BioTechniques News
Maddy Chapman
Age-related decline of chaperone-mediated autophagy alters the properties of senescent – or ‘zombie’ – cells, making them increasingly difficult to eliminate.
It’s officially spooky season, so it’s only fitting that we cover recent research into the accumulation of ‘zombie’ cells. Led by scientists at Albert Einstein College of Medicine (NY, USA), an international team has identified the process that causes a buildup of zombie cells as we age. Furthermore, they have highlighted a possible strategy for clearing this buildup, potentially lessening the severity of age-related diseases.
As the body ages, it begins to accumulate senescent cells – living cells that no longer function normally. Naturally, we look to malfunctioning cellular recycling systems for answers. Although we know these drivers of aging are linked, the nature of their interaction isn’t completely clear.
Now, researchers have characterized this link, demonstrating how declining activity of chaperone-mediated autophagy (CMA) – a process whereby specific cytosolic proteins are targeted for degradation in the lysosome – impairs senescent cells as well as the immune cells responsible for clearing them, which can lead to accumulation and disease.
They primarily used ear fibroblasts from 23- and 4-month-old mice to model aging in vitro, inducing senescence with the cancer drug palbociclib. ProteoSTAT staining was then employed to confirm loss of proteostasis and increased protein aggregation. The researchers attributed this to CMA decline due to the comparable results observed in fibroblasts from CMA-deficient mice. Further, fibroblasts from transgenic mice expressing a fluorescent CMA reporter allowed for CMA activity monitoring during senescence induction.
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The models revealed that CMA activity was upregulated following induced senescence in the 4-month-old fibroblasts. However, the 23-month-old fibroblasts showed lower CMA activity and lysosomal degradation. This resulted in a senescence-associated secretory phenotype, where zombie cells produce toxic substances that should have been broken down via CMA. These toxic substances then signal healthy cells around zombie cells to become senescent and interfere with the clearing capabilities of macrophages.
When tested in a model of lung fibrosis, activation of CMA using a small molecule called CA77.1 reduced senescent cell burden and attenuated disease progression in aged mice, demonstrating its potential as a therapeutic target.
“Our research connects two major drivers of aging – declining CMA and cellular senescence – and shows for the first time how their interaction allows senescent cells to evade clearance by the immune system in old organisms,” summarized Ana Maria Cuervo, senior author of the paper. “We’ve also found that instead of trying to kill zombie cells, we may be able to restore their interaction with the immune system so that the body can clear them naturally. The next challenge is determining whether this approach can eventually be developed into a safe treatment for age-related diseases in people.”
The post Digging up the thread of ‘zombie’ cell accumulation appeared first on BioTechniques.
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