Autophagy is one of those things that sounds horribly complicated until you strip it back to what it actually is: essentially the body’s own cellular housekeeping and recycling system at work. Our cells are constantly producing proteins, membranes, mitochondria and other bits and pieces that eventually become damaged, worn out or simply no longer useful, and autophagy is the process by which the cell identifies some of this material, breaks it down and recycles the components so they can either be reused or disposed of, meaning that rather than just allowing cellular rubbish to accumulate, the body has a built-in system for having a bit of a clear-out and keeping things functioning properly.
The interesting bit is what controls whether the cell is concentrating more on building and growing or more on maintenance and recycling, and one of the major players in that decision is mTOR, which stands for mechanistic target of rapamycin and is essentially one of the body’s major nutrient and growth sensors, so when nutrients and energy are readily available, mTOR is activated and the message to the cell is basically “we’ve got plenty of resources, let’s build”, which means increased protein synthesis, growth and repair, whereas when nutrients are scarce and those growth signals fall, mTOR activity decreases and the brakes come off some of the processes involved in autophagy.
However, when people talk about “switching mTOR off” to encourage autophagy, it is worth being a little bit careful with the wording because we don’t actually want mTOR permanently switched off because mTOR is absolutely essential for normal growth, protein synthesis, muscle maintenance, tissue repair and a whole load of other things, and what we are really talking about is periodically reducing mTORC1 activity sufficiently for the balance to move away from constant growth and towards cellular maintenance and recycling, which is a much more accurate way of looking at it.
One of the strongest nutritional signals involved in mTOR is leucine – one of the three branched-chain amino acids alongside 2 others: isoleucine and valine. Leucine in particular acts as a very important signal that amino acids are available and that the cell has the raw materials it needs to make proteins, so when leucine levels rise, mTOR is stimulated and protein synthesis increases while autophagy is suppressed, which makes perfect sense biologically because if you have just eaten a protein-rich meal, your body is being told that there is plenty of material available for building and repair, so there isn’t much point in the cell immediately going into recycling mode. Isoleucine and valine are also involved in this whole nutrient-sensing picture, although leucine is generally considered the more powerful direct activator of mTOR, and all three are important amino acids that we need, so this isn’t an argument for avoiding them, because that would be missing the point completely. It’s more about understanding that the presence of amino acids, particularly after eating protein, is one of the signals that tells the body that it is in a fed, resource-rich state, whereas during a period without food those circulating nutrient signals gradually fall and the environment becomes more favourable to autophagy.
Methionine is another interesting amino acid because it’s also essential to this process, meaning we cannot simply decide that we don’t need it, but its availability is also involved in nutrient sensing. Methylation and several metabolic pathways associated with growth and longevity, and research into methionine restriction has been particularly interesting because reducing methionine availability in experimental models can influence pathways involved in mTOR, autophagy and metabolic health, although that absolutely should not be interpreted as “methionine is bad” or as a reason to start deliberately restricting an essential nutrient without good reason, because biology is almost never that simple, despite what you might see on social media.
Then we have IGF-1, insulin-like growth factor 1, which sits within the broader insulin and growth-factor signalling system and is closely connected with the pathways controlling growth and nutrient availability. This means that higher insulin/IGF-1 signalling generally supports the message that nutrients are available and the body is in a growth and repair state, whereas reduced signalling can shift the balance towards maintenance mechanisms such as autophagy, which is one of the reasons fasting has become so interesting in this area – fasting doesn’t just mean “not eating”, it changes a whole collection of metabolic signals at the same time, including insulin, amino-acid availability and growth-factor signalling.
And that brings us neatly to one of the simplest ways of reducing mTOR activity, which is simply giving the body periods without food, because when you stop continually supplying amino acids and energy, insulin falls, nutrient signalling changes, amino-acid availability decreases and mTOR activity can be reduced, allowing autophagy to become more active, This is not to suggest that everyone suddenly hits some magical autophagy switch at exactly 16, 18 or 24 hours after the last time we ate, because this is far too simplistic. Autophagy is already happening at baseline, different tissues behave differently and the amount of autophagy occurring at any particular time is influenced by a whole range of factors rather than being controlled by an App telling you when to eat.
Exercise is another way of influencing the balance because it creates an energy demand within cells and activates signalling pathways associated with energy stress and cellular maintenance, while also affecting pathways such as AMPK that interact with mTOR. Hence exercise isn’t simply about burning calories or building muscle, it is also one of the things that tells the cell that it needs to adapt, repair itself and become more efficient, which is another reason why movement and exercise are relevant when talking about autophagy rather than treating fasting as the only lever we have in maintaining a healthy weight.
There are also naturally occurring compounds that have attracted a lot of attention because they appear to influence autophagy through mechanisms that aren’t simply about starving the body. Spermidine is one of the more interesting examples, because it is a naturally occurring polyamine found in foods and produced within the body and experimental research suggests that it can promote autophagy through effects on the cellular machinery involved in recycling, which makes it particularly interesting because it may influence the process without simply relying on mTOR being switched off by nutrient deprivation – one to watch for sure.
Urolithin A is interesting for a slightly different reason because it has been investigated in relation to mitophagy, which is essentially autophagy specifically directed at mitochondria – this matters because mitochondria are the little power stations inside our cells and, like anything else that works hard for years, they can become damaged or less efficient, so mitophagy is the process by which the cell identifies mitochondria that are no longer performing properly and removes them so that the components can be recycled and the mitochondrial population can be maintained. Research into urolithin A suggests that it may stimulate pathways involved in this mitochondrial quality-control process, although the human evidence is still developing and it is definitely not as simple as saying that taking urolithin A will “clean your mitochondria” – please be aware of simplistic suggestions you may see on social media.
