Ionizing Radiation-Induced Brain Cell Aging And The Potential Underlying Molecular Mechanisms Part 2
Apr 23, 2024
2. Radiation-Induced Senescence of Different Types of Brain Cells
The understanding of how IR affects brain aging begins with an elucidation of its influence on individual CNS cell types. CNS cells are broadly classified into two categories, glial cells-including microglia, astrocytes, and oligodendrocytes-and neurons [45].
The central nervous system is an important part of the human body and plays a vital role in our thinking and actions. At the same time, the central nervous system is also closely related to our memory.
The central nervous system includes the brain and spinal cord and is the "command center" of the human body. Our thinking activities, perceptions, movements, etc. all originate from the central nervous system. At the same time, the central nervous system is responsible for transmitting information to other organs and maintaining the coordinated operation of the entire body. Therefore, the normal function of the central nervous system is very important.
The central nervous system plays a very important role when we remember things. Our brains form complex neural networks through a series of neuron connections that can transmit and store information between them. At the same time, memory ability is also related to the health of our nervous system.
Research shows that there is a strong connection between the health of the central nervous system and memory. Neuronal degeneration and damage can affect our ability to think and remember. When our nervous system is damaged, it can lead to problems such as memory loss and cognitive impairment. Therefore, it is very important to maintain the health of the central nervous system, which can be protected by exercising, maintaining a good lifestyle, and timely treatment of neurological diseases.
At the same time, scientists have also found in research that our memory ability can be improved through specific training and exercise. These trainings promote connections and information transfer between neurons, thereby enhancing our memory. Continuous training and exercise can help us achieve better results in learning new knowledge and memorizing complex information.
In short, the central nervous system is an important part of us and is closely related to our thinking and actions. At the same time, keeping the central nervous system healthy can help us improve our memory and enhance our cognitive abilities. We should take active measures to protect and improve the function of the central nervous system, thereby enhancing our learning and memory abilities. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.
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The endothelial cells of cerebral blood vessels are also closely associated with the brain; they lead to the formation of the blood-brain barrier (BBB) and are important for maintaining CNS integrity [46].
IR has been proven to cause aging in all these cell types, especially microglia, astrocytes, cerebral vascular endothelial cells, and neurons (Table 2). The cumulative effects of senescence in these cells may lead to brain aging, related neurological and neuropsychological disorders, and a shortened lifespan [40].
2.1. Microglia
Microglia are yolk sac-derived phagocytes located in the CNS [51]. These cells are involved in immune responses and the maintenance of brain homeostasis. Microglia also respond to changes in the tissue environment by upregulating different cell surface receptors and producing a multitude of secreted factors [52]. As such, this class of glial cells has been affected by a glut of neurological diseases.
Under normal physiological conditions, there is a balance between pro- and anti-inflammatory mediators in the brain [53]. However, a shift towards the pro-inflammatory state is observed during brain aging. Interestingly, this shift is also observed after radiation exposure [54].
Thus, radiation-induced neuroinflammation could be a potential contributor to the development of brain aging and cognitive impairment [55]. Although microglial activation is necessary for protection against foreign substances, beyond a certain threshold, such activation can be damaging. Activated microglia exhibit a neurotoxic phenotype and can cause neuronal damage and death.
This phenotype has been implicated in various neurodegenerative diseases, radiation-induced brain injury, and brain aging [47,56]. Several features of this neurotoxic phenotype resemble those of aging. In microglia from aged mice, pro-inflammatory cytokines such as IL-6, IL-1β, and tumor necrosis factor-α (TNF-α) are upregulated [57], and telomeres appear to be shortened [58].
These factors are also upregulated in murine models of accelerated senescence [59]. In addition, microglia abnormally activated by radiation continuously produce neurotoxic cytokines, including IL-1β, TNFα, and IL-6 [60].
Moreover, these cells show elevated reactive oxygen species (ROS) levels, inducing oxidative stress and consequent DNA damage [61]. Furthermore, in vitro, chronically activated microglia exhibit multiple features of aging, leading to SA-β-Gal activity, metachromatic focus formation, and growth arrest [62]. Chronic aging is considered to be the driving force for age-related tissue dysfunction.
Studies show that SA-β-Gal and p16INK4a, key markers of senescence, are up-regulated in microglia treated with irradiation. Additionally, these markers continue to be expressed even one-month post-irradiation. Senescent cells often secrete large amounts of cytokines and matrix metalloproteinases (MMPs) and show sustained oxidative and genotoxic damage, eventually leading to tissue impairments and aging [63].
IR leads to progressive DNA damage; moreover, the consequent induction of oxidative stress can trigger the aging of normal cells [64]. Studies have demonstrated that IR can induce senescence in microglia [65], characterized by inflammation, DDR, and metabolic changes [66]. Irradiated microglia are involved in the pathology of radiation-induced brain damage [56] and aging-related diseases [48].
