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Calorie restriction

Calorie restriction (CR) is a dietary intervention that reduces caloric intake below habitual or ad libitum levels—typically by 20–40%—while ensuring adequate nutrition to avoid malnutrition.^[1]^[2] This approach has been extensively studied for its potential to promote longevity and health benefits across various organisms.^[3] The foundational research on CR dates back to the early 20th century, with initial observations by Osborne et al. in 1917, but Clive McCay's 1935 experiments on rats provided the first clear evidence that CR could extend median lifespan by up to 50% without nutrient deficiency.^[4] Subsequent studies confirmed lifespan extension in diverse species including yeast, nematodes, fruit flies, and rodents, often by 30–50%, and health benefits including delayed onset of age-related diseases such as cancer, diabetes, and neurodegeneration in nonhuman primates.^[1] In these models, CR consistently improves healthspan, marked by enhanced metabolic efficiency, reduced inflammation, and bolstered immune function.^[5] Human studies, though more limited due to ethical and practical challenges, suggest similar benefits on a milder scale. The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) trials, conducted by the National Institute on Aging, tested 25% CR in healthy, non-obese adults over two years, achieving an average 12% reduction that resulted in 10–15% body weight loss, improved cardiometabolic risk factors (including lower blood pressure, cholesterol, and inflammation), enhanced muscle specific force despite initial mass reduction, and upregulation of genes linked to energy metabolism and healthy aging.^[6]^[7] These changes mimic pathways observed in animal models, such as reduced oxidative damage and increased cellular repair mechanisms, without evidence of adverse effects on quality of life or cognition in compliant participants.^[1] Recent analyses as of 2023 have shown that CR slows the pace of biological aging in humans, and research into CR mimetics continues to advance.^[8]^[9]

Background

Definition and Principles

Calorie restriction (CR) is defined as a sustained reduction in daily caloric intake, typically by 20-40% below an individual's estimated energy needs, while ensuring adequate intake of essential nutrients to prevent malnutrition.^[1] This approach creates an energy deficit without compromising overall nutritional quality, distinguishing it from mere starvation by prioritizing balanced macronutrient and micronutrient profiles.^[1] In research contexts, CR is often implemented as a consistent daily practice rather than sporadic reductions, aiming to mimic the caloric moderation observed in certain longevity-promoting interventions.^[10] The core principles of CR emphasize achieving this energy deficit through nutrient-dense foods that maintain essential macronutrients, micronutrients, and protein levels. This involves selecting whole foods such as fruits, vegetables, lean proteins, and whole grains to meet requirements for vitamins, minerals, and fiber, thereby avoiding deficiencies common in unbalanced low-calorie diets.^[11] A key aspect is adjusting macronutrient ratios, often increasing protein intake to 20-30% of total calories to preserve lean muscle mass during weight loss, as higher protein supports satiety and metabolic function without excess energy.^[12] These principles ensure that CR promotes health optimization rather than mere caloric counting, focusing on quality over quantity to sustain long-term adherence.^[2] To implement CR effectively, caloric needs are first estimated using basal metabolic rate (BMR) calculations, such as the Harris-Benedict equation, which accounts for age, sex, weight, and height. For men, the equation is:

\text{BMR} = 88.362 + (13.397 \times \text{weight in kg}) + (4.799 \times \text{height in cm}) - (5.677 \times \text{age in years})

For women:

\text{BMR} = 447.593 + (9.247 \times \text{weight in kg}) + (3.098 \times \text{height in cm}) - (4.330 \times \text{age in years})

^[13] Total daily energy expenditure (TDEE) is then derived by multiplying BMR by an activity factor (e.g., 1.2 for sedentary lifestyles, up to 1.9 for very active individuals), providing the baseline from which the restriction percentage is subtracted.^[14] Unlike intermittent fasting, which involves periodic abstinence from food, CR entails a steady daily reduction in calories without complete elimination of eating windows, allowing for regular nutrient distribution throughout the day.^[3] This sustained approach supports metabolic stability and avoids the physiological stress associated with prolonged fasting periods.^[15]

