Lysosomal Function

•Mechanistic— Core organelle in autophagy + signalling

What it is

Lysosomes are acidic (pH ~4.5) membrane-bound organelles containing ~60 hydrolytic enzymes (proteases, glycosidases, lipases, nucleases). They degrade material delivered by:

• Autophagosomes (macroautophagy).
• Endosomes (receptor-mediated and bulk endocytosis).
• Direct cytosolic protein import (chaperone-mediated autophagy, CMA) via LAMP2A.

Beyond degradation, lysosomes are signalling hubs — mTORC1 sits on the lysosomal surface, sensing amino acid availability.

Why it matters in aging

• Acidification declines with age — reducing enzyme activity even when enzyme abundance is preserved.
• CMA falls steeply with age, especially in liver, contributing to proteostatic decline.
• Lipofuscin — autofluorescent indigestible material — accumulates in lysosomes of post-mitotic cells (neurons, cardiomyocytes), reducing capacity.
• TFEB (transcription factor EB) is the master lysosomal-biogenesis regulator. mTORC1 phosphorylates TFEB to keep it cytoplasmic; reduced mTORC1 activity (fasting, exercise, rapamycin) liberates TFEB to the nucleus, expanding lysosomal capacity.

Lysosomal storage diseases as aging models

Inherited deficiencies of specific lysosomal enzymes cause Tay-Sachs, Gaucher, Niemann-Pick, Pompe, and others. These are not aging diseases but illustrate what happens when lysosomal capacity collapses.

Pharmacology

• Enzyme replacement therapy (recombinant lysosomal enzymes) for several storage disorders.
• Substrate reduction therapy (e.g. miglustat).
• Pharmacological TFEB activators (gemfibrozil, trehalose) in pre-clinical neurodegeneration work.

Related entries

Disabled macroautophagy, Autophagy machinery, Loss of proteostasis, mTOR.