Caloric Restriction and Fasting Mimicking. Modulating AMPK, FGF21, GLUT4, IGF-1 & mTOR
- Alastair Hunt
- Aug 3
- 8 min read
Updated: Aug 17
In the science of healthy ageing, if you have followed the works of Profs. Luigi Fontana, Valter Longo and others, several key metabolic pathways are discussed as central regulators of how fast or slowly we age: GLUT4, IGF-1, mTOR, AMPK and FGF21. Understanding how to modulate these through lifestyle - particularly caloric restriction and 'fasting mimicking' - offers opportunities to extend healthspan and prevent chronic disease.
As ever, please talk to your doctor or medical practitioner most familiar with your medical history before implementing any changes in diet, exercise or lifestyle, especially if you are under treatment. Links to relevant studies are provided at bottom of page.
Cell Signalling Pathways
In the context of biology and health - particularly when we talk about ageing and longevity- "pathways" refer to networks of molecular signals and biochemical reactions that take place inside your cells. These pathways control how your body responds to food, stress, hormones, and other stimuli, and they often involve a series of proteins, enzymes, and genes working together.
Think of a pathway like a road system in a city. When a signal (like insulin or a nutrient) enters, it sets off a chain reaction, like a car triggering a series of traffic lights or detours. Depending on which pathway is activated, your cells might grow, divide, repair damage, store fat, clear waste or even self-destruct if they're too damaged.
Examples of key longevity-related pathways include:
GLUT4, which helps shuttle glucose into cells to maintain healthy blood sugar.
IGF-1 and mTOR (mTORC1) which promote growth and cell division.
AMPK and FGF21, which are activated in response to low energy or fasting and trigger repair and fat burning.
When we talk about 'modulating ageing pathways' we mean influencing these networks - slowing down the ones that drive damage, and boosting the ones that protect and repair - through diet, fasting, exercise, and other lifestyle practices. the diagram below shows the effects of key longevity lifestyle practices on these pathways.
AMPK: The Energy Sensor
AMPK (AMP-activated protein kinase) functions as the body's internal energy monitor. Activated when cellular energy is low - during fasting, calorie restriction, or exercise - AMPK enhances fat metabolism, glucose uptake, and mitochondrial health. It also inhibits mTOR and supports autophagy, much like FGF21.
From Longo’s perspective, AMPK helps drive the switch from growth to repair. Fontana adds that many longevity-enhancing interventions - including fasting, exercise, and polyphenol-rich plant foods - achieve their benefits through AMPK activation. When chronically overfed, this pathway is suppressed, and the body loses its capacity to self-regulate and protect.
FGF21: The Fasting Hormone
FGF21 (Fibroblast Growth Factor 21) is produced in response to fasting or protein restriction. It helps shift metabolism away from growth and towards fat burning, ketone production, and cellular stress resistance. Elevated during fasting or fasting-mimicking diets, FGF21 acts as a hormonal signal of repair, triggering anti-inflammatory responses and enhancing metabolic flexibility.
Fontana notes that in individuals with metabolic syndrome or obesity, FGF21 signalling is often impaired, suggesting that lifestyle strategies to periodically restore its function may be crucial for regaining metabolic health.
GLUT4: The Glucose Transporter
GLUT4 (glucose transporter type 4) is a key protein that enables glucose uptake into muscle and fat cells, helping regulate blood sugar after meals. It is activated by insulin but also independently stimulated by exercise and AMPK activation.
During fasting or physical activity, GLUT4 translocates to the cell surface, allowing cells to absorb glucose without requiring high insulin levels - thereby improving insulin sensitivity and metabolic control. In both Prof Longo’s fasting-mimicking protocols and Prof Fontana’s calorie-restriction studies, enhanced GLUT4 function emerges as a central mechanism for restoring metabolic flexibility. In contrast, individuals with metabolic syndrome or type 2 diabetes often show impaired GLUT4 responsiveness, contributing to chronic hyperglycaemia and insulin resistance.
