A new study has demonstrated how declining chaperone-mediated autophagy impairs both senescent cell self-regulation and macrophage-mediated clearance, creating a compounding cycle of tissue dysfunction in ageing.
A new study by scientists at the Albert Einstein College of Medicine have identified a potential new way to help the body clear so-called ‘zombie cells’ that accumulate with age and contribute to chronic inflammation and age-related diseases.
The research found that an age-related decline in a cellular recycling process makes it harder for both senescent cells and the immune cells responsible for removing them to function properly.
The findings suggest that restoring this recycling process could help reduce the accumulation of senescent cells and ease disease linked to ageing.
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. By restoring cellular recycling, we may be able to help the body’s own defenses clear these cells more effectively.”
Dr Ana Maria Cuervo, Distinguished Professor of Developmental & Molecular Biology and of Medicine, the Albert Einstein College of Medicine
When cellular recycling declines
The research focused on chaperone-mediated autophagy (CMA), a process that helps cells identify and recycle damaged or unwanted proteins.
Previous research by Dr Cuervo found that CMA activity declines with age. The new study investigated whether this decline could also contribute to the accumulation of senescent cells.
Most experiments were carried out in mice, while analysis of human lung tissue provided evidence that the findings could also be relevant to people.
Senescent cells can play a useful role during processes such as wound healing. However, they normally need to be removed once their role is complete. Macrophages, a type of immune cell, are responsible for clearing them while also regulating inflammation and tissue repair.
Researchers found that mice whose macrophages lacked CMA accumulated more senescent cells at wound sites and healed more slowly.
Ageing creates a vicious cycle
The researchers also found important differences between senescent cells from young and old mice.
Cells from young animals increased their CMA activity when they became senescent. Cells from older animals failed to make this adjustment because their CMA activity was already low.
As a result, certain proteins were not properly broken down. The senescent cells released substances that encouraged nearby healthy cells to become senescent and made it harder for macrophages to recognise and remove them.
CMA activity was also lower in macrophages from older animals, further reducing their ability to engulf and eliminate senescent cells.
Potential treatment
The researchers tested a small-molecule CMA activator called CA77.1 in aged mice. Five months of daily oral treatment reduced the accumulation of senescent cells in several organs and lowered signs of inflammation and fibrosis.
In a mouse model of idiopathic pulmonary fibrosis, an age-related disease in which scar tissue builds up in the lungs, early treatment with CA77.1 also reduced fibrosis, cellular senescence and inflammation.
“Our research connects two major drivers of ageing – 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.”
No comments yet