Caloric restriction
Reduced caloric intake without malnutrition; associated with lifespan extension across species.
Not eating, for a while. Eating meaningfully fewer calories without becoming malnourished. It's linked to longer lifespan across many species and is one of the classic ways researchers dial down mTOR signaling through diet.
Distinguish the two axes deliberately: total calories and macronutrient composition are not the same lever (SOL2014 found the RATIO mattered more than the intake for cardiometabolic outcome and lifespan in mice). Two-year caloric restriction is tolerable in non-obese humans (ROM2016) but that trial measured safety, not lifespan – no human longevity data exists for this or any other mTOR-lowering intervention.
TL;DR. Caloric restriction appears in 9 curated studies in Oliver's mTOR Atlas: 1 in people (1 human study); 5 in animal models; 1 at the molecular level (cells, biochemistry, structure); 1 review; 1 preprint, not peer-reviewed. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Fasting / caloric restriction inhibits mTORC1 mechanism: signal-relay · this link in full · on the map table | Eating less is expected to turn mTORC1 down, because the cell's fuel and amino-acid sensors both report scarcity. But this has not been measured here. The one study behind this arrow let mice eat freely on 25 different diets and found that the ratio of protein to carbohydrate, not the number of calories, went with health and lifespan, and lower-protein diets went with lower mTOR activity in the liver. So what has support is eating less protein, not eating less, and it is a correlation, not a test. Holds under: Supporting evidence is thinner than the claim's reputation. ROM2016 (two-year caloric restriction is tolerable in non-obese humans) and MAT2017 (rhesus survival) were removed as support in the 2026-09-21 audit because neither measured mTORC1; they belong to the CR-LONGEVITY edge. That leaves SOL2014, which is an ad-libitum 25-diet study whose own title states that the ratio of macronutrients, not caloric intake, dictates the outcome, and whose mTOR observation is correlative and confined to liver. Re-audit 2026-10-10: consensus was downgraded from established to emerging and the evidence kind from genetic epistasis to correlative, because neither matched what SOL2014 actually did. The edge is retained because the mechanistic expectation is sound and well motivated by the sensor arms, but it is an expectation, not a measured result in this corpus. 2026-10-18: YIL2012 added. In mouse intestine, calorie restriction lowered mTORC1 activity in Paneth cells, and rapamycin or Paneth-cell genetics reproduced the stem-cell effect, so the corpus now has one direct mTORC1 measurement under restriction. It is a single tissue in mice and does not show the same in people. plausible in people, not shown directly · emerging, few independent studies | A | SOL2014, YIL2012 |
| Fasting / caloric restriction activates Longevity mechanism: functional-consequence · this link in full · on the map table | Eating less improved health and survival in monkeys. But in mice that could eat as much as they wanted, cutting calories by watering down the food did not make them live longer; eating less protein compared with carbohydrate did. So whether it is the calories or the protein that counts is still open. Holds under: No human lifespan data exists. Effect direction is reproducible across several species; effect size and even the responsible variable (calories versus composition) are not settled. not tested in people · emerging, few independent studies | A | MAT2017 conflicting: SOL2014 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 5 |
| M | Molecular — cells, biochemistry, structure | 1 |
| PP | Preprint, not peer-reviewed | 1 |
| R | Review — secondary literature, not a new result | 1 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2016 | H | Safety of two-year caloric restriction in non-obese healthy individuals ROM2016 Two years of sustained 25% caloric restriction in healthy non-obese adults was safe overall, though it lowered bone density more than controls. |
| 2026 | A | Anticipatory metabolic regulation drives the distinct and improved metabolic state of caloric restriction compared to Fasting-Refeeding cycles. VEL2026 Comparing caloric restriction (CR, one meal/day) to a fasting-refeeding-fasting (FRF) regimen with matched food intake and fasting duration, CR engages anticipatory, circadian-clock-aligned metabolic control (hepatic mTOR signaling, ketogenesis, metabolic gene coordination), whereas FRF responses track direct nutrient/gastric-emptying cues and disrupt circadian rhythmicity. CR improved glucose and fatty-acid metabolism; FRF caused glucose intolerance and hepatic fat accumulation. |