Historical Development

The discovery of calorie restriction's effects on lifespan began in the 1930s with pioneering work by Clive McCay at Cornell University. In a seminal 1935 study, McCay and colleagues demonstrated that underfeeding rats—reducing their caloric intake without causing malnutrition—significantly extended both median and maximum lifespan compared to ad libitum-fed controls, extending the mean lifespan of male rats by 64-79%, with no significant extension observed in females.^[16] This finding, published in the Journal of Nutrition, established the foundational principle that caloric restriction could prolong life in rodents and shifted nutritional research toward exploring dietary impacts on aging. Following World War II, wartime rationing studies provided indirect human insights into caloric limitation, such as the Minnesota Starvation Experiment (1944–1945), which examined the physiological effects of semi-starvation on young men and highlighted metabolic adaptations to low-calorie intake, influencing subsequent animal research. In the 1950s and 1960s, numerous rodent experiments confirmed and expanded McCay's observations, showing consistent longevity benefits across strains and species, including increased survival rates in rats and mice subjected to 30–40% caloric reduction initiated at weaning or adulthood.^[17] These studies, often conducted at institutions like the National Institutes of Health, solidified caloric restriction as a reproducible intervention for delaying age-related decline in laboratory animals.^[18] The 1980s marked a resurgence in applying caloric restriction to human longevity, led by Roy Walford, a UCLA gerontologist who advocated for its translation to people through nutrient-dense, low-calorie diets. Walford's 1986 book, The 120-Year Diet: How to Double Your Vital Years, popularized the concept by proposing that 20–30% caloric reduction could extend human lifespan to 120 years, drawing on rodent data and his own restricted diet.^[19] This work gained prominence during the Biosphere 2 project (1991–1993), where Walford and participants inadvertently practiced caloric restriction (averaging 1,800 kcal/day), providing early human data on metabolic and immunological adaptations.^[20] In the 1990s and 2000s, the field advanced toward rigorous human trials, culminating in the launch of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study in 2007 by the National Institute on Aging.^[21] This multi-site, randomized controlled trial aimed to evaluate 25% caloric restriction's feasibility and effects over two years in non-obese adults, building on prior smaller pilots and nonhuman primate studies. During the 2010s, caloric restriction integrated deeply with broader aging research, linking it to mechanisms like sirtuin activation and autophagy in model organisms, while inspiring mimetic compounds.^[22] A notable recent milestone came in 2023 from NIH-supported analysis of CALERIE data, revealing that moderate caloric restriction (about 12% reduction over two years) preserved muscle strength and function in humans despite modest lean mass loss, activating gene pathways associated with healthy aging. These findings underscore caloric restriction's potential for muscle preservation, aligning human outcomes with longstanding animal evidence.^[23] In 2024, a study on genetically diverse mice demonstrated that the degree of caloric restriction proportionally extends lifespan, with 40% restriction yielding the greatest benefits alongside some trade-offs like lean mass loss.^[24]

Implementation

Dietary Guidelines

Calorie restriction (CR) typically involves a 20-30% reduction in daily caloric intake below an individual's total daily energy expenditure (TDEE), calculated based on age, sex, weight, height, and activity level to ensure sustainability without excessive deprivation.^[25] For moderate CR, this often translates to 1,500-1,800 kcal per day for sedentary adults, though targets should be personalized to avoid undernutrition.^[26] Macronutrient composition in CR diets emphasizes balance to maintain nutritional adequacy, with protein comprising 20-30% of total calories (approximately 1.2-1.6 g/kg body weight) from high-quality sources to help preserve muscle mass and prevent sarcopenia during energy deficit.^[27] Carbohydrates should account for 50-60% of calories, prioritizing complex sources like whole grains and legumes for sustained energy and fiber intake, while fats make up 25-30% from unsaturated options such as nuts, seeds, avocados, and olive oil to support essential fatty acid needs.^[28] Food selection focuses on nutrient-dense options to maximize vitamins, minerals, and fiber within the caloric limit, including a variety of vegetables (e.g., leafy greens, broccoli), fruits (e.g., berries, apples), whole grains (e.g., oats, quinoa), and lean proteins (e.g., fish, poultry, legumes).^[29] Sample daily meal plans might include breakfast of oatmeal topped with fresh berries and a handful of nuts (around 300-400 kcal); lunch as a large salad with mixed greens, grilled fish, cherry tomatoes, and a light vinaigrette (400-500 kcal); dinner featuring stir-fried vegetables with tofu or chicken over brown rice (500-600 kcal); and snacks like yogurt with cucumber slices or an apple (200-300 kcal total).^[30] CR is not suitable for everyone, including those who are underweight (BMI <18.5), pregnant, breastfeeding, or with histories of eating disorders or certain chronic conditions; professional medical advice is essential before starting.^[3] CR can be approached short-term (e.g., several months) for initial adaptation or long-term (e.g., years) for ongoing practice; some evidence from athletes suggests periodic refeeds (e.g., higher-carb days weekly) may help preserve metabolism and reassess needs, but consult a professional for personalization.^[31] Tracking tools such as mobile apps (e.g., MyFitnessPal or Cronometer) or food journals aid in monitoring intake, while consultation with a registered dietitian is recommended to tailor plans and ensure safety, particularly to mitigate risks like nutrient deficiencies if adherence lapses.^[32]^[33]

