Verified by 
Key points
- Senescence, infection, and tissue damage can all cause inflammation.
- Systemic inflammation caused by the accumulation of senescent cells spreads to the brain.
- Senescence-associated neuroinflammation leads to neurodegenerative disorders and cognitive decline.
The blood-brain barrier (BBB), which protects the brain from harmful substances present in the blood, is also considered a symbol of the separation between the mind and the body, similar to the walls that protect the Forbidden City. This unspoken duality has led scientists to give unequal value to these two parts of the body. Edward Bullmore, a professor of psychiatry at the University of Cambridge, wrote in “The Guardian” in 2022 that there is a false dichotomy between physical and mental health. Physical diseases are typically addressed by physicians, while mental illnesses are treated by psychiatrists [1].
However, it seems that the mutual interaction between the two entities exceeds our expectations. A large body of evidence revealed that mental disorders such as depression and anxiety promote physical illness and several physical diseases such as diabetes affect brain health [2]. Even the microbes that reside in body cavities and the signals they receive from the environment play pivotal roles in cognitive processes, despite being considered foreign signals.
The mind encompasses memory, thoughts, beliefs, will, and sensations. The dominant paradigm in neuroscience suggests that it is solely the product of brain activity. However, some observations imply that the body and the environment impact the formation of the mind.
The concept of the superior organ that simply receives signals from the body and the surrounding environment but interprets them based on its own interests, which often do not align with reality, may be simplistic. It seems that the interaction between the brain and body at each moment determines our self, identity, and mind. In my previous post, I discussed how the brain controls inflammation through various mechanisms and how it is related to conditions such as aging and metabolic disorders. This post highlights the impact of bodily inflammation on brain activity and cognition.
Inflammation is a natural process that occurs in response to tissue damage or infection. Upon release of pro-inflammatory compounds, immune cells migrate to the site of inflammation to eliminate the factors causing inflammation, clear cell debris, and initiate tissue repair. Then the immune system switches to an anti-inflammatory response. It stops the inflammation, a process known as the resolution of inflammation. Any interruption in the resolution of inflammation leads to chronic inflammation, which is linked to various diseases such as cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer.
One factor that may cause systemic inflammation is a cellular state known as cellular senescence. Cellular senescence occurs when cells are exposed to stress, including DNA damage, oncogene expression, or oxidative injuries resulting from free radicals. Senescent cells (SCs) are not capable of dividing and performing their functions. These cells begin to release inflammatory compounds to attract neighboring and immune cells eat them. Therefore, senescence is a physiological process that eliminates damaged cells which are susceptible to becoming cancerous if not removed. Chemical compounds secreted by SCs induce senescence in other cells and tissues. For this reason, SCs are known as "zombie cells."
The accumulation of SCs occurs in several pathological conditions, such as aging, due to the disruption of the normal immune response. This is mainly caused by the senescence of immune cells themselves. The accumulation of SCs and the inflammatory compounds secreted by them can cause systemic inflammation, which damages normal tissues and organs. Research has demonstrated that selectively destroying these cells in the elderly can mitigate age-related disorders such as muscle wasting, metabolic disturbances, immune dysfunction, bone fragility, cardiovascular disorders, and neurological and cognitive decline.
The brain has been affected by senescence in two aspects. First, brain aging is directly attributed to the accumulation of SCs in brain tissues, which leads to neuroinflammation and subsequent neurodegenerative illness and cognitive decline. On the other hand, accumulation of SCs in peripheral tissues due to aging, obesity or diabetes also causes mild to moderate systemic inflammation. Chemical inflammatory compounds can cross BBB or directly interact with the brain through areas with more permeable capillaries, known as circumventricular organs, such as the area postrema.
The inflammatory compounds associated with senescence can activate microglia, the immune cells of the central nervous system. This activation can lead to chronic neuroinflammation and oxidative stress, which in turn can impair neuronal function and contribute to the development of age-related cognitive decline and neurodegenerative diseases, such as Alzheimer's disease [3].
Furthermore, aging can also impact the operation of neural stem cells (NSCs), which play a role in producing new neurons in the brain. As we get older, the quantity and effectiveness of NSCs decrease, resulting in a decline in neurogenesis and a decrease in brain flexibility. Senescent cells can hinder NSC function by releasing inflammatory factors, which can disrupt NSC growth and specialization. Aging cells can compromise the integrity of the BBB by the same inflammatory factors, resulting in heightened permeability and the infiltration of immune cells into the brain [4].
Direct neuroinflammation or its induction by the accumulation of SCs in peripheral tissues and subsequent systemic inflammation can potentially affect the mind. The inflammation in the brain leads to impairment of cognition, memory problems, and changes in behavior and mood. The conditions that lead to a normal immune response in the removal of SCs cause systemic inflammation, including obesity, diabetes, and aging. The subsequent inflammation impacts indirectly on neuroinflammation and impairs normal brain functions and subjective experiences, which are known as the mind. Therefore, the physiological or pathological conditions of the body at any given moment determine our mood, feelings, perceptions, thoughts, and memory, and ultimately our state of mind.
References
2. Chris, G., & Anne, D. (2014). Diabetes and mental health. Clinical Medicine, 14(6), 669. doi:10.7861/clinmedicine.14-6-669
3. Zhang, P., Kishimoto, Y., Grammatikakis, I., Gottimukkala, K., Cutler, R. G., Zhang, S., . . . Mattson, M. P. (2019). Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model. Nat Neurosci, 22(5), 719-728. doi:10.1038/s41593-019-0372-9
4. Yousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., . . . Wyss-Coray, T. (2019). Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med, 25(6), 988-1000. doi:10.1038/s41591-019-0440-4
