Mind the Gap: Erasing Senescent Cells Alleviates Memory Loss Caused by Chronic Unprecedented Stress

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Mind the Gap: Erasing Senescent Cells Alleviates Memory Loss Caused by Chronic Unprecedented Stress

When stress persists for a long time, it can trigger serious health problems, particularly depression. The World Health Organization (WHO) recently reported that more than 300 million individuals of all ages have depression, estimating that 10% to 15% of the general population will experience clinical depression in their lifetime.

What’s more, recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress.

In an article published in the journal Neurobiology of Stress, researchers found that mice subjected to chronic unpredictable stress exhibit depression-like behaviors and cognitive decline that correlate with senescence — a stable state of cell cycle arrest that occurs because of damage or stress and is considered a sign of aging. They found that the levels of senescence markers were elevated in these mice and were strongly correlated to that severity of memory impairment. 

When the research team from National Cheng Kung University in Taiwan treated these chronically stressed mice with a pharmacological cocktail that targets senescent cells, they observed alleviated cognitive deficits, suggesting that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline.

“Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits,” proposed Lin and colleagues, the study’s authors. “Our work suggests that targeting senescent cells in the brain may serve as a new therapeutic target to prevent and treat chronic stress-related memory loss.”

Erasing Senescent Cells Alleviates Memory Loss Caused by Chronic Unprecedented Stress

Does stress cause brain aging?

Stress is not necessarily harmful. Mild stress can promote alertness, motivation, and readiness to respond to danger. However, excessive stress or chronic stress may increase the risk of health problems and lead to various mental diseases, particularly depression. Exposure to long-term unpredictable environmental stress is widely recognized as the main determinant of the risk and severity of mental illness.

Chronic stress not only induces depression that may lead to the worst outcome, suicide, but may also affect how individuals feel and even change how they think, causing cognitive impairment. Furthermore, previous studies have shown that individuals with chronic stress also have a higher risk of memory loss and increased neurodegenerative risk, including Alzheimer's disease. Studies show that depressed patients have a higher rate of brain aging than healthy subjects. So, there is value in exploring whether chronic stress could accelerate brain aging.

Clearing senescent cells alleviates stress induced brain aging

To better understand the link between stress and brain aging, Lin and colleagues exposed mice to chronic unprecedented stress — random, intermittent, and unpredictable exposure to various stressors for weeks, such as being deprived of water or food.

These mice displayed a major gain in depressive-like behaviors compared with non-stressed mice. Additionally, the stressed mice performed much more poorly on memory tasks. These behavioral changes were tied to increases in senescence markers in the brain, particularly in the hippocampus — the brain region tied to memory and learning.

However, with a cocktail of drugs that target senescent cells for elimination, consisting of dasatinib and quercetin, Lin and colleagues were able to reduce the number of senescent cells and improve cognitive functions compared with the outcomes observed for vehicle-treated mice. Importantly, the clearance of senescent cells by senolytics alleviated chronic stress-induced cognitive deficits.

“Our proof-of-principle experiments help improve the present understanding of the impact of cellular senescence and demonstrate that therapeutic interventions to clear senescent cells or block their effects may open a new avenue to treat or delay chronic stress-related dysfunctions and improve human health,” concluded Lin and colleagues.

Show references

Lin YF, Wang LY, Chen CS, Li CC, Hsiao YH. Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress. Neurobiol Stress. 2021;15:100341. Published 2021 May 18. doi:10.1016/j.ynstr.2021.100341

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