Why does psychological stress cause an apparent acceleration of measures of aging? Effects on immune function have been considered, given that stress produces measurable changes in immune-affecting signaling and inflammation, as well as on the average telomere length in immune cells taken from blood samples. That metric indicates increased replication stress placed on immune cells. Telomeres, caps of repeated DNA at the ends of chromosomes, shorten with each cell division. When too short, somatic cells - such as immune cells - become senescent or self-destruct. Immune cell replication is governed by the response to invasive threats, driven by signals that are also triggered to some degree by psychological stress and the molecular damage of aging.
The accumulation of senescent cells is a meaningful cause of aging. Even in late life, their numbers appear to be quite dynamic, but the rate of creation is raised and the rate of clearance by the immune system is reduced. Senescent cells secrete a mix of signals that provokes chronic inflammation and numerous forms of changed cell behavior that cause tissue dysfunction. Clearing senescent cells in mice results in a sizable degree of rejuvenation, achieved quite rapidly. Senescent cells actively maintain a distorted, dysfunction state of metabolism, and removing them is an important goal.
Here researchers provide concrete data for the effects of stress on the aging of the brain to involve an increased generation of senescent cells. In recent years, researchers have demonstrated that senescent supporting and immune cells in the brain are an important cause of neurodegeneration, with benefits achieved in mouse models via clearance of senescent cells. One can begin to form a hypothesis in which any situation in which immune cells are pressured into greater replication, such as persistent infection, presence of molecular waste such as amyloid-β, or psychological stress, will increase the number of problem senescent cells in the brain, thus contributing to neurodegeneration.
When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. 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. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging.
We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16INK4a was increased in the hippocampus, and senescence-associated β-galactosidase (SA-β-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-β-gal or p16INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits.
Our data suggests 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.