The whole thing therefore comes back to balance rather than trying to permanently force one pathway in one direction, because we need mTOR switched on when we are eating, building muscle, repairing tissue and making new proteins, just as we need periods when its activity is reduced so that the cellular maintenance and recycling systems can have more of a say, and this is why the fed-versus-fasted state is so interesting, because after eating, particularly after a protein-rich meal containing leucine and the other essential amino acids, the body receives a strong “build and repair” signal, whereas during a period without food those signals gradually diminish and the balance can shift towards maintenance and recycling.
What I find particularly fascinating about it is that the body isn’t waiting for us to discover some miracle supplement before it knows how to clean itself up, because these systems have been there for thousands of years and are constantly responding to what is happening around them. mTOR effectively helps to decide whether conditions are right for growth, nutrient availability influencing that decision through amino acids such as leucine, isoleucine, valine and methionine, insulin and IGF-1 providing additional growth signals, and pathways involving AMPK and autophagy becoming more prominent when energy and nutrient availability fall. Alongside this, compounds such as spermidine and potentially urolithin A may provide additional ways of influencing aspects of the recycling machinery, particularly when we start talking about mitochondrial quality control.
Perhaps the most important point is that we don’t actually want to spend our entire lives trying to maximise autophagy, because the body needs to build as well as recycle, and suppressing mTOR all the time would be just as ridiculous as keeping it permanently switched on, so the real objective is not to “kill mTOR” but to allow the body to move naturally between periods of growth, nourishment and repair and periods where cellular housekeeping and recycling get a little more attention, because it is that ability to switch between these different metabolic states that is arguably much more interesting than any single supplement, food or fasting protocol.
FAQs
What exactly is autophagy?
Autophagy is a natural cellular recycling process in which cells break down and remove damaged, old or unnecessary components and recycle some of their constituent parts. It is happening at a baseline level all the time, although its activity can increase when cells experience conditions such as nutrient or energy scarcity.
Why does mTOR matter for autophagy?
mTOR, particularly mTORC1, is a major nutrient and growth sensor. When nutrients and growth signals are plentiful, mTORC1 promotes processes such as protein synthesis and generally suppresses autophagy. When mTORC1 activity falls, the inhibition of autophagy is reduced, allowing cellular recycling processes to become more active.
Does mTOR need to be completely switched off for autophagy?
No. That is an important distinction. Autophagy does not simply switch off when mTOR is active and switch on when mTOR disappears. Autophagy operates at baseline and is regulated by multiple pathways, with reduced mTORC1 activity being one of the important signals that can increase it.
How does fasting affect mTOR?
Fasting reduces the availability of nutrients and amino acids and generally lowers insulin signalling, while also altering other metabolic signals. This can reduce mTORC1 activity and create conditions that favour autophagy, although the precise timing and magnitude of the response varies between tissues and individuals.
Does protein stop autophagy?
Protein, particularly amino acids such as leucine, can stimulate mTORC1 and therefore suppress autophagy temporarily, which is a normal part of the fed state. That does not mean protein is harmful or that we should avoid it, because protein is essential for muscle, tissue repair, enzymes, hormones and countless other biological processes.
Why is leucine particularly important?
Leucine is one of the branched-chain amino acids and acts as a particularly strong nutritional signal for mTORC1. When leucine is available, it helps signal that amino acids are present and that the cell has the resources required for protein synthesis and growth.
What do isoleucine and valine do?
Isoleucine and valine are the other two branched-chain amino acids. They contribute to protein synthesis and metabolism and are involved in the broader nutrient-sensing environment, although leucine is generally considered the strongest direct nutritional activator of mTORC1.
Why is methionine relevant?
Methionine is an essential amino acid involved in protein synthesis, methylation and several metabolic pathways, and its availability can influence nutrient-sensing and longevity-related pathways. Research into methionine restriction has produced interesting findings, particularly in experimental models, but this does not mean that methionine should simply be eliminated or aggressively restricted.
What is the connection between IGF-1 and mTOR?
IGF-1 is part of the insulin and growth-factor signalling system and contributes to signals promoting growth and nutrient utilisation. IGF-1 signalling can interact with pathways upstream of mTOR, helping to favour anabolic processes when nutrients and energy are available.
What is spermidine?
Spermidine is a naturally occurring polyamine found in the body and in a number of foods. It has attracted considerable research interest because experimental evidence suggests that it can promote autophagy and influence cellular maintenance pathways, although the effects seen in laboratory research should not automatically be interpreted as proven longevity benefits in humans.
What is mitophagy?
Mitophagy is essentially autophagy specifically directed at mitochondria. It allows cells to identify and remove damaged or dysfunctional mitochondria, helping maintain mitochondrial quality and cellular energy production.
What is urolithin A?
Urolithin A is a compound produced by the gut from certain dietary polyphenols, particularly ellagitannins and ellagic acid. It has attracted attention because research suggests that it may stimulate pathways involved in mitochondrial quality control and mitophagy, although research into its longer-term effects in humans is still developing.
Can supplements switch mTOR off?
Not in the simple way that some supplement marketing suggests. Nutrients, fasting, exercise and various compounds can influence mTOR and related pathways, but mTOR is a highly regulated system rather than a simple on/off switch, and deliberately suppressing it continuously would not be desirable.
Is autophagy always beneficial?
Autophagy is essential for normal cellular health, but more is not automatically better. Cells need a balance between growth, protein synthesis, repair and recycling, so the objective is not to maximise autophagy continuously but to maintain healthy regulation of these processes.
References
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