Biology: Autofagie

Time-restricted eating, the ketogenic diet and exercise are sold on a longevity promise, and the mechanism they invoke is usually autophagy. The core genes were first worked out in yeast by Yoshinori Ohsumi, who received the 2016 Nobel Prize in Physiology or Medicine. The same machinery runs from yeast to humans. The popular fasting story claims more than has been shown in people.

What It Is

Autophagy, from the Greek for self-eating, is how a cell breaks down and reuses its own worn-out parts. A double membrane forms around a piece of cargo, a clump of damaged protein or a worn-out organelle, and closes into a bubble called an autophagosome. The autophagosome fuses with the lysosome, where enzymes break the contents down and return the raw materials to the cell. That is recycling and quality control in one process.

Autophagy runs at two speeds. A low level runs constantly as housekeeping, clearing the daily buildup of damaged components. Under starvation it speeds up sharply, because a cell cut off from outside food can break down its own least essential parts to free amino acids and keep going.

The Switches

Autophagy exists and does this job; that much is settled biology. The open question is how much any particular behavior changes it in a person, and whether you would notice. The mechanism is fuel sensing. Autophagy tracks how much energy the cell has, and two enzymes push the same target in opposite directions. mTOR, the growth sensor, is active when nutrients and insulin are plentiful; it holds autophagy down, so the cell builds instead of recycling. AMPK, the energy sensor, switches on when fuel runs low and turns autophagy up.

Both act on the same starting enzyme, ULK1. When food is abundant, mTOR tags ULK1 at a site that keeps it inactive, and blocks AMPK from engaging it. When energy drops, mTOR lets go of ULK1, and AMPK tags it at a different site to switch it on.

This is why several practices produce the same output. Low insulin, low energy availability, and drugs that block mTOR all converge on this one enzyme. It is also why the practices that plausibly raise autophagy are the ones that lower mTOR or raise AMPK: going without food, restricting energy, and exercising.

What Turns It Up

In mice, 24 hours without food produced a sharp rise in autophagy, including in neurons, a tissue once thought to be spared. That is a clean demonstration in a living animal that going without food drives the process. A mouse metabolism runs far faster than a person's, so these fasting durations do not carry over directly to people.

In the roundworm C. elegans, eating less extends lifespan. Switch off the essential autophagy genes and that lifespan gain disappears. Autophagy does two jobs here: eating less switches it on, and it partly explains why eating less lengthens life.

Two other interventions do the same. Spermidine, a compound in foods like wheat germ and aged cheese, induces autophagy and extends lifespan in yeast, flies and worms. Rapamycin, an mTOR blocker, extends lifespan in mice even when started in old age.

Researchers engineered mice whose everyday autophagy worked normally but could not increase during exercise. Those mice had less endurance and lost the blood-sugar benefit exercise usually gives. Removing the exercise-triggered burst of autophagy removed one of exercise's metabolic payoffs, in a mouse.

Every result so far comes from yeast, worms, flies, mice or cultured cells, no human data yet.

In People

In people the evidence is thin, for one technical reason: autophagy is hard to measure in a living human. Measuring it means measuring a rate, the speed of capture and disposal.

Its most-cited marker, LC3-II, rises both when autophagy speeds up and when it stalls at the final disposal step, so a single measurement cannot tell the two apart.

The 2021 consensus guidelines (Klionsky) stress this. Telling a real rise from a stall at the disposal step needs rate measurements that are routine in cultured cells but largely impractical in living people. So a single blood marker cannot show that a fast raised autophagy in you.

The best direct human signal so far is small. In 11 adults with overweight, eating within an early six-hour window instead of a twelve-hour one raised expression of one autophagy gene, LC3A. It also lowered 24-hour average glucose by about 4 mg/dl over four days. LC3A messenger RNA sits upstream; a rise in it does not confirm autophagy actually ran. That is a single-gene signal in a crossover trial of eleven people over four days, far short of a health outcome driven by autophagy.

None of this means fasting does nothing, or that autophagy fails to respond in people. A lack of measurement is not a lack of effect. The mechanism is well worked out in simpler systems. Whether a sixteen-hour fast meaningfully changes autophagy in your body, and whether that would help you, has mostly not been shown either way.

