A hidden cellular cleanup trick could reverse aging

Progerin has a harmful "dominant-negative" effect on cells, meaning it interferes with normal cell function. This abnormal protein triggers multiple cellular problems, such as deformation of the nuclear envelope (NE), increased DNA damage, shortened telomeres, cell cycle arrest, and reduced ability to divide. Interestingly, growing evidence suggests that small amounts of progerin are also present during natural aging and in chronic kidney disease (CKD). Because of this, therapies that enhance the removal of progerin could hold promise for treating HGPS, CKD, and other conditions linked to aging.

Investigating How Cells Manage Progerin

A research team led by Professor Chuanmao Zhang from Peking University and Kunming University of Science and Technology has long been focused on uncovering the biological mechanisms behind aging and progeria. In a recent study published in Science China Life Sciences, the group identified a key process in which lysosomes -- tiny cellular compartments responsible for breaking down waste -- play a central role in clearing progerin.

Their study revealed that defects in lysosomes contribute to the accumulation of progerin in HGPS cells. More importantly, they demonstrated that stimulating lysosome activity can restore this cellular "cleanup" function, helping remove progerin and reducing signs of cell aging. These discoveries highlight lysosomes as an important new target for potential therapies in HGPS, CKD, and other age-related diseases.

How Progerin Builds Up Inside Cells

Using a combination of immunofluorescence imaging, live-cell observation, and biochemical analysis, the researchers tracked how progerin behaves inside cells. They observed that progerin, which first appears near the nuclear envelope, can move into the cell's cytoplasm through a process called nuclear envelope budding. Once in the cytoplasm, progerin should normally be degraded through the cell's autophagy-lysosome pathway -- a key recycling system.

However, in HGPS cells, this system fails to work efficiently, allowing progerin to accumulate. To investigate why, the team performed RNA sequencing on primary cells from two patients with HGPS. The results showed a significant reduction in the activity of genes linked to lysosome function. Further tests, including RT-qPCR, immunofluorescence, and biochemical assays, confirmed that lysosomes in these cells were indeed defective.

Restoring Lysosome Function to Fight Cellular Aging

Next, the researchers tested whether repairing the lysosomal defects could enhance progerin clearance and slow down cellular aging. They activated lysosome biogenesis -- the process by which new lysosomes are formed -- through two methods: by stimulating protein kinase C (PKC) or by inhibiting mammalian target of rapamycin complex 1 (mTORC1).

Both approaches successfully improved lysosome function, boosted the removal of progerin, and reduced signs of cellular aging, such as DNA damage, growth arrest, and loss of cell vitality. These findings suggest that reawakening the cell's own cleanup machinery could help reverse some of the harmful effects of progerin buildup.

Toward Anti-Aging Therapies Targeting Lysosomes

This research clearly establishes lysosomes as key players in removing progerin and maintaining cellular health. It also points to lysosome activation as a potential strategy for combating premature and natural aging. By targeting the body's built-in recycling systems, scientists may eventually find new ways to treat HGPS and a wide range of age-related diseases.