Ionizing Radiation-Induced Brain Cell Aging And The Potential Underlying Molecular Mechanisms Part 4
Apr 23, 2024
3.5. Inflammation
Inflammation is a defensive response in the body. Chronic inflammation is linked
to the onset and/or progression of a variety of diseases, such as age-related lesions and
neurodegenerative diseases [177,178].
Inflammation is the body's natural response to fight pathogens and injury, but long-term chronic inflammation can have negative health effects. It is generally believed that inflammation is associated only with physical illness, but recent research has shown that inflammation may also be related to human memory.
A large number of studies have shown that chronic inflammation has a great impact on the brain, leading to neuron death, brain structural damage, and synaptic decline. And these are all related to memory decline and cognitive decline. Therefore, people need to pay attention to controlling the body's inflammatory response to improve their memory and cognitive abilities.
The relationship between inflammation and memory can be analyzed from many aspects. First, inflammation leads to the death of neurons, which affects the formation and retention of memories. Secondly, inflammation can lead to the reduction of synapses, thereby reducing the ability to transmit and receive memories. Third, inflammation affects neurogenesis and shaping processes in adults, thereby affecting overall brain function and cognitive abilities.
To avoid the effects of chronic inflammation, we can take some effective measures. First, maintain a healthy lifestyle, including a balanced diet, adequate sleep, and moderate exercise. In addition, avoid tobacco and alcohol addiction, as these substances can increase the inflammatory response in the body. Finally, we can also choose some natural foods and herbs with anti-inflammatory effects, such as fish oil, turmeric, sesame, etc., to help us control the inflammatory response.
In general, inflammation is closely related to human memory and cognitive abilities. We need to be aware of the dangers of inflammation and maintain a healthy lifestyle to improve our health and quality of life. With the right diet and lifestyle management, we can reduce the body's inflammatory response and maintain a healthy body and a clear mind. 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 many active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in a variety of ways.
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IR induces microglial activation and the release of inflammatory cytokines and chemokines. Inflammation is a common characteristic of microglial aging and plays a vital role in radiation-induced brain damage [179] and aging-related diseases [55].
As mentioned previously, radiation exposure often results in abnormal microglial activation, causing these cells to continuously produce neurotoxic cytokines, the levels of which increase with the dose of radiation [4]. DDR signaling can also be mediated by paracrine/systemic mechanisms that shape the systemic environment by regulating tissue repair and immune responses.
Sustained DNA damage signals (telomere attrition) can cause DDR to send extracellular signals and induce SASPs [180–182]. The DDR/SASP signaling pathway regulates several bioactive pro-inflammatory mediators, such as interleukin-chemokine growth factor matrix-degrading enzymes and ROS [183]. Moreover, the pro-inflammatory transcription of NF-kB and the inflammasome are the primary factors that set up the secretome, further highlighting the functional contribution of this pathway in the response to tissue injury [184–186].
NF-kB transcription triggers s to the production of several inflammatory features of SASP, such as IL-6, IL-1, and TNF-α, which are vital autonomic cellular modulators of aging [187,188]. Furthermore, a single dose of 10-Gy γ-irradiation can increase the levels of IL-6 and IL-8 in human endothelial cells in vitro [189].
In addition, an elevation in the inflammatory mediators TNF-α, IL-6, and IL-10 is observed with increasing radiation doses and age among survivors of atomic bombs [190]. Both IR and inflammation are related to an increase in ROS levels in tissues. In a mouse limb ischemia model, acute irradiation with two Gy was found to promote mast cell recruitment and tissue revascularization [191].
High-dose irradiation of the rat abdomen leads to neutrophil recruitment into the irradiated tissue [192]. Radiation-activated microglia express an inducible NO synthase and generate large amounts of NO, leading to neuronal oxidative damage. In addition, microglial toll-like receptors (TLRs) are involved in neuroinflammation, thereby contributing to age-related brain diseases [193].
Chronic inflammation may lead to excess ROS and RNS production, resulting in DNA damage and disease. The persistent presence of ROS and RNS in the microenvironment can lead to the further development of chronic inflammation, causing oxidative damage to DNA and DNA repair pathways, further leading to senescence and age-related diseases.
In age-related neurodegenerative disease models, experimental activation of microglial TLRs can aggravate neuron degeneration, and pharmacological inhibition of microglial activation shows neuroprotective effects [194].
In addition to microglial activation, radiation-induced telomere shortening can also contribute to inflammation. Short telomeric ends induce DNA damage repair responses, leading to the production of NF-kB, a key regulator of inflammatory components such as the nod-like receptor 3 inflammasomes, and the secretion of inflammatory cytokines in the brain [195].
3.6. Autophagy
IR can cause macromolecular (mainly DNA) damage and endoplasmic reticulum (ER) stress induction, both of which can induce autophagy. [196]. Among the key molecules activated during radiation exposure, the inducible nitric oxide synthase (iNOS) gene and nitric oxide (NO) are involved in radiation-induced autophagy and apoptosis [197,198].
The activation of the iNOS promoter will increase the production of NO, leading to the induction of autophagy mediated by protein nitration. The activation of the iNOS promoter is related to its containing multiple transcription factor motifs such as NF-κB and Kruppel-like factor 6 (KLF6). [197]. Radiation-induced oxidative stress not only causes DNA damage, but also causes ER stress, impaired mitochondrial function, and protein misfolding.
Most of these factors have been shown to induce autophagy [199,200]. Radiation-induced mitochondrial dysfunction and biogenesis are known to be related to mitochondrial autophagy [201].
