Fasting and autophagy: what the evidence really shows

Few ideas in the biology of ageing have travelled as far, as fast, as the link between fasting and autophagy. The claim is simple and appealing: go without food for a while, and the cell begins to tidy itself up. The underlying science is real, but it is also more nuanced than the headlines suggest. Much of the strongest evidence comes from animals or from indirect markers, and the human picture is still taking shape. Here is what autophagy is, why nutrient scarcity is thought to switch it on, and what the research does and does not yet establish.

What autophagy is, in brief

Autophagy, from the Greek for self-eating, is the cell’s recycling process. It is a controlled way of breaking down and reusing the cell’s own components: damaged proteins, worn-out organelles, and other debris that accumulates through ordinary wear. Membranes form around this material, package it up, and deliver it to the cell’s disposal compartments, where it is dismantled into building blocks that can be put back to use. This housekeeping runs quietly at a low level all the time, and it is one of the ways a cell keeps itself functional. When autophagy falters, damaged material lingers, and the gradual decline of this process is one of the changes associated with ageing. Our separate explainer on autophagy covers the mechanics in more depth.

How nutrient scarcity is thought to switch it on

The connection between fasting and autophagy rests on how cells sense their fuel supply. Two signalling systems sit at the centre of this. The first is mTOR, a sensor that is active when nutrients are plentiful. When mTOR is switched on, it promotes growth and the building of new molecules, and it holds autophagy in check. The cell, in effect, is told that times are good and there is no need to recycle. When nutrients become scarce, mTOR activity falls, and that brake on autophagy is released.

The second system is AMPK, which behaves almost as a mirror image. AMPK is an energy gauge. When a cell’s available energy runs low, AMPK becomes active and helps switch on autophagy, encouraging the cell to break down and reuse its own components for fuel and raw materials. Periods without food are thought to shift the balance of these two signals, lowering mTOR activity and raising AMPK activity, and this shift is the proposed mechanism by which fasting and calorie restriction encourage the recycling process. A 2018 review in Ageing Research Reviews sets out this signalling logic and the evidence that fasting or calorie restriction can induce autophagy.

Spermidine and other compounds under study

Fasting is not the only route researchers are exploring towards the same end. Attention has turned to whether certain compounds can encourage autophagy while a person continues to eat normally, an idea sometimes described as mimicking the effects of calorie restriction. Spermidine, a naturally occurring molecule found in many foods and in our own cells, is one of the most studied. In laboratory and animal work it has been shown to induce autophagy, and it has been linked to effects on lifespan and tissue function in those models. A 2022 paper in Nature Aging reported on spermidine-induced autophagy and its protective effects in experimental systems, and a broad 2018 review in Science surveyed spermidine’s roles across health and disease.

The wider category these compounds belong to is sometimes called calorie restriction mimetics, the subject of a 2019 review in Cell Metabolism. The aim is to capture some of the cellular responses associated with eating less without the fasting itself. This is an active area of investigation rather than a settled one, and much of the supporting evidence remains preclinical.

What the human evidence does and does not show

This is where care matters most. A great deal of the mechanistic work on fasting and autophagy has been done in yeast, worms, flies and mice. These models are genuinely informative about how the pathways work, but they are not people, and they are often studied under controlled conditions that do not match everyday human life. In humans, autophagy is difficult to measure directly. Researchers usually rely on indirect markers in blood or tissue samples, and these markers are an imperfect window onto what is actually happening inside cells. A rise or fall in a marker is suggestive, not conclusive.

A 2016 review in Ageing Research Reviews examined the effects of intermittent fasting on health and disease and found encouraging signals across a range of measures, while also being clear that the human evidence is less complete than the animal work. A 2023 review in Advances in Nutrition looked specifically at the autophagic response to fasting and calorie restriction, and it makes an important point that is easy to overlook: the response is not uniformly beneficial. Autophagy is a finely balanced process, and both too little and, in some contexts, too much can be problematic. The relationship between fasting and autophagy in humans is therefore better described as plausible and partly supported than as proven.

What the evidence does and does not show

Pulling the threads together, a measured summary looks like this. The signalling biology is well characterised: nutrient scarcity lowers mTOR activity and raises AMPK activity, and both changes are linked to autophagy. In animal models, fasting, calorie restriction and compounds such as spermidine can induce autophagy and are associated with benefits to tissue function. In humans, the direct evidence is thinner. Autophagy is hard to measure, the available markers are indirect, and the long-term effects of different eating patterns on this process are not fully mapped. None of this makes the idea wrong. It simply means the honest position is one of cautious interest rather than confident conclusion. This is a field where the mechanisms are clearer than the human outcomes, and where good studies are still being done.

Further reading

Continue reading from the journal: Autophagy, explained without the jargon and The hallmarks of cellular ageing, in plain English.

Sources

• Bagherniya M, Butler AE, Barreto GE, Sahebkar A. The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Research Reviews, 2018. doi:10.1016/j.arr.2018.08.004
• Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Research Reviews, 2016. doi:10.1016/j.arr.2016.10.005
• Shabkhizan R, Haiaty S, Moslehian MS, et al. The beneficial and adverse effects of autophagic response to caloric restriction and fasting. Advances in Nutrition, 2023. doi:10.1016/j.advnut.2023.07.006
• Hofer SJ, Daskalaki I, Bergmann M, et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nature Aging, 2022. doi:10.1038/s43587-022-00322-9
• Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science, 2018. doi:10.1126/science.aan2788
• Madeo F, Carmona-Gutierrez D, Hofer SJ, Kroemer G. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential. Cell Metabolism, 2019. doi:10.1016/j.cmet.2019.01.018