Monitoring Nutrient Intake and Safety

Effective monitoring of nutrient intake during calorie restriction (CR) is essential to prevent deficiencies while achieving energy reduction goals. Periodic blood tests, as recommended by a healthcare provider, to assess levels of key vitamins such as B12 and D, minerals including iron and calcium, and biomarkers like albumin for evaluating protein status. In trials like CALERIE, tests occurred at baseline and intervals such as 1, 3, 6, 12, and 24 months, including hematology (e.g., hemoglobin for iron status) and hormone assays, to detect imbalances early.^[34]^[35] In addition to laboratory assessments, self-tracking tools such as detailed food diaries or nutrition software facilitate daily logging of macronutrients and micronutrients to ensure adherence to balanced intake patterns.^[34] For instance, apps like Cronometer allow precise recording of up to 80 nutrients, aiding users in maintaining nutritional quality during CR without malnutrition.^[36] Safety protocols begin with consultation from a healthcare provider for baseline screening to identify suitable candidates and mitigate risks, including BMI assessment (>18.5 kg/m² recommended), evaluation for eating disorders or contraindications (e.g., abnormal lipid profiles, low bone mineral density), and physical exams. Protocols also account for individual factors, with calorie targets adjusted based on age, sex, and activity level—for example, 1200–1500 kcal/day for women and 1500–1800 kcal/day for men during moderate CR in some trials, while athletes benefit from higher protein intake (2.3–3.1 g/kg fat-free mass) to preserve lean mass.^[26]^[37] Ongoing monitoring should include regular check-ups and tests like dual-energy X-ray absorptiometry (DXA) scans for bone health if advised, with criteria to stop if severe issues like persistent electrolyte imbalances or excessive weight loss occur. In CALERIE, this involved monthly check-ins and vital signs tracking.^[34] Common pitfalls in CR include over-restriction, which can lead to amenorrhea in women due to hormonal disruptions or accelerated bone density loss from reduced mechanical loading and nutrient deficits.^[38]^[34] Authoritative guidelines, such as those from the National Institute on Aging, emphasize limiting reductions to less than 25% of baseline energy intake without professional supervision to minimize these hazards while ensuring adequate nutrition.^[3] Interventions to address emerging issues include targeted supplementation, such as daily multivitamins providing 100% of the recommended dietary allowance for essential micronutrients and 1000 mg calcium citrate to support bone health, as used in trials like CALERIE.^[34]^[11] Practitioners should watch for warning signs like fatigue, hair loss, or dizziness, prompting immediate dietary adjustments or further testing to restore balance.^[34]

Human Studies

Key Clinical Trials

The Minnesota Starvation Experiment, conducted from 1944 to 1945 at the University of Minnesota under the direction of Ancel Keys, involved 36 healthy young men aged 20 to 33 who were conscientious objectors.^[39] The study design included a 12-week baseline period with approximately 3,200 kcal/day intake, followed by a 24-week semi-starvation phase limited to 1,570 kcal/day to induce a 25% body weight loss, and a 12-week controlled refeeding phase.^[39] Participants underwent comprehensive assessments of physical and psychological changes, including body composition, metabolic rate, and mood, with all maintaining normal weight at baseline and no pre-existing metabolic disorders.^[40] The Biosphere 2 experiment, from 1991 to 1993 in Arizona, unintentionally imposed calorie restriction on its 8 participants (4 men and 4 women, aged 25 to 50, all healthy and non-obese).^[41] Designed as a closed ecological system simulation, the trial featured self-grown food production that yielded only about 1,750 to 2,100 kcal/day per person, resulting in an average 30% reduction from expected intake.^[42] Over the two-year confinement, participants experienced 10% to 20% body weight loss, primarily in the first six months, alongside shifts in metabolic parameters such as decreased resting energy expenditure; inclusion required physical fitness and absence of chronic conditions.^[43] The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials, spanning phases 1 (2002–2007, 6 months) and 2 (2007–2010, extended follow-ups to 2016), examined sustained calorie restriction in over 200 healthy, non-obese adults with body mass index (BMI) 22 to 28 kg/m² and ages 21 to 51.^[44] In phase 2, 218 participants were randomized 2:1 to either 25% calorie restriction (achieving ~12% on average) or ad libitum intake for two years, with interventions including dietary counseling to ensure nutrient adequacy.^[45] Primary measurements focused on biomarkers like insulin-like growth factor 1 (IGF-1), which decreased by 20% to 25% in the restriction group, alongside body weight reductions of 10% to 15%; eligibility excluded metabolic disorders, smoking, and recent weight changes.^[21] A 2023 National Institutes of Health (NIH)-supported analysis of CALERIE phase 2 data from 191 adults (achieving 12% to 15% calorie restriction over two years, ages 21 to 50, non-obese BMI 22 to 28) demonstrated preserved muscle strength despite 10% lean mass loss.^[6] The study design involved randomized assignment to restriction or control, with assessments of thigh muscle function via magnetic resonance imaging and strength testing; participants were healthy without diabetes or cardiovascular disease.^[46] A 2022 randomized trial in 139 obese adults (BMI 28 to 45 kg/m², ages 18 to 75 years) compared 12-month 12% calorie restriction alone versus combined with 8-hour time-restricted eating, resulting in weight losses of 8.0 kg and 6.3 kg respectively (P=0.11) with similar adherence.^[26] A 2025 randomized clinical trial in 90 adults with overweight/obesity (BMI 25-35 kg/m², ages 18-60 years) compared 3-month energy restriction alone (~500 kcal deficit) to combined with early or late time-restricted eating, finding greater fat mass and BMI reductions with early TRE+energy restriction.^[47] Inclusion criteria varied across trials, with early studies targeting non-obese healthy adults aged 20-50 without metabolic disorders, while recent comparisons included obese or overweight individuals.^[2]

