Science published an atlas of lysosomes from old mice, revealing a signature of lysosomal storage diseases

Science published an atlas of lysosomes from old mice, revealing a signature of lysosomal storage diseases

On July 30, Science published a study in which researchers measured lysosomal contents in young and old mice. Lysosomes in the brain, heart, skeletal muscle, and white adipose tissue of old animals contained more cystine and glycerophosphodiesters.

A lysosome is a cellular compartment where molecules are broken down. If an enzyme or transporter protein does not function, breakdown products remain inside. This causes lysosomal storage diseases. In Batten disease, mutations in CLN3 impair the export of glycerophosphodiesters, while in cystinosis, cystine accumulates in lysosomes.

In the Science paper, Anna Puchynska, Jonathan Weissman, and their colleagues isolated lysosomes from mouse tissues and measured their contents. The same signature appeared across four tissues in animals aged 24–26 months: glycerophosphodiesters, which are fragments of membrane lipids, and cystine. Whole tissue analysis did not detect this signature because the lysosomal contents were mixed with those of the rest of the cell.

In these mice, aging left a chemical signature within lysosomes rather than changing the average composition of the tissue. Researchers can now test whether this pattern is related to molecular transport across the lysosomal membrane, lipid breakdown, or metabolism between cellular compartments.

The authors repeated the measurements in ordinary mice without a genetic label and again observed accumulation in the brain and heart. The same two classes of compounds were elevated in the brains of old rats. The open author manuscript links this signature in the old brain to microglia and neurons.

The similarity to lysosomal storage diseases indicates where researchers can look for the mechanism. Specific defects underlying these rare inherited diseases are already known, including which protein transports a molecule, which enzyme breaks it down, and where the cargo remains. Researchers can now test which of these processes leave glycerophosphodiesters and cystine inside lysosomes in aging tissues.