| 2017 | A | Caloric restriction improves health and survival of rhesus monkeys MAT2017 Direct comparison of two long-term primate CR studies (NIA, Wisconsin) supports consistent health benefits; the survival effect depended on study design and control-diet composition. |
| 2009 | A | 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila ZID2009 Connected the dots between diet, mTOR, and lifespan. 4E-BP, an mTOR target, is upregulated on dietary restriction and here was shown to be REQUIRED for the lifespan boost, working by selectively boosting translation of mitochondrial genes. A rare case pinning a specific mTOR effector to the longevity benefit of eating less. |
| 2008 | A | A role for autophagy in the extension of lifespan by dietary restriction in C. elegans HAN2008 Makes autophagy a necessary step between dietary restriction and a longer life, not a side effect of it: blocking autophagy genes abolishes the lifespan extension produced both by dietary restriction and by TOR inhibition. The paper is equally careful about what autophagy cannot do on its own, because autophagy still runs in animals lacking DAF-16/FOXO and yet those animals are not long-lived. Boundary: worms; necessity was shown, sufficiency was not. |
| 2007 | A | Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans HAN2007 The authors systematically tested whether lowering protein synthesis extends lifespan in the worm C. elegans. Reducing ribosomal proteins, the S6 kinase homologue rsks-1 or translation-initiation factors increased lifespan, and these perturbations, like TOR inhibition, increased resistance to heat stress. Different kinds of translation inhibition split into two groups: one that needed the FOXO transcription factor DAF-16 for the lifespan and stress effects and one that did not. The results linked TOR, but not sir-2.1, to the lifespan extension caused by dietary restriction in worms, and suggested that neither TOR inhibition nor dietary restriction works simply by reducing total protein synthesis. Boundary: Nematode only, with gene knockdown by RNAi or mutation; drafted from the abstract only, so effect sizes and which TOR experiments were new in this paper are not given here. |
| 2012 | M | mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake YIL2012 Mice kept on calorie restriction (60% of normal intake) had more intestinal stem cells and Paneth cells, the cells that form the stem-cell niche (Lgr5+ stem cells 5.6% vs 4.3% of crypt cells, Paneth cells 9.8% vs 6.7%), and their crypts were nearly twice as likely to form organoids. In co-culture, Paneth cells from restricted mice, not stem cells, carried the boost. Restriction lowered S6 and S6K1 phosphorylation in crypts, and feeding or insulin switched on mTORC1 in Paneth cells but not in stem cells; forcing mTORC1 back on during restriction (Rheb induction or Tsc1 deletion) cancelled the effect, while one week of rapamycin copied it and did not add to restriction. The niche signal ran through higher Bst1 in Paneth cells, an enzyme that makes the paracrine messenger cyclic ADP ribose, and knocking down Bst1 removed the restriction effect in culture. Boundary: Mouse intestine and ex vivo organoid assays; restriction started in young adult mice, and no lifespan or human tissue was studied. |
| 2010 | R | Extending healthy life span--from yeast to humans FON2010 Influential review proposing that dietary restriction and reduced nutrient-sensing signalling (mTOR, GH/IGF-1) may slow ageing through similar, evolutionarily conserved mechanisms. Lifespan extension is shown in yeast, invertebrates, rodents and rhesus monkeys; in humans the evidence is limited to protective biomarker changes and genetic associations. |
| 2026 | PP | Redox activation of ATG5 licenses autophagy upon nutrient restriction SHI2026 Dietary restriction selectively oxidizes a specific, tissue-resolved set of cysteines rather than oxidizing the proteome broadly. One of the most strongly oxidized is Cys19 on the core autophagy protein ATG5; this oxidation is required for ATG5 to bind ATG10 and form the ATG5-ATG12 conjugate that lipidates LC3B and builds the autophagosome. In mice lacking this redox switch, nutrient restriction fails to trigger autophagy, causing severe tissue pathology and early death -- a single oxidized cysteine gates the autophagic response to fasting. |
Related entities
Was this page useful?
Thank you. Your answer was counted anonymously.