Ionizing Radiation-Induced Brain Cell Aging And The Potential Underlying Molecular Mechanisms Part 1

Abstract: 

Population aging is occurring rapidly worldwide, challenging the global economy and healthcare services. Brain aging is a significant contributor to various age-related neurological and neuropsychological disorders, including Alzheimer's disease and Parkinson's disease. 

As the aging of the population accelerates, people are paying more and more attention to the relationship between brain aging and memory. According to research, the human brain will gradually lose some functions during aging, especially memory. So what is the relationship between brain aging and memory?

First of all, brain aging is not a problem that everyone faces. We can delay the aging process of the brain through a healthy lifestyle. It is scientifically proven that exercising, maintaining good eating habits, and engaging in regular cognitive training can have a positive impact on brain health and promote the proliferation and connections of neurons.

In addition, we can also try some specific methods to improve memory. For example, we can strengthen memory by reviewing multiple times, using associations, and creating a sense of language. These methods can help us activate memory-related areas such as the hippocampus and amygdala in the brain, and improve our memory efficiency.

In addition, we can also make appropriate use of technical means for memory training. Various memory games, apps, and tools can help us improve memory and concentration, such as Flipd, BrainHQ, Elevate, etc. These apps and tools use the latest cognitive science research to create personalized memory training programs tailored to our needs and interests.

All in all, the impact of aging brains on memory doesn't have to scare us. As long as we adhere to a healthy lifestyle, focus on cognitive training, and try various methods to improve memory, we can effectively delay the aging process of the brain, improve our memory and concentration, and enjoy a healthier and more fulfilling life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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Several extrinsic factors, such as exposure to ionizing radiation, can accelerate senescence. Multiple human and animal studies have reported that exposure to ionizing radiation can have varied effects on organ aging and lead to the prolongation or shortening of life span depending on the radiation dose or dose rate. 

This paper reviews the effects of radiation on the aging of different types of brain cells, including neurons, microglia, astrocytes, and cerebral endothelial cells. Further, the relevant molecular mechanisms are discussed. Overall, this review highlights how radiation-induced senescence in different cell types may lead to brain aging, which could result in the development of various neurological and neuropsychological disorders. 

Therefore, treatment targeting radiation-induced oxidative stress and neuroinflammation may prevent radiation-induced brain aging and the neurological and neuropsychological disorders it may cause.

Keywords: ionizing radiation; aging; brain; oxidative stress; mitochondrial dysfunction; DNA damage.

1. Introduction

Global population aging is currently occurring at an unprecedented rate. There has been a demographic shift toward an older population, and this may have far-reaching consequences. Population aging is considered a crisis from a global economy and healthcare perspective [1]. 

In most species, the geriatric stage of life involves the impairment of adaptation and self-balancing mechanisms, leading to increased susceptibility to environmental or internal pressure, disease, and mortality [2]. 

In humans, aging is associated with progressive cognitive and physical impairment, as well as an increasing risk of diseases such as neurodegenerative diseases. Age-related disability and morbidity negatively affect the quality of human life, ultimately increasing the risk of mortality, and leading to problems at the individual, family, and community levels [3]. 

Brain aging, which involves complex cellular and molecular mechanisms that ultimately lead to cognitive decline, is the primary contributor to neurodegeneration [4].

Aging causes a gradual deterioration in the brain's functional capacity, which leads to impaired learning and memory, attention deficits, reduced decision-making speed, and impaired sensory and motor incoordination [5]. 

The age-related deterioration of brain function occurs almost parallel to the functional deterioration of other organ systems, and the decline in performance is significantly accelerated after the age of 50 years [6]. 

Nonetheless, aging-related alterations in cellular integrity and molecular pathways are shared across tissues, including the brain [7]. These alterations include mitochondrial dysfunction; intracellular accumulation of oxidative damage to macromolecules; dysregulation of energy metabolism; impairments in cellular waste disposal (autophagy-lysosome and proteasome functions), adaptive stress response signals, and DNA repair; and inflammation. Further, abnormal neuronal network activity, altered Ca2+ processing in neurons, and reduced neurogenesis are also observed in the aging brain [8,9]. 

All living organisms undergo aging and are exposed to ionizing radiation (IR) throughout their lifespan. Several studies have linked IR to accelerated aging [10]. Kuzmic et al. used glp-1 sterile Caenorhabditis elegans to evaluate the impact of chronic gamma radiation on lifespan and confirmed that IR can accelerate aging [11]. Exposure to IR is known to cause a wide array of physiological changes. 

IR can lead to DNA double-strand breaks (DSBs), which cause genetic instability DNA damage and oxidative stress, leading to brain endothelial cell senescence and cell death [12,13]. Cellular senescence, an irreversible state of growth stagnation, can help us understand the relevance of aging to several other biological processes, from embryonic development to tissue repair and aging-related diseases [14,15]. 

High-dose exposure may cause acute radiation sickness, whereas prolonged exposure to low-dose radiation often results in chronic disorders such as neurodegenerative diseases. While the harmful effects of high-dose/dose-rate IR on human health are well-established, the effect of low-dose/dose-rate exposure is often overlooked despite its ubiquitous nature. 