Evidence

The Research & Studies

Everything here is based on the research we have collected and checked, sorted into groups and ordered with the strongest evidence first. Click any claim to open the studies behind it.

How it works

Cells wrap up their worn-out parts and recycle them in the lysosomeStrong

In plain terms

Autophagie, wat zelf-eten betekent, is hoe een cel zijn eigen kapotte onderdelen opruimt en de grondstoffen hergebruikt. Het loopt continu op een laag niveau en versnelt wanneer voedsel schaars is.

In detail

This review lays out the process: a double membrane forms around cytoplasmic cargo, damaged proteins and organelles, closes into an autophagosome, and fuses with the lysosome where the contents are degraded and the building blocks returned to the cell. The genes that run it were first identified in yeast, work for which Yoshinori Ohsumi received the 2016 Nobel Prize in Physiology or Medicine, and are conserved across eukaryotes. Basal autophagy is constant quality control; starvation-induced autophagy is a survival response that liberates nutrients when external supply is cut off.

Who this may not transfer to:A mechanism established in cells across eukaryotes, including human cells; there is no participant group.

The study · 1

Mizushima, Autophagy: process and function · Genes Dev 2007

mTOR keeps autophagy off when fuel is plentiful; AMPK switches it on when fuel is lowStrong

In plain terms

Autophagy has an on-off switch tied to how much fuel the cell has. Plenty of food keeps it off through a sensor called mTOR; running low turns it on through a fuel gauge called AMPK.

In detail

Kim and colleagues showed that AMPK promotes autophagy by directly phosphorylating and activating ULK1, while under nutrient-rich conditions mTOR phosphorylates ULK1 at a different residue that prevents AMPK from engaging it. So the same initiating enzyme is held off by the growth sensor and switched on by the energy sensor, which is the molecular reason fasting, energy restriction and mTOR inhibitors all raise autophagy. This is biochemistry and cell-culture evidence, not a human outcome.

Who this may not transfer to:Biochemistry and cell-culture work, including human cell lines; not a measured human outcome.

The study · 1

Kim et al., AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 · Nat Cell Biol 2011

No simple blood test shows autophagy running, because it is a flux markers read two waysStrong · mixed

In plain terms

There is no simple blood test that shows autophagy is running in you. The usual markers can move for opposite reasons, and measuring it properly needs techniques that are hard to do in living people.

In detail

The consensus guidelines for monitoring autophagy set out that autophagy must be assessed as a flux, the rate at which cargo is delivered and degraded, not as the level of any one marker. LC3-II, the most-cited marker, accumulates both when autophagy is induced and when the final lysosomal degradation step is blocked, so a single measurement is ambiguous without a flux control. These controls are routine in cultured cells but largely impractical in living humans, which is why confident claims that a set fasting duration triggers autophagy in a person are extrapolations from cells and animals, not direct measurements.

Who this may not transfer to:A statement about measurement drawn from consensus assay guidelines, not a human outcome.

The study · 1

Klionsky et al., Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) · Autophagy 2021

A 24-hour fast sharply raised autophagy in mouse neurons once thought sparedModerate

In plain terms

When mice were fasted for a day or two, autophagy switched on strongly even in brain cells, which had been assumed to be spared.

In detail

Alirezaei and colleagues found that a short fast produced profound upregulation of autophagy in the neurons of mice, measured by conversion of the LC3 marker and the appearance of autophagosomes, rising at 24 hours and further at 48 hours. The result mattered because neurons had been considered protected from starvation-induced autophagy. It is a clean demonstration that fasting drives autophagy in a living organism, in a specific tissue.

Who this may not transfer to:Measured in mice, whose metabolism runs far faster than a person's, so the fasting durations do not transfer directly.

The study · 1

Alirezaei et al., Short-term fasting induces profound neuronal autophagy · Autophagy 2010

Eating less extends worm lifespan only when the autophagy genes workModerate

In plain terms

In worms, eating less makes them live longer, but only if their autophagy genes are working. Switch autophagy off and the life extension from dietary restriction disappears.