Lifestyle strategies that periodically activate GLUT4 - through movement, nutrient timing, and fasting - are therefore essential not only for blood sugar regulation but also for reducing disease risk and supporting healthy ageing.
IGF-1: The Growth Pathway
IGF-1 (Insulin-like Growth Factor 1) is a hormone that drives growth and cell proliferation. While essential in childhood and adolescence, persistently elevated IGF-1 in adulthood is linked to increased risks of cancer, type 2 diabetes, and accelerated ageing.
Both Professors Longo and Fontana have shown that lowering IGF-1 - via moderate protein restriction, particularly from animal sources and periodic fasting - shifts the body from growth mode into repair and maintenance mode. Both cautions that IGF-1 levels must be managed by life stage: too little in older adults may impair immune function and muscle maintenance, increasing frailty risk. The key is modulation, not elimination.
mTOR (mTORC1) : The Nutrient Sensor
mTOR (mechanistic Target of Rapamycin) acts as a cellular switchboard that responds to nutrients - especially amino acids like leucine - and promotes growth, protein synthesis, and fat storage. Chronically high mTOR signalling, common in modern high-protein, high-calorie diets, is associated with age-related diseases, including cancer and neurodegeneration.
Fasting, plant-rich diets, and reduced protein intake inhibit mTORC1, the branch most associated with disease and ageing. This inhibition activates autophagy - a cellular recycling process that clears damaged components and helps delay ageing.
Both professors agree that cycling mTOR activity - periods of suppression through fasting, followed by refeeding phases - can promote both regeneration and metabolic balance, particularly when adapted for age and health status.
Leading a Longevity Lifestyle
These pathways represent the biological crossroads between ageing and health. When left chronically activated by constant nutrition, especially high protein and excess calories, the body stays locked in growth mode - great for youth but harmful in later life.
The solution lies in a strategic cycling between nourishment and nutrient scarcity. Longo’s Fasting Mimicking Diet and Fontana’s emphasis on whole-food, plant-based diets with moderate protein both point towards a unified message: the body thrives when given time to repair.
To support these pathways:
Prioritise a predominantly plant-based diet with modest protein.
Use periodic fasting or fasting-mimicking protocols to trigger cellular repair and reset metabolic signals.
Engage in regular physical activity to naturally activate AMPK and improve metabolic flexibility.
Avoid constant snacking and overfeeding, which suppress the body’s innate repair mechanisms.
Read more about Caloric Restriction, Diet and Exercise for Healthspan
What this looks like in practice, from Prof Fontana...
In essence, the science of ageing is teaching us an old truth in new terms: restraint, rhythm, and balance - in diet, activity, and metabolism - are the cornerstones of long life and lasting health.
Supporting your body through balanced nutrition, physical activity, stress reduction, quality sleep and meaningful social connection (these are known as the Pillars of Health) are some of the most powerful health 'tools' we have. Changing health for the better is about consistent progress, not perfection, and even small changes can make a meaningful difference over time.
As always, the best health strategy is one you can stick with - one that fits your personal lifestyle profile. Improving health is about finding motivation, prioritising self-care and taking action. If you want to take effective and targeted steps to that fit into your unique lifestyle, The Whole Health Practice is here to help. Whether you want to improve eating practices, beat chronic illness or enhance your overall well-being, our consultations and programs deliver results that are tailored to your needs.
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Stay Healthy,
Alastair
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Related Resources and Studies
Suggested reading: The Path to Longevity
Suggested reading: The Longevity Diet
Brandhorst S, Levine ME, Wei M, Shelehchi M, Morgan TE, Nayak KS, Dorff T, Hong K, Crimmins EM, Cohen P, Longo VD. Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk. Nat Commun. 2024 Feb 20;15(1):1309. doi: 10.1038/s41467-024-45260-9. PMID: 38378685; PMCID: PMC10879164.