Health and Longevity Outcomes

Calorie restriction (CR) in human studies has shown promising metabolic effects, particularly in improving glucose homeostasis and insulin sensitivity. Participants in randomized controlled trials like the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) experienced reduced fasting glucose levels and enhanced insulin sensitivity following moderate CR, with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index decreasing by approximately 20-30% in the initial phases of intervention.^[48]^[49] These changes are attributed to weight loss and adaptations in energy metabolism, observed across non-obese adults over 1-2 years.^[10] Cardiovascular health outcomes also benefit from CR, with consistent reductions in blood pressure and LDL cholesterol reported in clinical trials. In the CALERIE study, systolic and diastolic blood pressure declined significantly after 2 years of ~12% CR, alongside lower LDL levels compared to controls.^[49] Meta-analyses of human weight loss interventions, including CR, indicate a 10-15% reduction in overall heart disease risk through these improvements in lipid profiles and hemodynamic factors.^[50]^[51] Regarding longevity markers, CR activates pathways associated with delayed aging, such as upregulation of AMPK, a key regulator of cellular energy homeostasis. Analysis of 2023 NIH data from the CALERIE trial revealed that 2 years of CR slowed the pace of biological aging by 2-3% as measured by DNA methylation clocks, including DunedinPACE, in healthy adults.^[52]^[53] For inflammation and cancer risk, CR reduces circulating C-reactive protein (CRP) levels, with studies showing decreases of up to 30% in long-term adherents.^[54] Despite these benefits, limitations persist in human CR research: no direct evidence exists for extended lifespan, as long-term mortality data are unavailable, and physiological improvements often plateau after 2 years without ongoing adherence.^[10]^[52]

Psychological Effects

Calorie restriction (CR) often induces initial mood alterations, including irritability and heightened hunger, as participants adjust to reduced energy intake. However, adaptation typically occurs within weeks, leading to improved overall mood and quality of life in a majority of individuals. In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) phase 2 trial, sustained 25% CR over two years resulted in enhanced mood scores and no adverse psychological effects, with approximately 60-70% of participants reporting positive shifts in emotional well-being after the initial adaptation period.^[55]^[56] A 2025 analysis of National Health and Nutrition Examination Survey (NHANES) data (2007-2018) found that calorie-restricted diets were associated with higher depressive symptom scores (0.29-point increase in PHQ-9), particularly among overweight individuals (0.46-point increase).^[57] Cognitive effects of CR vary by duration and intensity. Short-term restriction may enhance focus and processing speed, as evidenced by improvements in inhibition and working memory tasks in controlled trials. In contrast, prolonged or severe CR can lead to deficits in cognitive flexibility and sustained attention. The Minnesota Starvation Experiment, conducted in 1944-1945, demonstrated these risks, where semi-starvation (about 50% CR) over six months caused obsessive thoughts about food, reduced alertness, and impaired decision-making among healthy men.^[58]^[59]^[39] Behaviorally, CR initially prompts increased physical activity as individuals compensate for reduced intake, but this often transitions to fatigue and apathy with sustained adherence. Long-term studies report adherence rates declining to around 50% after one year, attributed to persistent hunger and motivational challenges. The CALERIE trial observed initial boosts in spontaneous movement, followed by reports of tiredness in about 30% of participants by year two.^[1]^[60]^[40] A 2023 randomized trial in adults with obesity found that 12-month time-restricted eating combined with calorie restriction had no significant impact on mood or quality of life, similar to calorie restriction alone.^[61]

