Highlights:
CR improves cardiometabolic health markers: Well-designed studies like CALERIE 2 demonstrate that even healthy, non-obese adults can experience meaningful improvements in cardiovascular risk factors, insulin sensitivity, inflammation, and body composition through moderate calorie restriction (10–25%).
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A modest, nutrient-dense approach appears safe: For healthy adults, a moderate calorie reduction (10–25%) combined with a highly nutritious diet—inspired by traditional Okinawan eating patterns—offers low risk and potentially significant health benefits. The key is adequate nutrition: restriction without malnutrition.
Optimal BMI shifts with age: The traditional “healthy” BMI range (18.5–24.9) may not apply uniformly across the lifespan. For older adults (≥65 years), BMIs in the 24–30 range are associated with lower mortality, challenging the assumption that lower is always better.
What We Mean by “Calorie Restriction”
- Common human-trial definition (aligned with National Institutes of Health guidelines): sustained energy intake below pre-intervention requirements with adequate nutrition. This initially causes weight loss, then metabolic adaptation and a stable lower body weight (Most & Redman, 2020).
- Flanagan et al. (2020) define calorie restriction (CR) as reducing intake below energy requirements while maintaining optimal nutrition. Diets ranging from 10–30% CR have shown beneficial effects on ageing biomarkers and healthspan in animals and humans.
- Alternative framing: intake well below ad libitum consumption—typically ≥10% in humans and ≥20% in animals (Bales & Kraus, 2013).
Protocols, baselines, and adherence tracking differ between studies, so “CR” means different things across papers.
Practical constraints matter. Severe CR ( ≥40%) can put patients at risk of adverse physical and psychological effects (Flanagan et al., 2020). Achieving adequate nutrition alongside CR can be challenging in practice without professional guidance.
Who Should Avoid CR?
Underweight individuals, those with a history of eating disorders, and patients with sensitive medical conditions (such as during active cancer therapy) should avoid calorie restriction. It is generally contraindicated due to risks of undernutrition and interference with treatment.
Who Can Benefit from CR?
- Overweight and obese individuals clearly benefit from energy restriction. For this group, it may be the most effective intervention to improve cardiometabolic risk and extend healthspan, assuming no contraindications.
- CR is a cornerstone of secondary prevention for cardiovascular disease, with well-established benefits for mortality, hospital readmission, functional capacity, and quality of life (Mueller & Kim, 2025).
- Weight loss can produce remission of type 2 diabetes in a dose-dependent manner. A weight loss of ~15 kg through calorie restriction as part of an intensive management program can lead to remission in ~80% of patients with obesity and type 2 diabetes (Magkos et al., 2020).
But the key question here is: can a healthy person with normal body weight (BMI 18.5–24.99 kg/m²) benefit from calorie restriction in terms of longevity? Can CR extend healthspan (defined as “the part of a person’s life during which they are generally in good health”)?
BMI and Age: Rethinking Optimal Weight for Longevity
Before answering that question, we need to examine how we define normal body weight—and what problems might exist concerning that definition.
The WHO defines a healthy BMI range for adults as 18.5–24.9 kg/m², primarily based on a reduced mortality risk in younger populations. However, this standard may not apply uniformly across all age groups.
Research in older adults paints a more complex picture. Winter et al. (2014) found that for adults aged 65 and older, the relationship between BMI and all-cause mortality is U-shaped, with the lowest mortality risk occurring at BMIs between 24.0 and 30.9—considerably higher than the traditional “healthy” range (Winter et al., 2014).
This finding is what Sorkin (2014) describes as “the slaying of a beautiful hypothesis by an ugly fact.” The widely held belief that lower BMI always predicts better longevity has been challenged by robust epidemiological evidence showing that optimal BMI varies substantially with age.
Key insights from this editorial include:
- The BMI-mortality relationship is U-shaped, not linear. Both low and high BMI are associated with increased mortality, with minimal risk typically occurring at BMIs of 26–29 in older adults—substantially higher than the conventional recommendation of around 21.
- Optimal BMI shifts upward with age. In adults ≥65 years, BMIs in the overweight or mildly obese range are often associated with lower mortality compared to the “normal” BMI range, contradicting the hypothesis that lower BMI universally promotes longevity.
- Earlier studies advocating low BMI often failed to adequately control for confounding factors such as smoking, preexisting illness, or reverse causation (where illness causes weight loss before death).
- Modern large-scale studies using advanced statistical methods consistently show that minimum mortality BMI increases with age and does not differ significantly between genders.
Let’s remember that BMI is a population-level tool, not a precise measure of individual health. It doesn’t account for body composition, fitness, muscle mass, or underlying health conditions—all critical factors in assessing longevity risk.
Okinawa as a Case Study (Signal, Not Proof)
Okinawa’s reputation for healthy ageing is often linked to diet, with calorie restriction (CR) being highlighted as a possible key factor.