In detail

Hansen and colleagues showed that dietary restriction in C. elegans requires functional autophagy genes to extend lifespan: knocking down core autophagy genes prevented the lifespan extension that dietary restriction otherwise produced, and blunted the longevity of related low-nutrient-signalling mutants. It is among the cleanest evidence that autophagy is part of why eating less lengthens life, in an invertebrate model.

Who this may not transfer to:Established in the worm C. elegans; there is no human equivalent and it could not be tested the same way.

The study · 1

Hansen et al., A role for autophagy in the extension of lifespan by dietary restriction in C. elegans · PLoS Genet 2008

Spermidine switched on autophagy and extended lifespan in yeast, flies and wormsModerate

In plain terms

Spermidine, a compound in foods like wheat germ and aged cheese, switched on autophagy and lengthened life in yeast, flies and worms, and its life-extending effect needed autophagy to be working.

In detail

Eisenberg and colleagues reported that spermidine triggered autophagy and extended lifespan in yeast, fruit flies and nematodes, and suppressed markers of oxidative stress and necrosis in cultured human immune cells. When autophagy genes were deleted, the lifespan benefit disappeared. Spermidine has since been studied as a caloric-restriction mimetic, a compound that reproduces some effects of eating less without the food restriction.

Who this may not transfer to:Model organisms plus cultured human immune cells; not a demonstrated human lifespan effect.

The study · 1

Eisenberg et al., Induction of autophagy by spermidine promotes longevity · Nat Cell Biol 2009

Muizen die autofagie niet konden opvoeren, verloren het bloedsuikervoordeel van inspanningModerate

In plain terms

Muizen die alledaagse autofagie konden uitvoeren maar deze niet konden opvoeren tijdens inspanning, kregen niet het gebruikelijke bloedsuikervoordeel van inspanning, wat suggereert dat de toename in autofagie deel uitmaakt van de reden waarom inspanning helpt.

In detail

He en collega's maakten een knock-in-muis waarvan de autofagiemachinerie niet kon worden gestimuleerd door inspanning of vasten, terwijl de basale autofagie normaal bleef. Deze muizen vertoonden een verminderd uithoudingsvermogen tijdens acute inspanning en kregen niet de gebruikelijke bescherming die inspanning biedt tegen door een vetrijk dieet veroorzaakte glucose-intolerantie. Het verwijderen van de door inspanning veroorzaakte piek in autofagie verwijderde één metabool voordeel van inspanning, wat de twee met elkaar verbond bij een muis.

Who this may not transfer to:A mouse-genetics result; exercise-induced autophagy has not been measured this way in people.

The study · 1

He et al., Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis · Nature 2012

Longevity And Mortality

Rapamycine verlengde de levensduur van muizen met 9 tot 14 procent, zelfs wanneer het op oudere leeftijd werd gestartStrong

In plain terms

A drug that blocks the mTOR sensor, one of the ways autophagy gets switched on, made mice live longer even when given in old age.

In detail

In het NIA Interventions Testing Program verlengde rapamycine, gevoerd aan genetisch heterogene muizen vanaf de leeftijd van 600 dagen (ruwweg overeenkomend met leeftijd 60 bij mensen), zowel de mediane als de maximale levensduur. Op basis van de leeftijd bij 90 procent sterfte was de toename 9 procent voor mannetjes en 14 procent voor vrouwtjes, en het effect hield stand op drie onafhankelijke testlocaties. mTOR-remming verhoogt onder andere autofagie, en het resultaat is herhaald in meerdere laboratoria, waardoor het een van de meer robuuste farmacologische levensduurverlengingen bij zoogdieren is. Rapamycine heeft ook immunosuppressieve en metabole bijwerkingen.

Who this may not transfer to:Measured in mice; rapamycin has immune and metabolic side effects and no human lifespan effect has been shown.

