Breakthrough in Aging Research: Lysosomal Cleanup Mechanism Revealed

Hutchinson-Gilford progeria syndrome, or HGPS, is a rare genetic disorder that accelerates aging in children, leading to symptoms like early skin wrinkling, loss of skin elasticity, and hardened arteries.

Research indicates that about ninety percent of HGPS cases involve a defective protein known as progerin. This protein has a dominant-negative effect, disrupting normal cell functions and causing issues such as nuclear envelope deformation, increased DNA damage, and reduced cell division.

Interestingly, progerin is also found in small amounts during natural aging and chronic kidney disease, suggesting that therapies enhancing progerin removal could have broader applications. A research team led by Professor Chuanmao Zhang has unveiled a critical process involving lysosomes, which are cellular compartments responsible for waste breakdown, in clearing progerin.

Their study, published in Science China Life Sciences, reveals that defects in lysosomal function lead to progerin accumulation in HGPS cells. By stimulating lysosome activity, researchers found they could restore the cellular cleanup process, helping to remove progerin and mitigate signs of aging.

This was achieved through immunofluorescence imaging, live-cell observations, and biochemical analyses, which tracked progerin behavior in cells. The researchers noted that progerin begins near the nuclear envelope and subsequently moves into the cytoplasm.

Typically, progerin is degraded by a critical recycling system known as the autophagy-lysosome pathway, but this system is inefficient in HGPS cells. RNA sequencing of primary HGPS cells revealed significant reductions in the activity of genes related to lysosome function, confirming the lysosomal defects.

To counteract this, the team activated lysosome biogenesis by stimulating protein kinase C or inhibiting mTORC1, successfully enhancing lysosomal function. The improvements led to increased progerin removal and reduced cellular aging markers like DNA damage and loss of cell vitality.

These findings establish lysosomes as vital agents in maintaining cellular health and suggest that therapies targeting lysosome activation could combat both premature and natural aging, potentially leading to new treatments for HGPS and various age-related diseases.

This research underscores the importance of harnessing the body’s own recycling mechanisms to address the challenges posed by aging and age-related disorders.