Researchers at the Albert Einstein College of Medicine revealed in Nature Aging that age-related declines in a cellular recycling system called chaperone-mediated autophagy allow lingering zombie cells
to evade immune clearance, driving chronic inflammation and tissue damage across the body as organisms age.
As organisms grow older, their tissues accumulate senescent cells—living cells that have stopped dividing or functioning normally yet refuse to die. Formally known as senescent cells, these lingering entities release inflammatory substances that damage surrounding tissue and contribute to various age-related conditions. While scientists have long understood that these cells build up over time, a new international study demonstrates that the breakdown of an internal cellular cleanup crew prevents the immune system from sweeping them away.
Chaperone-Mediated Autophagy Breakdown Impairs Macrophage Clearance
The research focuses on chaperone-mediated autophagy, or CMA, a specialized cellular recycling process that identifies damaged or unnecessary proteins and targets them for degradation. Previous work directed by Ana Maria Cuervo established that CMA activity declines with age, resulting in internal cellular trash accumulation. The latest experiments show that this age-related decline strikes both the senescent cells and the macrophages—specialized immune cells responsible for clearing cellular debris.
When researchers evaluated macrophages from young and aged mice, they observed a significant reduction of CMA activity in older animals. Furthermore, experiments involving mice genetically engineered to lack CMA in their macrophages revealed that these animals accumulated more senescent cells at wound sites, leading to slower tissue healing. According to the study, reduced CMA altered the secretions of senescent cells, which in turn suppressed CMA within macrophages and crippled their ability to engulf the damaged cells.
“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.”
Ana Maria Cuervo, Albert Einstein College of Medicine
Describing the mechanics of this cellular breakdown, immunologist Roel de Maeyer of the University of Oxford noted that rejuvenating the body’s immune system could rectify numerous downstream problems associated with aging. In addition, Povsin pointed out that senescent cells often deploy CD47—a so-called don’t eat me
signal—to actively suppress macrophages from destroying them. Andreasson remarked upon discovering that old mice accumulated many senescent neutrophils that the findings offered a striking perspective on how short-lived immune cells accumulate.
Restoring Cellular Recycling Reduces Senescent Cell Burden in Mice
To test this hypothesis, investigators administered CA77.1, a small-molecule CMA activator previously developed by the team.
Aged mice receiving CA77.1 orally every day for five months exhibited a reduced accumulation of senescent cells across multiple organs, alongside marked decreases in systemic inflammation and tissue fibrosis. Treating macrophages from aged mice with the same small molecule successfully restored their engulfment capabilities.
The collaborative effort behind these findings involved a team of researchers based at the Albert Einstein College of Medicine.
Treating Idiopathic Pulmonary Fibrosis in Human Aging
The investigators also examined human lung tissue samples to determine whether the findings translate to human pathology, focusing on idiopathic pulmonary fibrosis, an age-associated disease characterized by progressive scarring in the lungs.
Analysis of lung samples from patients with idiopathic pulmonary fibrosis revealed diminished CMA activity. When researchers tested CA77.1 in a mouse model of the disease, early treatment successfully attenuated disease progression, reduced tissue scarring, and lowered markers of cellular senescence and inflammation.
The study demonstrates that reactivating cellular recycling could offer a viable therapeutic strategy. Will further evaluation prove that these interventions can be safely adapted into treatments for human age-related diseases?