Not quite alive and not quite dead, either. Such is the state of senescent cells, which accumulate as we age, promoting inflammation and hampering the function of our tissues and organs, including our brains. Senescent cells have even been called zombie cells, although that moniker can be misleading. Senescent cells, unlike zombies, do not eat brains. When senescent cells do accumulate in the brain, they alter neuropsychiatric function, heightening anxiety—particularly in obese people and mice.

To detail the relationship between obesity and obesity-induced anxiety, scientists based at the Mayo Clinic used mouse models of senescence to uncover a relationship between the accumulation of senescent brain cells and the accumulation of fat deposits in the brain. When senescent cells in the brains of obese mice were eliminated by senolytic drugs, the scientists observed that neurogenesis was restored and that symptoms of anxiety were alleviated.

These findings suggest that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.

Additional details of the Mayo team’s work appeared in the journal Cell Metabolism, in an article titled, “Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis.” This article describes how the Mayo team, led by Diana Jurk, PhD, and James Kirkland, MD, PhD, used the INK-ATTAC mouse model, from which p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin.

“We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs,” the article’s authors wrote. “Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed ‘accumulation of lipids in senescence.’ Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior.”

Essentially, the scientists determined that the study mice developed more fat cells in the lateral ventricle, a brain area that controls anxiety, and that the mice had a significant increase of senescent cells in that region. Clearing the cells with senolytic drugs in the two mouse models resulted in anxious behavior ending; lipid cells in the brain disappearing; and neurogenesis, or normal neurological cell growth, resuming.

How do you tell if a mouse has anxiety? Several tests are used. An anxious mouse tends to avoid open areas in its environment, and it tends to move only along the outside walls or corners of its enclosure. Also, anxious mice behave differently in mazes, performing poorly and with hesitation, often not completing the test. After removal of the zombie cells, the mice did much better even though they were still obese.

In their paper, the authors say, “Our data demonstrating a link between obesity, senescence, and anxiety-like behavior provide critical support for the potential feasibility of administering senolytics to treat obesity-associated anxiety-like behavior, provided that clinical trials validate this approach.”

“When lipids are available, senescent cells cannot effectively metabolize them, which in turn results in increased genomic instability, release of cytoplasmic chromatin fragments, and induction of the senescence-associated secretory phenotype,” the article’s authors speculated. “Despite increasing evidence that anxiety is associated with decreased quality of life, increased depression, and suicide in obesity, there are currently no mechanism-based treatments available. Here, we show that cellular senescence provides a potential explanation for increased anxiety in obese individuals and that targeting senescent cells holds promise as a therapeutic strategy.”

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