Animal Studies

Non-Human Primates

The National Institute on Aging (NIA) initiated a landmark study in 1987 involving 121 rhesus macaques (Macaca mulatta), divided into control and calorie-restricted (CR) groups with a 30% reduction in caloric intake without malnutrition, aimed at assessing impacts on aging and longevity. This research demonstrated health benefits from CR, including delayed onset of age-related pathologies, though survival results were mixed.^[62] Specifically, CR monkeys exhibited a lower incidence of diabetes (reduced by about 50%), cardiovascular disease, and cancer, alongside protection against sarcopenia and neurodegeneration.^[63] Additionally, neuroimaging revealed preserved brain volume and reduced atrophy in CR subjects, contrasting with progressive loss in ad libitum-fed controls. Differences in diet composition (e.g., lower sucrose in NIA controls) contributed to varying survival outcomes between studies. Concurrently, the University of Wisconsin (UW) study, launched in 1989 with 76 rhesus macaques subjected to 30% CR starting in young adulthood, provided complementary insights into physiological adaptations. CR in this cohort reduced sarcopenia and improved markers of metabolic health, though cancer outcomes were mixed, with no overall reduction in neoplasia incidence.^[64] Early findings from the UW study in 2009 demonstrated health benefits and delayed mortality, with significant lifespan extension confirmed in the 2014 analysis. In the UW study, CR extended median lifespan to 28 years in males vs. 26 years in controls (approximately 8% increase); NIA results showed no significant extension overall. A 2012 study from the NIA reported no survival benefit, but a 2017 integrated analysis of both studies confirmed survival advantages primarily in the UW cohort, particularly in males, with CR reducing all-cause mortality risk by about 46% in UW and mixed in NIA.^[64]^[63] These primate studies underscore translational relevance to humans, as rhesus macaques share similar metabolic rates, body compositions, and disease susceptibilities, including diabetes and cardiovascular conditions, making them superior models to shorter-lived species for evaluating CR's anti-aging effects.

Rodents and Invertebrates

Calorie restriction (CR) has been extensively studied in rodents, providing foundational evidence for its lifespan-extending effects. In 1935, Clive McCay and colleagues conducted pioneering experiments on rats, demonstrating that a 40% reduction in calorie intake, initiated early in life and without inducing malnutrition, extended median lifespan by 30-50% compared to ad libitum-fed controls. This discovery established CR as a potent intervention for delaying aging. Subsequent replications in mice confirmed these benefits, showing that 30-40% CR not only prolongs lifespan by 20-40% but also delays the onset of spontaneous tumors and other age-related pathologies, such as cancer and immune dysfunction.^[65] A comprehensive 2024 study on genetically diverse diversity outbred (DO) mice showed that 40% CR increased median lifespan by 36%, with benefits proportional to the degree of restriction; intermittent fasting protocols (1-2 days/week) also extended lifespan, with 2-day fasting achieving approximately 12% caloric reduction and proportional benefits.^[24] Invertebrate models have similarly demonstrated robust lifespan extensions under CR, offering rapid insights into conserved mechanisms. In the budding yeast Saccharomyces cerevisiae, research from the 1990s onward showed that 50% CR, achieved by limiting glucose availability, doubles replicative lifespan by enhancing cellular resistance to stress and reducing genomic instability.^[66] For the nematode Caenorhabditis elegans, the eat-2 mutants, which reduce pharyngeal pumping to mimic 30% CR, extend mean lifespan by up to 50% through improved metabolic efficiency and delayed reproductive aging.^[67] In fruit flies (Drosophila melanogaster), moderate CR regimens, typically involving 20-40% reductions in dietary yeast or sugar, consistently produce 20-30% lifespan extensions, often accompanied by enhanced fertility and stress tolerance in early adulthood.^[68] The dose-response relationship in these shorter-lived species underscores the importance of moderation in CR implementation. Optimal benefits occur with 30-40% calorie reductions, balancing energy conservation with nutrient adequacy to maximize longevity; excessive restriction beyond 50-60%, however, can shorten lifespan by promoting frailty, reproductive failure, or essential nutrient deficiencies.^[65] Additionally, CR elevates spontaneous physical activity in rodents by 20-50%, as measured by increased wheel-running or exploratory behavior, which supports energy expenditure and mitigates fat accumulation without compromising overall vitality.^[69] These observations in rodents and invertebrates highlight CR's role in promoting healthy aging across taxa, informing higher-model validations.

Mechanisms

Sirtuin Pathway

The sirtuin family comprises seven NAD⁺-dependent deacetylases (SIRT1–SIRT7) that function as key regulators of cellular metabolism and stress responses in mammals, with SIRT1 serving as the predominant isoform involved in mediating energy homeostasis.^[70] Calorie restriction (CR) upregulates SIRT1 expression and activity approximately 2- to 3-fold across tissues such as liver, muscle, and adipose, enhancing its role in adaptive responses to nutrient scarcity.^[71] This upregulation is tissue-specific, with increases observed in metabolic organs while potentially decreasing in others like the brain under certain conditions.^[72] CR activates the sirtuin pathway primarily by elevating intracellular NAD⁺ levels through a shift toward oxidative metabolism, which reduces NADH accumulation and thereby increases the NAD⁺/NADH ratio without necessarily boosting total respiration.^[73] The heightened NAD⁺ availability allosterically activates SIRT1, enabling it to deacetylate downstream targets such as the transcriptional coactivator PGC-1α, which in turn promotes mitochondrial biogenesis and enhances fatty acid oxidation to support energy efficiency during nutrient limitation.^[74] This deacetylation process fine-tunes gene expression for adaptive metabolic reprogramming, linking reduced calorie intake directly to sirtuin-dependent cellular resilience. However, the precise role of sirtuins in CR-induced longevity remains debated, with some studies challenging their necessity across species.^[75] The sirtuin pathway's connection to longevity is conserved across species, as evidenced by the yeast homolog Sir2, whose overexpression or activation by CR extends replicative lifespan by silencing ribosomal DNA and reducing age-related toxicity.^[73] In mammals, this link is highlighted by studies showing that SIRT1 knockout in mice abolishes key CR benefits, including lifespan extension and increased physical activity, demonstrating SIRT1's essential role in transducing CR signals for longevity assurance.^[76] Evidence from the CALERIE trial suggests activation of the sirtuin signaling pathway in skeletal muscle after 2 years of CR, correlating with improved metabolic markers such as reduced inflammation and enhanced insulin sensitivity.^[77] Therapeutic strategies targeting the sirtuin pathway include resveratrol, a natural polyphenol that acts as a partial SIRT1 activator by lowering the enzyme's Km for peptide substrates, thereby partially mimicking CR's metabolic effects in rodent models, such as improved insulin sensitivity and delayed age-related decline without full lifespan extension.^[78] This partial mimicry underscores resveratrol's potential as a pharmacological tool to harness sirtuin benefits in contexts where CR is impractical, though clinical translation is limited by modest efficacy and ongoing debates regarding its mechanisms.^[79]