2.2. Astrocytes
Astrocytes, one of the most common brain cells, were previously considered nonfunctional cells providing packing for brain networks. Nevertheless, recent research has demonstrated their functional roles in several processes.
Previous studies have reported that microglia and astrocytes interact with each other, and astrocytes are known to participate in immune activity [67]. Astrocytes provide osmotic balance and therefore contribute to the maintenance of CNS homeostasis [68].
They also provide metabolic support to neurons [69] and help in the establishment and maintenance of the BBB [70]. Astrocytes promote neuronal communication and are involved in neurotransmitter recovery.
They also help protect the brain against trauma, infections, and neurodegeneration, thus maintaining its health and function [71]. With age, the number of astrocytes expressing p16INK4a and MMP3 (protease closely associated with the senescence-associated secretion phenotype) increases [72]. Primary astrocytes isolated from human brain tissues acquire senescence-related characteristics after multiple passages [48].
Incidentally, exposure to IR has also been found to induce the senescence-associated secretory phenotype (SASP) and aging in irradiated human astrocytes, likely due to excessive DNA damage accumulation [73]. In a mouse model of radiation-induced brain injury, changes in the expression of TNF-α and IL-1β mRNA and related signaling pathways have been observed in the hippocampus.
It has also been observed that the release of pro-inflammatory cytokines and inhibition of hippocampal neurogenesis may be related to the activation of microglia and may play a critical role in radiation-induced brain injury [74]. Additionally, irradiated astrocytes showed an increase in the expression of the senescence-related markers p16INK4a and p21, cell size, and number of multinucleated cells [75].
In contrast, they showed a decrease in cell number and the expression of glial fibrillary acidic protein (GFAP), which is also observed during aging [76]. Altogether, these findings suggest that irradiated astrocytes not only promote neuroinflammation but also contribute to radiation-induced accelerations in brain aging.
2.3. Brain Endothelial Cells
Radiation-induced senescence is also observed in brain microvascular endothelial cells [49]. Cell surface proteins on brain endothelial cells communicate with both the blood and the brain.
Thus, these cells are involved in signal transmission and transduction across the BBB. Exposure to IR can cause premature degeneration of endothelial cells and thinning of the cerebral blood vessels, resulting in the temporary loss of contextual learning, interruption of working memory, gradual spatial learning impairments, and an increased risk of dementia [77].
Both cell culture and live animal studies have shown that radiation promotes stress-induced progeria-like phenotypes in endothelial cells [78–80]. Studies of brain microvascular endothelial cells from rats exposed to γ-irradiation have demonstrated that cerebral vascular endothelial cells are more radiosensitive than microglia and neurons. γ-irradiation has also been observed to destroy the clone formation and proliferative abilities of cerebral vascular endothelial cells, which are essential for intracranial angiogenesis.
Cerebral microvascular damage caused by γ-irradiation has also been found to promote the accelerated aging of healthy tissues and result in progressive cognitive decline in <50% of tumor patients receiving radiotherapy [81]. In addition, acute γ-irradiation leads to increased production of ROS in cerebral vascular endothelial cells, causing premature aging [82].
Concomitantly, IR may also induce the expression of p16INK4a, the main driver of cell cycle arrest during cerebral vascular endothelial cell senescence, leading to permanent cell cycle arrest [83,84]. Such radiation also increases the proportion of SA-β-Gal-positive cerebral vascular endothelial cells [3].
Similar to astrocytes, cerebral vascular endothelial cells also express IR-induced SASP, including an enhancement in the production of pro-inflammatory molecules, cytokines, chemokines, growth factors, and MMPs [85]. Therefore, radiation-induced SASP may promote neuroinflammation and cause neuronal damage by altering the microenvironment of endothelial cells [86].
Recently, Remes et al. examined the epidemiology of cerebrovascular disease in long-term childhood brain tumor survivors 20 years after the end of radiotherapy.
They found that the incidence of ischemic infarction, microhemorrhage, and lacunar infarction in this population was similar to or higher than that observed in the general population over 70 years of age [87]. Such clinical data supports the hypothesis that radiation triggers the accelerated aging of the cerebrovascular system.
2.4. Neurons
Neurons are the most basic structural and functional unit of the nervous system. They interact with other functional cells in the brain and influence each other. Microglial senescence has a profound effect on neuronal activity and cognition during natural aging [88].
In a study on the effects of age on the response to radiation, it was observed that although the number of immature neurons in old rats did not decrease continuously after whole-brain irradiation, the inflammatory reaction was greater than that in younger rats.
