Fasting-duration thresholds that step up autophagy
Nutrients keep mTOR active and autophagy locked down.
Amino acids and insulin keep mTORC1 fully active.
Active mTORC1 phosphorylates ULK1, blocking the initiation complex.
Fed mTOR directly blocks the ULK1 autophagy switch.
Liver glycogen covers energy demand right after meals.
No AMPK stress signal is generated yet.
A small constitutive flux clears damaged organelles.
This floor stays active even in the fed state.
Glycogen depletes and AMPK starts to stir.
Liver glycogen reserves fall close to empty.
Blood glucose starts drifting lower.
Falling ATP nudges AMPK toward activation.
This is the first measurable metabolic shift.
12h marks the first detectable AMPK signal rise.
Autophagosome formation increases only modestly.
mTOR still restrains most of the machinery.
The mTOR brake loosens as AMPK gains ground.
AMPK directly inhibits mTORC1 at two points.
This is the classic 16:8 fasting window.
16h is where popular time-restricted eating lands.
Reduced mTORC1 phosphorylation releases ULK1.
Initiation complex assembly becomes possible.
Fat-derived ketones start supplementing glucose.
This further signals a fasted metabolic state.
A full day fasted flips the switch decisively.
Low mTORC1 lets ULK1 phosphorylate Beclin-1.
Phagophore nucleation ramps up broadly.
24h fasting produces a clear step-change in flux.
Cells show a marked jump in vesicle count.
Damaged proteins and organelles get tagged fast.
FOXO3 and related transcription factors activate.
Autophagy gene expression rises broadly.
Extended fasting reaches peak autophagy activation.
Further fasting yields diminishing extra activation.
The system has reached a functional ceiling.
48h is the practical ceiling for fasting-driven activation.
TFEB activation expands degradation capacity.
This supports the sustained autophagosome load.
A single meal restores mTOR within hours.
The threshold system resets quickly after eating.