Metabolic and Epigenetic Changes

Calorie restriction (CR) induces profound metabolic shifts that enhance cellular efficiency and promote longevity. Activation of AMP-activated protein kinase (AMPK), a key energy sensor, occurs in response to reduced nutrient availability during CR, leading to decreased ATP consumption and upregulation of catabolic processes such as autophagy to recycle cellular components and maintain energy homeostasis.^[80]^[81] This AMPK-mediated inhibition of the mechanistic target of rapamycin (mTOR) pathway slows anabolic processes like protein synthesis, which has been shown to extend lifespan in model organisms including fruit flies (Drosophila melanogaster) and nematodes (Caenorhabditis elegans).^[82]^[83] Hormonal adaptations under CR further contribute to these anti-aging effects by altering growth signaling. CR significantly lowers circulating levels of insulin-like growth factor 1 (IGF-1), with reductions of 30-50% observed in rodents; in humans, CR reduces the IGF-1:IGFBP-1 ratio, mimicking aspects of diminished IGF-1 signaling seen in longevity models where reduced IGF-1 delays aging-related pathologies.^[84] In the CALERIE trial, two years of moderate CR resulted in a 42% decrease in the IGF-1:IGFBP-1 ratio, underscoring the pathway's conservation across species.^[84] Epigenetic modifications represent another critical mechanism through which CR influences aging trajectories. CR alters DNA methylation patterns, as evidenced by a 2-3% slowing of the pace of aging measured by the DunedinPACE algorithm in participants of the CALERIE trial following two years of intervention.^[8] Additionally, CR affects histone modifications via histone deacetylases (HDACs), which regulate chromatin structure and gene expression to suppress age-associated transcriptional noise and promote cellular resilience.^[85]^[86] CR also attenuates chronic low-grade inflammation, a hallmark of aging known as inflammaging. Downregulation of the nuclear factor kappa B (NF-κB) pathway under CR reduces production of pro-inflammatory cytokines, including interleukin-6 (IL-6), with decreases of 20-40% reported in human and rodent studies.^[87]^[88] Recent 2024 research highlights CR's role in reshaping the gut microbiome, enriching populations of beneficial bacteria such as Lactobacillus species that produce anti-aging metabolites like lithocholic acid, thereby linking microbial shifts to enhanced longevity.^[89]

Applications and Comparisons

Therapeutic Uses

In intensive care settings, hypocaloric feeding regimens resembling calorie restriction, typically providing 11-22 kcal/kg/day, have been investigated for critically ill patients, particularly those with sepsis. A 2024 meta-analysis indicated that permissive underfeeding may reduce ICU mortality (RR 0.90, 95% CI 0.82-0.99), though results vary across broader ICU populations, with no significant difference observed in the 2015 PermiT trial.^[90]^[91]^[92] For obesity management, supervised calorie restriction at 25% below baseline energy needs has shown sustained weight loss in clinical trials. A 2024 analysis of long-term data from the CALERIE study reported approximately 13% body weight reduction after 12 months of 25% calorie restriction, with maintenance thereafter.^[93] Comparative 2024 trials confirm 10-15% weight loss over 12-24 months with such regimens, with benefits for metabolic improvements.^[60] As an adjunct therapy for age-related diseases like type 2 diabetes, calorie restriction improves glycemic control, with clinical studies showing reductions in HbA1c levels by 0.5-1% alongside weight loss.^[94] In metabolic syndrome, the American Diabetes Association endorses supervised calorie restriction as part of lifestyle interventions to achieve 5-10% weight loss, emphasizing individualized plans to enhance insulin sensitivity and cardiovascular risk factors.^[95] For neurodegeneration, preclinical evidence from Parkinson's disease models indicates potential benefits; a 6-month calorie restriction protocol in rodents improved motor function, basal ganglia dopamine levels, and neuronal survival by reducing oxidative stress.^[96] In cancer therapy, perioperative calorie restriction enhances chemotherapy efficacy in rodent models by sensitizing tumor cells to treatment while protecting healthy tissues. Studies in mice with breast and colorectal cancers showed 20-50% tumor growth inhibition when combining short-term (48-72 hour) calorie restriction with doxorubicin or cisplatin, attributed to differential stress resistance.^[97] Human pilot studies support reduced side effects; a phase I trial in patients with various solid tumors reported lower fatigue and gastrointestinal toxicity during chemotherapy with 25-50% calorie reduction cycles, without compromising efficacy.^[98] These findings suggest calorie restriction as a supportive strategy in oncology, potentially via mechanisms like autophagy induction.^[99]