Under conditions of extensive mitochondrial damage, the cell undergoes mitophagy to eliminate the damaged and dysfunctional mitochondria. Radiation induces a variety of responses, including autophagy and senescence. It is commonly thought that autophagy and senescence may promote cell survival.
However, preclinical studies have demonstrated that autophagy can sometimes have opposite effects, such as cytotoxicity or other non-protective effects [202]. Free amino acids released by lysosomes during aging support the production of inflammatory cytokines that synthesize SASP [203]. Autophagy regulation is the core link between aging, age-related diseases, and neurodegenerative diseases.
In the process of aging and neurodegeneration, the regulation of autophagy will have step defects, leading to the accumulation of damaged organelles and protein aggregates, affecting cell metabolism and homeostasis, thereby exacerbating autophagy-related dysfunction and forming a vicious circle, which eventually leads to neuronal damage and cell death. [204].
Impaired autophagy in neurons contributes to the aggregation of toxic proteins and damaged organelles associated with neurodegenerative diseases [205]. Age is a vital risk factor for many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and tauopathy [206].
Over time, the age-dependent decline in autophagy and the corresponding decline in protein metabolism and accumulation of protein toxicity together contribute to disease development and/or progression. Since post-mitotic neurons cannot eliminate protein-toxic damage in daughter cells during mitosis, they are more susceptible to age-related protein toxicity [207].
Impaired autophagy in glial cells, which have a critical homeostatic role in the central nervous system, may influence autophagic activities in neurons [208]. Altogether, these factors can interact and promote the degeneration of specific neurons in different neurodegenerative diseases, suggesting that neuronal population-specific therapeutic approaches may be warranted [204].
4. Conclusions and Future Research Directions
Current experimental studies on animal brains suggest that radiation induces aging in neural stem cells; mature and immature neurons; glial cells, including astrocytes, microglia, and oligodendrocytes; and endothelial cells of cerebral vessels.
Cumulatively, these effects result in brain aging, leading to cognitive impairment and the development of aging-related brain disorders in individuals who are exposed to radiation, such as survivors from the Chornobyl nuclear power plant accident or individuals receiving radiotherapy.
At the molecular level, radiation-induced oxidative stress and neuroinflammation may trigger different signal transduction pathways, resulting in the shortening of telomeres in brain cells, and eventually, brain aging.
Our current understanding of radiation-induced brain aging remains quite limited. With an increase in deep-space exploration, including space tourism, and the use of IR in medical diagnosis and treatment, extensive studies are required to obtain an in-depth understanding of how low-dose radiation affects brain aging and the molecular mechanisms that underlie this process.
Furthermore, most radiation-related brain aging studies involve high doses of radiation, and few studies have examined the sensitivity of each CNS cell type and its progenitors to radiation and radiation-induced aging. Senescent cells are considered effective treatment targets because they accumulate due to aging and other exogenous effects.
Senotherapeutics drugs, a new class of drugs, can selectively kill senescent cells (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics have been identified and examined via clinical trials.
Preclinical data indicate that senolytics alleviate disease-related effects in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even among old patients [209]. In addition, new drugs can delay the patient's disease recurrence. Accurate assessment of radiation response may provide the possibility to increase the sensitivity of cancer cells to radiation therapy while reducing damage to normal tissues [202].
Many senolytics have already been shown to be effective as they mediate the activation or inactivation of redox-sensitive hubs. Consequently, ROS-dependent pathways that specifically mediate the apoptosis of senescent cells may represent novel preventive/therapeutic targets for increasing treatment efficacy. As cells divide, telomere shortening, a process linked to cellular senescence occurs.
Therefore, although senolytics temporarily alleviate cellular senescence and its deleterious effects, they could potentially cause accelerated aging and related dysfunction [210]. Drugs targeting aging-related mitochondrial dysfunction or specifically targeting mitochondrial ROS may also allow alterations in the SASP and downstream negative outcomes.
However, further elucidation of the complex mechanisms via which redox-regulated signaling pathways or mitochondria affect the SASP is required. It is necessary to note that exacerbated antioxidation could also lead to severe adverse effects. Only a tight control of redox homeostasis can eventually allow effective xenomorphic-based therapies [211].
Hence, we propose that future exploration should focus on the following areas: (1) effect of low-dose IR on the aging of different cell types; (2) radiosensitivity of different progenitors and differentiated cells in the brain to radiation-induced aging; (3) epidemiology of brain aging in patients exposed to frequent radiodiagnosis and radiotherapy for brain disorders; and (4) the application of different -omics approaches for understanding the molecular mechanisms underlying low dose radiation-induced brain aging. This information could significantly aid in the development of protective and therapeutic approaches against radiation-induced brain aging and other related neurological and neuropsychological disorders.
Author Contributions: All authors have read and agreed to the published version of the manuscript.
Funding: The present study was supported by the Nature Science Foundation of Hubei Province (grant no. 2017CFB786), the Hubei Province Health and Family Planning Scientific Research Project (grant no. WJ2016Y10), the Jingzhou Science and Technology Bureau Project (grant no. 2017-93), the Graduate innovation fund of the Health Science Center, the Yangtze University (200201), the National innovation and entrepreneurship training program for College Students (grant no. 202010489017) and the National Research Foundation of Singapore to Singapore Nuclear Research and Safety Initiative (TFR).
Data Availability Statement: Data sharing does not apply to this article, as no datasets were generated or analyzed during the present study.
Conflicts of Interest: The authors declare no conflict of interest.
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