Autophagy Machinery

What it is

Macroautophagy proceeds through five steps:

1. Initiation — ULK1 complex assembles at the ER (suppressed by mTOR, activated by AMPK).
2. Nucleation — Beclin-1 / VPS34 / PI3KC3 complex generates PI3P.
3. Elongation — LC3 lipidation (LC3-I → LC3-II) and ATG12–ATG5 conjugation expand the phagophore.
4. Closure & cargo recognition — p62/SQSTM1 and NBR1 tag cargo for selective autophagy.
5. Fusion & degradation — autophagosome fuses with the lysosome.

Why it matters in aging

ATG protein expression and lysosomal acidification decline with age, and flux at every step slows. The cell loses its main route for removing damaged organelles and aggregates, contributing to loss of proteostasis and mitochondrial dysfunction.

Selective subtypes

• Mitophagy — PINK1/Parkin pathway, BNIP3/NIX.
• Aggrephagy — p62, NBR1 (aggregates).
• Pexophagy — peroxisomes.
• Lipophagy — lipid droplets.
• Chaperone-mediated autophagy — LAMP2A-mediated, separate machinery.

What boosts autophagy

Rapamycin, caloric restriction, spermidine, exercise, intermittent fasting.

Related entries

Disabled macroautophagy, mTOR, AMPK.