Relation to Other Diets

Calorie restriction (CR) involves a continuous reduction in daily caloric intake without malnutrition, typically by 20-40%, distinguishing it from intermittent fasting (IF), which alternates periods of normal eating with fasting windows of 16-48 hours. Recent studies indicate that IF regimens, such as alternate-day fasting, achieve comparable weight loss to CR, with average reductions of 5-8% over 12 months, while demonstrating better long-term adherence due to less frequent calorie monitoring.^[100]^[101] Time-restricted eating (TRE), a subset of IF, confines food intake to an 8-10 hour daily window, metabolically mimicking aspects of CR by enhancing insulin sensitivity and autophagy without requiring precise calorie tracking, and it is often perceived as psychologically less demanding. Clinical trials from 2024 have shown TRE to be particularly effective in reducing systemic inflammation and improving gut microbiome diversity compared to continuous CR, with benefits including lower levels of pro-inflammatory cytokines in obese individuals.^[102]^[103] Calorie restriction mimetics, such as pharmacological agents, aim to replicate CR's benefits without dietary changes; for instance, metformin activates the AMPK pathway to improve metabolic health and has been shown to extend lifespan in male mice by approximately 5-10% when administered mid-life.^[104] Similarly, resveratrol targets sirtuin pathways and extends lifespan in obese mice by 10-15% under high-fat diet conditions, though effects are less consistent on standard chow.^[105] Low-carbohydrate diets, including ketogenic variants, produce CR-like outcomes such as reduced oxidative stress and enhanced longevity markers through ketosis, without the need for explicit calorie counting, as demonstrated in 2025 research showing decreased biological aging in patients with relapsing-remitting multiple sclerosis—a study presented at the ACTRIMS Forum that found ketogenic diet reduced metabolomic age by 1.12 years per month. These diets shift metabolism toward fat oxidation, yielding benefits like improved insulin signaling that parallel CR's effects.^[106] Across these approaches, a key overlap is the reduction in insulin-like growth factor 1 (IGF-1) levels, which correlates with longevity promotion; CR, IF, TRE, and low-carbohydrate diets all lower circulating IGF-1, though CR remains the most extensively studied for sustained lifespan extension in animal models despite its challenges in human adherence.^[107]^[108]