The most detailed look at CR in Okinawa drew on fifty years of nutrition, health, and population data. From the 1950s through the 1960s, surveys and health records suggested that Okinawan adults ate roughly 11% fewer calories per day (about 1,785 kcal) than the Harris-Benedict equation would predict for maintaining body weight. They appeared to be in a mild but sustained “energy deficit.” This pattern showed up in their bodies: lower weight, shorter stature, and a lean average BMI of 21 kg/m². Most people reach their peak weight in early adulthood and stay stable until old age. All of this fits the textbook picture of long-term calorie restriction as defined by NIH experts (Willcox & Willcox, 2014).
That said, calorie restriction remains one of the most debated factors in Okinawan longevity. The likely reason for our focus on CR is that in lab animals—yeast, worms, flies, and mice—it reliably delays disease and extends both average and maximum lifespan, provided nutrition remains adequate (Xie et al., 2021)
“Calorie restriction is currently one of the most feasible and effective anti-ageing methods” (Xie et al., 2021)
While we know this to be true in laboratory settings, we cannot confirm with complete certainty that the same effects occur in humans (Willcox & Willcox, 2014).
Worth noting: the traditional Okinawan diet in the 1960s was incredibly nutrient-dense and rich in polyphenols. Other important factors likely include regular, moderate physical activity, favourable genetics, and strong community support—all contributing to a low-stress, balanced lifestyle. Among the most underestimated factors may be the psychological and philosophical dimensions.
Ikigai (literally “a reason for being”) and nagomi (usually translated as “calm” or “harmony,” but referring to a broader philosophical concept of calmness and relaxation) are central to Japanese culture, yet their meaning can feel abstract and difficult to pursue within a Western lifestyle.
For a more scientific perspective on these ideas, I recommend “Flow: The Psychology of Optimal Experience” by Mihály Csíkszentmihályi. The book explores how the flow experience—finding joy and fulfilment through complete engagement in what you are doing—can lead to a richer, more meaningful life. It’s a must-read!
With so many factors at play, it’s impossible to pinpoint which one matters most for longevity. That said, I’ll revisit this topic in the future and share more about traditional Okinawan lifestyle practices as I find them truly fascinating.
Evidence from Other Human Studies
Research in healthy, non-obese adults offers some clues. Most et al. (2018) ran a landmark trial asking whether sustained CR could improve healthspan in people who were already “healthy” and not obese. Their hypothesis: CR would reduce cardiovascular disease risk and mortality while fundamentally enhancing the quality of ageing. The most striking finding? Even subjects without obesity or high CVD risk showed significant improvements in cardiometabolic markers with CR. Those benefits appeared to stem from improved body composition rather than enhanced aerobic fitness—CR reduced fat accumulation across adipose tissue depots without improving fitness measures. Whether these improvements can prevent or delay metabolic complications later in life for non-obese individuals remains an open question.
Much of this work has used the CALERIE 2 protocol, including the Most et al. (2018) study. Another major CALERIE 2 trial (Kraus et al., 2019) randomly assigned young and middle-aged adults (21–50 years) with healthy BMIs (22.0–27.9 kg/m²) to either 25% calorie restriction or an ad libitum control diet across three U.S. clinical centres. After two years, moderate calorie restriction significantly reduced multiple cardiometabolic risk factors in these young, non-obese participants—suggesting real potential for cardiovascular health benefits when healthy individuals practice moderate CR.
A comprehensive meta-analysis by Caristia et al. (2020) pulled together eight randomised controlled trials involving 704 participants (67.9% women, 10.5% lost to follow-up). The analysis found that CR prompted favourable changes across numerous health predictors of quality ageing: anthropometric measures, body composition, energy homeostasis, oxidative stress and inflammation markers, cardiovascular disease risk, insulin sensitivity, mood, well-being, and quality of life. But the authors noted important limitations. The relatively small number of studies and short follow-up periods prevented clear conclusions about CR’s relationship with chronic disease development. Current evidence also can’t identify an optimal “golden” calorie restriction level for improving long-term cardiometabolic health across all ages and weights, particularly after the restriction regime ends.
Bottom line: we need more well-designed controlled trials with larger sample sizes, normal-weight subjects, and longer follow-ups to better understand the mechanisms underlying CR’s health effects and to establish the safety of prolonged restriction regimens.
Mechanisms by Which Calorie Restriction Promotes Health and Longevity
The figure below illustrates the interconnected pathways through which calorie restriction (CR) influences ageing and disease prevention. CR triggers multiple molecular cascades:
CR activates heat shock proteins (HSF/HSP70) that maintain protein quality and reduce cellular senescence (def. loss of a cell’s power of division and growth). It also modulates key longevity pathways by decreasing insulin/IGF-1/mTOR signalling while increasing FOXO, SIRT, and AMPK activity, leading to enhanced autophagy, DNA repair, and reduced oxidative stress. Additionally, CR reduces chronic inflammation and lowers thyroid hormone T3 levels, which decreases metabolic rate and oxidative damage.
These molecular changes produce beneficial metabolic effects: improved insulin sensitivity with reduced compensatory hyperinsulinemia, decreased central adiposity, and favourable changes in sex hormones and IGFBP1 levels. The improved central adiposity further leads to better lipid profiles, lower blood pressure, and improved glucose control.