Thus, this reaction may have a greater contribution to the development of radiation-induced cognitive impairments in older adults [50]. Furthermore, neurons are one of the most highly oxygenated cells and experience oxidative genomic damage after long-term exposure to endogenous ROS, a by-product of cellular respiration [88]. These cells are extremely vulnerable to the DNA damage induced by genotoxic substances such as oxidative stress and IR.
When DNA damage occurs, powerful DNA repair mechanisms are activated to limit the accumulation of oxidative damage [89]. However, the accumulation of unrepaired DNA may cause aging and several neurodegenerative diseases [90]. Chronic low-dose-rate γ-irradiation can induce brain aging and reduce neuronal density [34].
In mouse studies, high-dose rate γ-irradiation was shown to reduce the activity of superoxide dismutase and increase the amounts of free radicals, which may be related to aging [91].
In mice, several hours after whole-body irradiation (100 mGy), expression-level changes in molecules and networks involved in cognitive function, advanced aging, Alzheimer's disease, and neuropsychiatric diseases are observed [35,36].
Tang et al. studied the expression of γH2AX in the brains of mice exposed to radiation on different postnatal days. They suggested that persistent radiation-induced DNA damage at 120 days and 15 months after irradiation in the early life of mice may be associated with brain aging and shortened life expectancy [92].
Radiation-induced oxidative stress and inflammation prevent neurogenesis in the subgranular zone and induce aging of the granule cell assembly, leading to cognitive impairment [93–95].
3. Effect of Radiation-Induced Brain Aging
With an increase in life expectancy owing to improvements in medical interventions, it has become crucial to understand the advantages of radiation protection among older individuals. Increased inflammation, loss of the redox balance, continued telomere wearing, decreased efficiency of the DDR, mitochondrial dysfunction, and autophagy are all changes that occur during aging and can negatively impact genome integrity (Figure 1).
Further, as radiation can exacerbate these changes, it is important to understand the mechanisms involved in the effects of radiation exposure and brain aging. Radiation-induced ROS can directly cause mitochondrial respiratory chain breakage and water molecular decomposition inducing respiratory chain dysfunction and reduced antioxidant capacity.
NADPH oxidase is a family of multi-subunit complex enzymes that activate the conversion of oxygen to superoxide anions (O2 −) with NADPH as the electron source and exists in vascular endothelial cells. In addition, cyclooxygenases-2 (COX-2) and 5-lipoxygenase (5-LPO) catalyzes the production of prostaglandin H2 (PGH2) and the formation of ROS during arachidonic acid metabolism.
Cells exposed to IR can be destroyed directly by secondary electrons and/or indirectly by ROS, resulting in DSBs [18] followed by the DDR [19,20,96–100]. The onset of this response generally does not exceed a few minutes after DNA damage.
The damaged DNA is recruited by a complex reaction network that depends on damaged cells. The response produced by the cell depends on the type of DNA damage and environmental factors.
For example, a response through transient activation of cell cycle checkpoints and DNA repair, namely cell survival. [101]. DSBs are usually repaired by error-prone nonhomologous terminal junctions, which are coordinated by DNA-dependent protein kinases. Homologous recombination is operated only during the S or G2 phases of the cell cycle [101].
Unrepaired and/or incorrectly repaired DSBs may lead to genomic instability and cell death or cell senescence (an irreversible state of cell cycle arrest) [19,102]. Radiation exposure directly alters mitochondrial DNA, most notably the common deletion mutation. IR also indirectly alters mitochondrial dysfunction by producing ROS, resulting in disruption of the electron transport chain, and increases the production of antioxidant enzymes through nuclear factor E2-related factor 2 (Nrf2) [103].
Cells enter senescence with shortened telomeres, and short telomeres increase the sensitivity of cells to radiation, with human cells that are sensitive to radiation having shorter telomeres than normal cells [104]. Individuals with short telomeres have a higher frequency of radiation damage than individuals with long telomeres [105]. The mechanism of telomere maintenance is directly or indirectly related to DNA damage [106]. Telomere shortening is an important sign of aging.
Under normal conditions, nuclear factor κB (NF-κB) associates with the inhibitory protein (IKB) to compose a protein complex and remains sleepy. However, when cells are exposed to IR, NADPH oxidase activity and other oxidative stress reactions are increased, mitochondrial electron transfer is impaired and occurs rapidly.
ROS are over-generated in oxidative stress reactions, and IL-1 and TNF are produced by inflammatory cells to link to the IL-1 receptor and TNF receptor, respectively, which in turn activates downstream NF-κB signaling and leads to transcription of inflammation-related genes.
Activated NFκB induces COX-2 and 5-LPO expression, leading to ROS production, which forms a positive feedback loop to increase inflammation and oxidative stress. Intracellular ROS directly stimulate NF-κB which may up-regulate the expression of cytokines including IL-1 and TNF. These cytokines increase inflammation by attracting white blood cells and activating NF-κB.
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