Disabled Macroautophagy

What it is

Macroautophagy (commonly just “autophagy”) is the process by which the cell encloses portions of its own cytoplasm in a double-membrane vesicle, the autophagosome, and fuses that vesicle with the lysosome for degradation. It is the cell’s main quality-control pathway for organelles and large protein aggregates.

Why it matters in aging

Autophagic flux declines with age across nearly all tissues studied. The consequences include accumulation of dysfunctional mitochondria, persistence of damaged proteins that the proteasome cannot handle, and inflammatory signalling driven by damage-associated molecular patterns.

Mechanisms

• mTORC1 inhibition activates autophagy; mTORC1 stays chronically high on Western diets.
• AMPK activation (energy stress) promotes autophagy.
• Selective subtypes: mitophagy (mitochondria), pexophagy (peroxisomes), aggrephagy (aggregates), lipophagy (lipid droplets).
• Lysosomal acidification declines with age, capping the throughput of the whole pathway.

What’s being studied

Rapamycin, spermidine, and caloric restriction all up-regulate autophagy in model organisms and (less robustly) in humans. Intermittent fasting raises autophagy markers in mouse studies; human translation is mixed.

Related entries

See also: Loss of proteostasis, Mitochondrial dysfunction, Rapamycin.