The study · 1

Harrison et al., Rapamycin fed late in life extends lifespan in genetically heterogeneous mice · Nature 2009

Heart And Vascular

Mensen die meer spermidine aten, hadden een lagere bloeddruk en minder hartziekte, een verbandEmerging

In plain terms

Mensen die meer voedsel rijk aan spermidine aten, hadden een lagere bloeddruk en minder hartziekte. Dit is een verband in een enquête, geen bewijs dat spermidine dit veroorzaakte.

In detail

Eisenberg en collega's combineerden dierstudies, spermidine gevoerd aan muizen verminderde cardiale veroudering en verlengde de levensduur, met een epidemiologische analyse bij mensen waarin een hogere inname van spermidine via de voeding correleerde met een verlaagde bloeddruk en een lagere incidentie van hart- en vaatziekten. Het menselijke deel is observationeel: het toont een correlatie, en de inname van spermidine via de voeding gaat samen met een plantrijk dieet, dus kan het op zichzelf niet vaststellen dat spermidine het werkzame bestanddeel is.

Who this may not transfer to:A mixed-sex community cohort; the mechanism arm was in mice, so the human data point to spermidine as a correlation and cannot show it is the cause on their own.

The study · 1

Eisenberg et al., Cardioprotection and lifespan extension by the natural polyamine spermidine · Nat Med 2016

Blood Sugar

Een 6-urig eetvenster verhoogde licht één autofagiegen en verlaagde de 24-uurs glucose met 4 mg/dl bij 11 volwassenenEmerging

In plain terms

In een kleine cross-overstudie zorgde het samenpersen van maaltijden in een 6-urig ochtendvenster voor een lichte stijging van één autofagiegen en verlaagde het bescheiden de gemiddelde bloedsuiker vergeleken met een normaal eetvenster.

In detail

Jamshed en collega's voerden een 4-daagse gerandomiseerde cross-overstudie uit bij 11 volwassenen met overgewicht, waarbij vroeg tijdsbeperkt eten (8 uur 's ochtends tot 14 uur) werd vergeleken met een 12-urig venster (8 uur 's ochtends tot 20 uur). Vroeg tijdsbeperkt eten verhoogde de ochtendexpressie van het autofagiegen LC3A (p<0.04) en het verouderingsgen SIRT1, verlaagde de gemiddelde 24-uurs glucose met 4 plus of min 1 mg/dl en verminderde glykemische schommelingen, en verschoof de expressie van circadiane klokgenen. LC3A-boodschapper-RNA is één enkele upstream-marker van autofagiecapaciteit, geen meting van autofagische flux, dus dit toont een aanwijzing van een autofagiesignaal, geen bewijs dat autofagie toenam.

Who this may not transfer to:Eleven adults with overweight, 7 men and 4 women, over four days, measured through a single gene-expression marker instead of autophagy running.

The study · 1

Jamshed et al., Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans · Nutrients 2019

Nearly all this work was done in animals and cells. You cannot run a controlled experiment that gives people a different autophagy system. The mechanism is settled in animals; the two human results are a single-marker crossover and an observational association.

Go Deeper

Related practices and processes, two of them sold on a longevity promise:

• Time-restricted eating and the ketogenic diet, the eating patterns most often tied to autophagy, each studied in people for its effect on glucose and weight.
• Hormesis, why a limited stress, followed by real recovery, leaves the body stronger.
• Mitochondria, among the worn-out organelles autophagy clears.

Common Questions

Does a sixteen-hour fast trigger autophagy?

In animals, clearly. The popular sixteen-hour figure is borrowed from mouse studies, where metabolism runs far faster than ours, so the timing does not transfer cleanly. No human trial has yet measured a set fasting length driving autophagy up in a person.

If most of the evidence is from animals, is fasting pointless?

No. Fasting and time-restricted eating carry their own human evidence for glucose and weight, covered on the two pages linked above. What has not been shown is the last step of the popular story: that a given fast produces a measured autophagy increase in you, and that this increase is what delivers the benefit.

What about spermidine or rapamycin supplements?

Higher dietary spermidine intake tracks with better heart outcomes in people, though that association is tangled up with an overall plant-rich diet. Rapamycin carries immune and metabolic side effects, and its longevity use is off-label. Neither has been shown to extend human life.