At the bottom of the diagram, these interconnected mechanisms converge to reduce the risk of three major age-related diseases: cancer, type 2 diabetes, and cardiovascular disease. Ultimately, by reducing cellular and molecular damage, enhancing stress resistance and repair mechanisms, and maintaining metabolic homeostasis, calorie restriction promotes increased healthspan and lifespan.
Take-Home Message
Calorie restriction (CR) shows promise as a method to improve healthspan in humans, but the evidence is still evolving, and context matters significantly.
While proclaiming CR as a universal anti-ageing prescription is premature, the available evidence suggests that modest (10-25%), well-nourished calorie restriction can be a plausible and effective strategy for many healthy adults to improve healthspan-related risk factors. More research with longer follow-ups is needed to confirm these benefits and determine optimal restriction levels across different ages and populations.
References
Bales, C. W., & Kraus, W. E. (2013). Caloric restriction: Implications for human cardiometabolic health. Journal of Cardiopulmonary Rehabilitation and Prevention, 33(4), 201–208. https://doi.org/10.1097/HCR.0b013e318295019e
Caristia, S., Vito, M., Sarro, A., Leone, A., Pecere, A., Zibetti, A., Filigheddu, N., Zeppegno, P., Prodam, F., Faggiano, F., & Marzullo, P. (2020). Is caloric restriction associated with better healthy aging outcomes? A systematic review and meta-analysis of randomized controlled trials. Nutrients, 12(8), 2290. https://doi.org/10.3390/nu12082290
Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie restriction and aging in humans. Annual Review of Nutrition, 40, 105–133. https://doi.org/10.1146/annurev-nutr-122319-034601
Kraus, W. E., Bhapkar, M., Huffman, K. M., Pieper, C. F., Das, S. K., Redman, L. M., Villareal, D. T., Rochon, J., Roberts, S. B., Ravussin, E., Holloszy, J. O., & Fontana, L. (2019). 2 years of calorie restriction and cardiometabolic risk (CALERIE): Exploratory outcomes of a multicentre, phase 2, randomised controlled trial. The Lancet Diabetes & Endocrinology, 7(9), 673–683. https://doi.org/10.1016/S2213-8587(19)30151-2
Magkos, F., Hjorth, M. F., & Astrup, A. (2020). Diet and exercise in the prevention and treatment of type 2 diabetes mellitus. Nature Reviews Endocrinology, 16(10), 545–555. https://doi.org/10.1038/s41574-020-0381-5
Most, J., & Redman, L. M. (2020). Impact of calorie restriction on energy metabolism in humans. Experimental Gerontology, 133, 110875. https://doi.org/10.1016/j.exger.2020.110875
Most, J., Gilmore, L. A., Smith, S. R., Han, H., Ravussin, E., & Redman, L. M. (2018). Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance. American Journal of Physiology-Endocrinology and Metabolism, 314(4), E396–E405. https://doi.org/10.1152/ajpendo.00261.2017
Most, J., Tosti, V., Redman, L. M., & Fontana, L. (2017). Calorie restriction in humans: An update. Ageing Research Reviews, 39, 36–45. https://doi.org/10.1016/j.arr.2016.08.005
Mueller, A. S., & Kim, S. M. (2025). Cardiac rehabilitation in the modern era: Evidence, equity, and evolving delivery models across the cardiovascular spectrum. Journal of Clinical Medicine, 14(15), 5573. https://doi.org/10.3390/jcm14155573
Sorkin, J. D. (2014). BMI, age, and mortality: The slaying of a beautiful hypothesis by an ugly fact. The American Journal of Clinical Nutrition, 99(4), 759–760. https://doi.org/10.3945/ajcn.113.079343
Willcox, B. J., & Willcox, D. C. (2014). Caloric restriction, caloric restriction mimetics, and healthy aging in Okinawa: Controversies and clinical implications. Current Opinion in Clinical Nutrition & Metabolic Care, 17(1), 51–58. https://doi.org/10.1097/MCO.0000000000000019
Willcox, Donald & Willcox, Bradley & Todoriki, Hidemi & Suzuki, Makoto. (2009). The Okinawan Diet: Health Implications of a Low-Calorie, Nutrient-Dense, Antioxidant-Rich Dietary Pattern Low in Glycemic Load. Journal of the American College of Nutrition. 28 Suppl. 500S-516S. 10.1080/07315724.2009.10718117.
Winter, J. E., MacInnis, R. J., Wattanapenpaiboon, N., & Nowson, C. A. (2014). BMI and all-cause mortality in older adults: A meta-analysis. The American Journal of Clinical Nutrition, 99(4), 875–890. https://doi.org/10.3945/ajcn.113.068122
Xie, S.-H., Li, H., Jiang, J.-J., Quan, Y., & Zhang, H.-Y. (2021). Multi-omics interpretation of anti-aging mechanisms for ω-3 fatty acids. Genes, 12(11), 1691. https://doi.org/10.3390/genes12111691
