Caloric Restriction and its Mimetics. Still the Core of Longevity Science and Biohacking?
- Alastair Hunt
- Apr 18
- 7 min read
Updated: May 3
Much of what we know about extending lifespan started with the simplest intervention of all: eating less. Caloric restriction - reducing calorie intake without malnutrition - has been shown to extend life in yeast, worms, flies, mice and even monkeys. But while the lab results are compelling, it’s not exactly a lifestyle most of us want to sign up for. This is where caloric restriction mimetics, or CRMs, come in - compounds that aim to reproduce the benefits of caloric restriction without the hunger, mood swings or social awkwardness of saying no to dinner plans.
So how much of modern longevity research still revolves around these ideas? Quite a lot, actually. But the field has evolved, becoming more sophisticated, more human-centred, and much more multidimensional. Let’s take a closer look.
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 supporting studies at bottom of page.
The Origins: Caloric Restriction as the Gold Standard
The foundational data on caloric restriction comes from a century of experiments. The classic rodent studies showed that reducing calorie intake by 30 to 40% (without causing malnutrition) reliably increased lifespan. But it wasn’t just about living longer - it was about living better. The animals developed fewer tumours, retained better cognitive function, and maintained lean mass and metabolic health far into old age.
When similar experiments were conducted on rhesus monkeys - the National Institute on Ageing (NIA) and the University of Wisconsin studies - the findings were mixed but largely positive. The monkeys on calorie restriction had fewer age-related diseases and healthier metabolisms, though the effect on overall lifespan varied between the two studies.
What’s more relevant to us are the human trials. Dr Luigi Fontana, one of the world’s leading experts on nutrition and longevity, has been at the forefront of translating these findings to real-life applications. His work with the CALERIE trial (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) showed that just a 12% reduction in calorie intake over two years in healthy, non-obese adults led to significant improvements in insulin sensitivity, blood pressure, LDL cholesterol and markers of inflammation like TNF-α and IL-6.
Fontana has long argued that caloric restriction, when practised sensibly and with appropriate nutritional support, can help delay ageing and reduce the risk of chronic diseases. But he also acknowledges its limits. Caloric restriction is hard to stick to, and for many people, it’s simply not sustainable. That’s why the search for mimetics became so important.
Enter the Mimetics
CR mimetics aim to activate the same cellular and molecular pathways as caloric restriction - particularly those involved in stress resistance, autophagy, and metabolic flexibility - without reducing calorie intake. Some of the most studied CRMs include:
Metformin: Originally used for type 2 diabetes, metformin activates AMPK, a key energy sensor in the cell, and dampens mTOR signalling. It’s currently being trialled for its longevity effects in the TAME study (Targeting Ageing with Metformin).
Rapamycin: This mTOR inhibitor has shown perhaps the most dramatic lifespan extension in mice, though its immunosuppressive properties raise concerns for long-term use in healthy humans.
Resveratrol: A polyphenol found in red wine, resveratrol activates sirtuins and was once the darling of the anti-ageing world. But its results in humans have been underwhelming so far.
Spermidine: Found in foods like pomegranate, walnuts, natto and aged cheese, spermidine appears to induce autophagy - a kind of cellular spring cleaning associated with healthier ageing.
NAD+ precursors: Molecules like NMN and NR aim to boost mitochondrial function and DNA repair, supporting cellular resilience.
Each of these compounds targets key pathways that overlap with those activated by caloric restriction: AMPK, mTOR, sirtuins, and autophagy. They don’t promise immortality but they do aim to slow down the biological clock.
What About GLP-1 Agonists Like Wegovy and Ozempic?
Another class of drugs that's quickly gaining attention in longevity and metabolic health circles is the GLP-1 receptor agonists - particularly semaglutide, sold under brand names like Wegovy and Ozempic. Originally developed for type 2 diabetes, these drugs mimic the gut hormone GLP-1, which increases insulin secretion, slows gastric emptying and promotes satiety. While their primary use has been for glycaemic control and, more recently, substantial weight loss, researchers are now exploring their broader potential for improving cardiometabolic health and reducing inflammation - two key drivers of ageing.
Though not traditional CR mimetics in the molecular sense, GLP-1 agonists may indirectly replicate some benefits of caloric restriction by reducing overall calorie intake and visceral fat, thereby improving metabolic flexibility and lowering age-related disease risk. However, their long-term impact on biological ageing itself - beyond weight loss and disease prevention - remains an open question.