Clifton KK, Ma CX, Fontana L, Peterson LL. Intermittent fasting in the prevention and treatment of cancer. CA Cancer J Clin. 2021 Nov;71(6):527-546. doi: 10.3322/caac.21694. Epub 2021 Aug 12. PMID: 34383300.
de Groot S, Lugtenberg RT, Cohen D, Welters MJP, Ehsan I, Vreeswijk MPG, Smit VTHBM, de Graaf H, Heijns JB, Portielje JEA, van de Wouw AJ, Imholz ALT, Kessels LW, Vrijaldenhoven S, Baars A, Kranenbarg EM, Carpentier MD, Putter H, van der Hoeven JJM, Nortier JWR, Longo VD, Pijl H, Kroep JR; Dutch Breast Cancer Research Group (BOOG). Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun. 2020 Jun 23;11(1):3083. doi: 10.1038/s41467-020-16138-3. PMID: 32576828; PMCID: PMC7311547.
Most J, Tosti V, Redman LM, Fontana L. Calorie restriction in humans: An update. Ageing Res Rev. 2017 Oct;39:36-45. doi: 10.1016/j.arr.2016.08.005. Epub 2016 Aug 17. PMID: 27544442; PMCID: PMC5315691.
Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, Dubeau L, Yap LP, Park R, Vinciguerra M, Di Biase S, Mirzaei H, Mirisola MG, Childress P, Ji L, Groshen S, Penna F, Odetti P, Perin L, Conti PS, Ikeno Y, Kennedy BK, Cohen P, Morgan TE, Dorff TB, Longo VD. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015 Jul 7;22(1):86-99. doi: 10.1016/j.cmet.2015.05.012. Epub 2015 Jun 18. PMID: 26094889; PMCID: PMC4509734.
AMPK
He L, Zhou X, Huang N, Li H, Tian J, Li T, Yao K, Nyachoti CM, Kim SW, Yin Y. AMPK Regulation of Glucose, Lipid and Protein Metabolism: Mechanisms and Nutritional Significance. Curr Protein Pept Sci. 2017;18(6):562-570. doi: 10.2174/1389203717666160627071125. PMID: 27356941.
GLUT4
Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem. 2020 Nov 27;11(3):76-98. doi: 10.4331/wjbc.v11.i3.76. PMID: 33274014; PMCID: PMC7672939.
FGF21
Tezze C, Romanello V, Sandri M. FGF21 as Modulator of Metabolism in Health and Disease. Front Physiol. 2019 Apr 17;10:419. doi: 10.3389/fphys.2019.00419. PMID: 31057418; PMCID: PMC6478891.
IGF1
Li S, Zou T, Chen J, Li J, You J. Fibroblast growth factor 21: An emerging pleiotropic regulator of lipid metabolism and the metabolic network. Genes Dis. 2023 Aug 2;11(3):101064. doi: 10.1016/j.gendis.2023.06.033. PMID: 38292170; PMCID: PMC10825286.
Rahmani J, Montesanto A, Giovannucci E, Zand H, Barati M, Kopchick JJ, Mirisola MG, Lagani V, Bawadi H, Vardavas R, Laviano A, Christensen K, Passarino G, Longo VD. Association between IGF-1 levels ranges and all-cause mortality: A meta-analysis. Aging Cell. 2022 Feb;21(2):e13540. doi: 10.1111/acel.13540. Epub 2022 Jan 20. PMID: 35048526; PMCID: PMC8844108.
Knuppel A, Fensom GK, Watts EL, Gunter MJ, Murphy N, Papier K, Perez-Cornago A, Schmidt JA, Smith Byrne K, Travis RC, Key TJ. Circulating Insulin-like Growth Factor-I Concentrations and Risk of 30 Cancers: Prospective Analyses in UK Biobank. Cancer Res. 2020 Sep 15;80(18):4014-4021. doi: 10.1158/0008-5472.CAN-20-1281. Epub 2020 Jul 24. PMID: 32709735.
mTOR
Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017 Mar 9;168(6):960-976. doi: 10.1016/j.cell.2017.02.004. Erratum in: Cell. 2017 Apr 6;169(2):361-371. doi: 10.1016/j.cell.2017.03.035. PMID: 28283069; PMCID: PMC5394987.
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