The use of IR in medical diagnosis and cancer treatment has increased significantly. Consequently, nuclear waste from hospitals accounts for approximately 14% of the world's total annual radiation exposure [16]. 

Several studies have shown that long-term exposure to low-dose IR in catheterization laboratories increases the risk of cardiovascular diseases, indicating that it causes enhanced vascular aging and early atherosclerosis [17]. 

More than 50% of cancer patients will be treated with radiotherapy. Radiotherapy will kill the tumor tissue while also damaging the surrounding normal tissues, leading to radiation toxicity. [18]. Radiotherapy exposes both tumor tissue and surrounding healthy IR, causing DNA damage, which triggers the DNA damage response (DDR). In this reaction, ionizing radiation will cause the cell cycle to stop and cause cell damage, and then these damaged cells will automatically repair. If the DNA is fully repaired, these cells can recover as before. 

However, when internal and external factors affect the ability of DNA repair, senescence (i.e., permanent cell cycle arrest) or cell death (such as apoptosis or mitotic disaster) will occur. [19,20]. Furthermore, as IR is often required for obtaining high-resolution images during neuroimaging, the contribution of low-dose/dose-rate IR toward neurodegenerative diseases must be examined [21]. 

Radiation exposure, particularly natural radiation exposure, occurs in daily human life. Some radioactive elements in the earth's crust such as uranium (238U), potassium (40K), thorium (232T), and their radioactive decay products, e.g., radon (222Rn) and radium (226Ra) act as natural sources of radiation exposure [22]. 

Areas with high levels of background radiation are considered ideal for investigating the long-term effects of chronic low-dose radiation exposure in humans [23]. Some studies on high natural background radiation have been performed in Brazil, China, India, and Iran [24–26]. High-dose radiation exposure can cause cancer. 

In addition, it is worth noting that the high natural background radiation observed in Yangjiang, China also increases the incidence of some non-cancer diseases, such as tuberculosis, digestive diseases, and cerebrovascular diseases. [27]. High natural background radiation in the environment can be considered a type of natural pollution. It can reach the human body through both internal and external sources, and it can damage human DNA. 

In addition, natural background radiation also enters the ecosystem through human activities, affecting the health and quality of life of individuals residing in areas with high natural background radiation. A long-term follow-up study of the 1986 Chornobyl disaster revealed an increased incidence of an extensive array of diseases in exposed individuals across all contaminated regions assessed. 

In particular, alterations to the central nervous system (CNS), resulting in radiation-induced neurocognitive dysfunction, were observed in many individuals [28]. Further, surviving Chornobyl liquidators showed signs of inflammation that could be associated with premature aging [29]. Radiation-induced immune system impairments are important contributors to the physiological changes that occur shortly after radiation exposure and have been implicated in delayed effects of radiation such as tumor development and early aging [30]. 

Chronic low-dose IR exposure can accelerate the aging of blood vessels, including cerebral vessels. This has been shown to correlate with age-related encephalopathy in individuals over 40 years of age, as well as with systemic atherosclerosis [31,32]. 

Of the 306 workers exposed to the Chornobyl nuclear accident examined in a previous study, 81% and 77% of men and women, respectively, exhibited signs of accelerated aging. 

In addition, those younger than 45 years of age appeared to be more susceptible to radiation-induced accelerated aging [33]. In humans, sensitivity to radiation decreases with age until an individual matures. However, this sensitivity increases in old age.

Experimental data from animals also supports the theory that IR induces aging. Brizzee observed that with increasing age, some changes occur in the cerebral cortices of Rhesus monkeys and albino rats [34]. 

Analyses of transcriptomic profiles from murine brains revealed that the molecular responses observed hours after full-body low-dose irradiation (100 mGy) were similar to those associated with premature cognitive decline, Alzheimer's disease, and various neuropsychiatric disorders [35,36]. The transcriptomic profiles of microglia obtained one day and one-month post-irradiation were also similar to those observed during aging, pointing to the aging-enhancement effects of radiation [37]. 

In vitro high-dose (2–8 Gy) irradiation of primary cerebrovascular endothelial cells in rats promotes a secretory phenotype associated with aging, characterized by the upregulation of pro-inflammatory cytokines and chemokines, including IL-6, IL-1α, and MCP-1 [38]. 

It has been reported that IR increases cellular senescence, and senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p12, and Bcl-2) are highly expressed in irradiated bone marrow-derived macrophages [39]. These findings corroborate the in vivo evidence pointing to the potential senescence-inducing effects of radiation on the endothelial cells of cerebral blood vessels.

Altogether, it is clear that the biological effects of IR exposure, not limited to oxidative stress, chromosomal damage, apoptosis, stem-cell failure, and inflammation, all contribute to accelerated aging [40]. Furthermore, the contribution of IR exposure to the development of non-malignant conditions such as neurodegenerative diseases is also becoming evident through epidemiological studies [21], and many medical conditions are related to exposure to different types of low-dose/dose rate radiation (Table 1).

In this review, we will focus on the impact of IR on brain aging, including the aging of various CNS cell types (microglia, astrocytes, cerebral endothelial cells, and neurons). Further, the relevant molecular mechanisms will be discussed, and future research directions aimed at elucidating the true impact of radiation-induced brain aging will be proposed.

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