Still at the Centre, But Not the Whole Story
While caloric restriction and its mimetics remain foundational, the field of longevity has expanded well beyond them. We’re now looking at:
Epigenetic reprogramming: Using Yamanaka factors to reverse ageing in cells. In 2012, Drs Yamanaka and Gurdon were awarded the Nobel Prize for Physiology or Medicine for their discovery that mature cells can be converted to stem cells.
Senolytics: Drugs that remove senescent cells, which accumulate with age and drive inflammation.
Gut microbiome: An emerging player in systemic inflammation and immune ageing.
Chrononutrition and circadian rhythm: When you eat may matter as much as what you eat.
There’s also a move towards developing biological ageing clocks - such as Horvath’s epigenetic clock and DunedinPACE (learn more here) - to give us better tools to measure the effectiveness of these interventions. That’s a crucial point. In animals, it’s easy to track lifespan. In humans, we need proxies that can tell us whether we’re slowing ageing, not just managing disease.
Final Thoughts
Caloric restriction is still the benchmark. It’s the intervention that works across species and mechanisms. Dr Luigi Fontana and others have shown that it can meaningfully improve markers of ageing in humans, even without extreme dietary reduction. CR mimetics may offer a practical bridge, especially as part of a wider strategy, but the results are still out.
The science of ageing is evolving, but the core message remains surprisingly familiar - eat wisely, move often, sleep well and manage stress. CR and its mimetics may help us fine-tune the process, but the fundamentals still matter most.
Changing health for the better is about progress, not perfection, and even small changes can have a powerful and positive effect on health. For most people, improving health is about finding motivation and prioritising self-care - with an ultimate goal of taking action. If you want to take effective and targeted steps that fit into your unique lifestyle and circumstances, The Whole Health Practice is here to help.
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Stay Healthy,
Alastair
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Related Studies
Franzago M, Alessandrelli E, Notarangelo S, Stuppia L, Vitacolonna E. Chrono-Nutrition: Circadian Rhythm and Personalized Nutrition. Int J Mol Sci. 2023 Jan 29;24(3):2571. doi: 10.3390/ijms24032571. PMID: 36768893; PMCID: PMC9916946.
Raffaele M, Vinciguerra M. The costs and benefits of senotherapeutics for human health. Lancet Healthy Longev. 2022 Jan;3(1):e67-e77. doi: 10.1016/S2666-7568(21)00300-7. PMID: 36098323.
Kim M, Benayoun BA. The microbiome: an emerging key player in aging and longevity. Transl Med Aging. 2020;4:103-116. Epub 2020 Jul 21. PMID: 32832742; PMCID: PMC7437988.
Kraus WE, Bhapkar M, Huffman KM, Pieper CF, Krupa Das S, Redman LM, Villareal DT, Rochon J, Roberts SB, Ravussin E, Holloszy JO, Fontana L; CALERIE Investigators. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019 Sep;7(9):673-683. doi: 10.1016/S2213-8587(19)30151-2. Epub 2019 Jul 11. PMID: 31303390; PMCID: PMC6707879.
Most J, Gilmore LA, Smith SR, Han H, Ravussin E, Redman LM. Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance. Am J Physiol Endocrinol Metab. 2018 Apr 1;314(4):E396-E405. doi: 10.1152/ajpendo.00261.2017. Epub 2017 Dec 12. PMID: 29351490; PMCID: PMC5966756.
Meydani SN, Das SK, Pieper CF, Lewis MR, Klein S, Dixit VD, Gupta AK, Villareal DT, Bhapkar M, Huang M, Fuss PJ, Roberts SB, Holloszy JO, Fontana L. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. Aging (Albany NY). 2016 Jul;8(7):1416-31. doi: 10.18632/aging.100994. PMID: 27410480; PMCID: PMC4993339.
Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun. 2014 Apr 1;5:3557. doi: 10.1038/ncomms4557. PMID: 24691430; PMCID: PMC3988801.
Colman A. Profile of John Gurdon and Shinya Yamanaka, 2012 Nobel laureates in medicine or physiology. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):5740-1. doi: 10.1073/pnas.1221823110. Epub 2013 Mar 28. PMID: 23538305; PMCID: PMC3625362.
Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986 Apr;116(4):641-54. doi: 10.1093/jn/116.4.641. PMID: 3958810.
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