Restoring Cellular Recycling Helps Clear Zombie Cells in Aging Mice

As the body ages, cells that have stopped dividing or functioning properly—often called “zombie cells”—build up in tissues, contributing to chronic inflammation and age-related disease. A study led by researchers at Albert Einstein College of Medicine, published in Nature Aging, helps explain why these cells, formally known as senescent cells, become increasingly difficult to eliminate, and points to a possible strategy for helping the body clear them.

Working with mice, the researchers found that declining activity in a cellular recycling process called chaperone-mediated autophagy (CMA) impairs both senescent cells and the immune cells responsible for removing them. Restoring this recycling process reduced senescent-cell buildup and lessened the severity of lung fibrosis, a disease tightly connected to senescence.

“In older animals, age-related changes in both senescent cells and the immune cells responsible for removing them allow these zombie cells to accumulate and play a role in disease,” said study leader Ana Maria Cuervo. “By restoring cellular recycling, we may be able to help the body’s own defenses clear these cells more effectively.”

CMA relies on chaperone molecules that target damaged or unnecessary proteins for digestion. Dr. Cuervo had previously found that CMA activity declines with age, allowing cellular waste to build up in neurons and other cells and contributing to Alzheimer’s disease along with vascular and metabolic conditions such as atherosclerosis and diabetes. In the new study, her team investigated whether declining CMA also drives the accumulation of senescent cells, using experiments in mice alongside analyses of human lung tissue.

Senescent cells can be useful during wound healing, recruiting other cells to assist with tissue repair before being cleared by macrophages. Mice with macrophages genetically altered to lack CMA accumulated more senescent cells at wound sites and healed more slowly, indicating that CMA in macrophages is important for clearing cells that can interfere with repair.

When the researchers induced senescence in fibroblasts from young and old mice, cells from young mice increased CMA activity, while cells from old mice failed to do so, leading to undigested, toxic secretions and reduced recognition by macrophages, which themselves showed lower CMA activity with age. 

Daily treatment of aged mice with a CMA-activating compound called CA77.1 for five months reduced senescent-cell buildup, inflammation, and fibrosis, and restored macrophage function to levels seen in younger mice. In a mouse model of idiopathic pulmonary fibrosis, early treatment with CA77.1 reduced disease severity, and human IPF lung samples showed markedly reduced CMA activity.

“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,” said Dr. Cuervo. “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.”