a series of protein complexes that create an electrochemical gradient that facilitates electron transfer in reduction-oxidation reactions (redox)) (2). Further evidence suggests that age-related decline in brain mitochondrial function is attributed to a decrease in cellular levels of nicotinamide adenine dinucleotide (NAD+) (NAD is a coenzyme that plays a significant role in metabolism and redox reactions) (2, 8).
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Oxidative damage molecules accelerate the brain aging process

Mitochondrial dysfunction coupled with the accumulation of abnormal proteins leads to oxidative imbalance, which happens due to increased reactive oxygen species (ROS) production and/or reduced antioxidant defense (2). Many of these ROS result from mitochondrial respiration and are generated in response to an elevation in calcium levels. Research highlights that oxidative damage resulting from nitric oxide (NO) plays a role in the aging of the cerebral cortex (which contains sensory, motor, and associative areas). This is because NO modifies the function of various proteins, impairing their activity, thus disrupting cell metabolism and survival. In this context, the accumulation of lipid peroxidation products resulting from NO interactions in dog brain samples was associated with AD manifestations (2, 9). In parallel, reduced antioxidant capacity leads to ROS accumulation, causing neuronal damage. The literature highlights that reducing superoxide dismutase-2 (an enzyme that acts as a scavenger for free radicals) in mice leads to increased motor dysfunction, neuronal DNA damage, and neurodegenerative disorders.

The link between lysosomal activity and brain aging

To maintain their activity, neurons need to preserve their structural and functional integrity, requiring the removal of damaged organelles or cells (2). Lysosomes are acid-containing organelles that play a role in cellular defense and integrity by removing damaged components through autophagy (self-digestion). With aging, the efficiency of this process decreases, leading to the accumulation of autophagosomes with undegraded content, aged and dysfunctional mitochondria, and abnormal proteins (2, 10, 11). Studies on rat models demonstrated that the accumulation of these defective components and proteins affected certain brain regions more than others. For example, the hippocampus and cerebral cortex were found to be more affected than the brainstem (which controls subconscious bodily functions like breathing).

Defective adaptive stress response

In addition to oxidative stress, neurons fall under various types of stressors resulting from metabolic activities. These stressors result from the normal functioning of neurons and are handled through activating adaptive stress pathways like the AMP-activated protein kinase (AMPK plays a role in metabolism and cellular homeostasis) (12). With aging, the capacity to respond to stressors decreases, leading to an increased risk of neuronal injury and the development of neurodegenerative disorders. In this context, disruption of insulin growth factor-1 (IGF-1 is a pathway that plays a role in the cell cycle, apoptosis, and many other functions) has been found to reduce the neuronal capacity to handle oxidative stressors accumulation resulting from the aging process (2).

Impaired DNA repair

In healthy young cells, many mechanisms check and fix DNA damage, replacing defective base pairs with the correct ones. This process is essential for the normal functioning of neurons (2). According to the literature, analysis of brain tissues obtained from aged humans has demonstrated increased proportions of damaged nuclear material in cellular and mitochondrial DNA (13). In addition, research highlights that the levels of DNA repair proteins and enzymes were reduced, making the nuclear material more prone to damage. This is particularly important because premature aging syndromes are characterized by mutations that impair DNA repair, leading to accelerated aging, including that of the brain (2).

Inflammation

Inflammation is a process that affects many organs and is a cornerstone of the aging process. Local inflammation in brain cells also leads to the same outcome (2). In this context, research has highlighted that aged microglia (a type of cells located throughout the brain that has a defensive role) produce pro-inflammatory cytokines (14). In addition, evidence suggests that overt activation of the microglia produces large amounts of NO, leading to oxidative damage of neurons and synapses. Eventually, inflammation leads to the formation of abnormal protein molecules that damage the neural membrane and result in the pathogenesis of conditions like AD (2).

Impaired neural cells formation

The majority of neurons in mammals are developed during the embryonic or early postnatal stage. In contrast, others, like these of hippocampal dentate gyrus, are generated in adult brains (15). These neurons play a role in learning, memory, and spatial patterns detection. With aging, the neurogenerative capacity of these hippocampal neurons is reduced, leading to a decline in cognitive and other functions controlled by these cells (2). Many factors contribute to the latter, like reduced metabolic capacity associated with the aging process and increased oxidative stress, inflammation, and other of the aforementioned mechanisms.

Can the brain aging process be slowed down?

According to the literature, the answer is yes, yet this answer would require further investigation to validate and confirm it. Research on mammals revealed that intermittent fasting, caloric restriction, and mental stimulation through learning and social interaction were effective means to hamper the structural and functional brain decline resulting from the aging process (2, 20, 21). In the form of aerobic exercises, physical activity has been shown to possess positive effects on hippocampal volume. In the same context, the said interventions were found to counteract the effects of oxidative damage, ECT abnormalities, and calcium homeostasis and stimulate mitochondrial biogenesis in brain neurons. Additionally, diet and physical activity have been found to contribute to the inflammatory process, where excess calories and a sedentary lifestyle leading to obesity have been linked to accelerated inflammation.
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Conclusions

The aging process brings about a decline in cognitive function, driven by structural and functional changes resulting from age-related defects in mechanisms important for neuronal homeostasis. Many of the processes are attributed to mitochondrial changes that lead to increased levels of ROS and other damaging molecules. This leads to deteriorated functioning in many neurons, which, when combined with little regenerative capacity, leads to progressive, permanent changes. Fortunately, some evidence suggests dietary means and physical activity as tools to slow down the effect of brain aging.  

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