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Ability of the Harris Benedict formula to predict energy requirements ...
This prediction formula takes into account gender, body weight, height, and age. The calculated REE must then be modified by an activity factor to predict total ...
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Perspective: Time-Restricted Eating Compared with Caloric ... - NIH
Jan 19, 2021 · The standard diet strategy for weight loss and maintenance is caloric restriction (CR), defined as a sustained daily reduction of calories.Missing: definition | Show results with:definition
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Honoring Clive McCay and 75 Years of Calorie Restriction Research
By 1956 the use of CR without malnutrition as a means to extend lifespan was beginning to gain acceptance as a viable research method, although its use remained ...
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Effect of age and dietary restriction on expression of heat shock ...
Research in the 1950s and 1960s demonstrated that dietary restriction (DR), i.e. undernutrition not malnutrition, significantly increased the survival of ...
[17]
Subfield History: Caloric Restriction, Slowing Aging, and Extending ...
In our studies, the rats on caloric restriction had an increased food intake per gram of body weight for most of the life-span, a finding clearly not in ...
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Beyond the 120 Year Diet: How to Double Your Vital ... - Goodreads
Rating 4.0 (74) He argues that longevity can be significantly increased by a diet that contains all the required nutrients but about a third fewer calories.Missing: 1986 | Show results with:1986
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Calorie Restriction in Biosphere 2 | The Journals of Gerontology
During seven eighths of that period they consumed a low-calorie (1750–2100 kcal/d) nutrient-dense diet of vegetables, fruits, nuts, grains, and legumes, with ...Missing: 1986 | Show results with:1986
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Study Details | NCT00427193 | CALERIE: Comprehensive ...
The purpose of this study is to test the hypothesis that two years of sustained 25% caloric restriction (CR) in men age 21-50 (inclusive) and women age 21-47 ( ...
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Calorie restriction as an intervention in ageing - PMC
Calorie restriction (CR) is a non‐genetic intervention that prevents age‐associated diseases and extends longevity in most of the animal models studied so far.
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Impact of calorie restriction on energy metabolism in humans - PMC
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Calorie Restriction with or without Time-Restricted Eating in Weight ...
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During negative energy balance induced by a calorie-reduced diet, inadequate protein intake augments the weight-loss–induced loss of lean body mass (,). However ...
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The effect of dietary carbohydrate and calorie restriction on weight ...
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Make every calorie count with nutrient-dense foods
Apr 9, 2021 · Fruits, vegetables, whole grains, lean meats, nuts, beans, seeds and certain oils are all considered nutrient dense.
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A 1,500-Calorie Diet: Food Lists, Meal Plan and More - Healthline
Mar 27, 2023 · This article explains how to follow a 1,500-calorie diet, including foods to eat, foods to avoid and tips for healthy, long-term weight loss.Calorie Needs · Foods to Eat · Foods to Avoid · Meal Plan
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Intermittent Energy Restriction Attenuates the Loss of Fat Free Mass ...
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The 8 Best Calorie Counter Apps - Healthline
MyFitnessPal is a very popular calorie counter. It tracks your weight and calculates a recommended daily calorie intake. It also has a food diary and an ...Our picks · Comparison chart · Word of caution · How to choose
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Medical Nutrition Therapy for Weight Loss | Johns Hopkins Medicine
Most people should aim to lose about 1 to 1.5 pounds per week. Your dietitian will tell you how many calories to eat per day to lose weight steadily and safely.
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[PDF] CALERIE Phase 2 Protocol
The overall aim of CALERIE Phase 2 is to test the hypothesis that two years of sustained caloric re- striction (CR), involving a reduction in energy intake to ...
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Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial
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Our guide to food-tracking apps
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A systematic review of dietary protein during caloric restriction in ...
Oct 2, 2013 · There is evidence that protein needs increase when athletes restrict calories or have low body fat.
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New Insights into Calorie Restriction Induced Bone Loss - PMC - NIH
Reduced mechanical loading has long been thought to be the primary cause of weight loss-induced bone loss from calorie restriction. Despite fat loss in ...
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The psychology of hunger
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They starved so that others be better fed: remembering Ancel Keys ...
During the experiment, the participants were subjected to semistarvation in which most lost >25% of their weight, and many experienced anemia, fatigue, apathy, ...
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Energy metabolism after 2 y of energy restriction: the biosphere 2 ...
Unexpectedly, the food supply was markedly restricted during most of the confinement and all subjects experienced a marked, sustained weight loss (9.1 +/- 6.6 ...Missing: 1991-1993 calorie 30% unintentional participants
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The crew experienced 10-20 percent weight loss, most of which occurred in the first six months of the closure reflecting adaptation to the diet and lower ...Missing: restriction 30% participants metabolic
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Energy metabolism after 2 y of energy restriction: the Biosphere 2 ...
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The CALERIE Study: Design and methods of an innovative 25 ...
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Comprehensive Assessment of the Long-term Effects of Reducing ...
Oct 5, 2010 · Primary outcomes are resting metabolic rate and core temperature, and are assessed at baseline and at 6-month intervals. Secondary outcomes ...
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Calorie restriction modulates the transcription of genes related to ...
Oct 12, 2023 · Our findings provide the first evidence that even moderate intensity CR preserves skeletal muscle health through molecular pathways previously ...
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Comparing the influence of early and late time-restricted eating with ...
Jul 29, 2025 · It remains unclear whether adding time-restricted eating (TRE) to energy restriction (ER) offers additional cardiometabolic benefits, ...
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Two Years of Calorie Restriction and Cardiometabolic Risk Factors
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Targeting Cardiovascular Risk Factors Through Dietary Adaptations ...
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Cutting calories may slow the pace of aging in healthy adults
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Caloric restriction slowed the pace of aging, measured by DunedinPACE DNAm, but did not significantly change biological age estimates.
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Long-term calorie restriction is highly effective in reducing the risk for ...
The present finding of extremely low CRP levels in the CR group provides preliminary evidence that CR also reduces inflammation in humans.
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lessons learned from 30 years of calorie restriction research
As we have previously reviewed, observational studies further support the notion that CR has beneficial effects on longevity and cancer risk in humans ( 4 ).
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Effects of caloric restriction on human physiological, psychological ...
The results of CALERIE 2 provide evidence that sustained, moderate (11.9%) CR in individuals without obesity improves a multitude of physiological, ...
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Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and ...
Calorie restriction (CR) increases longevity in many species and reduces risk factors for chronic diseases. In humans, CR may improve health span, ...
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Jun 3, 2025 · Diet affects depression risk, with healthy eating patterns associated with reduced symptoms and unhealthy diets linked to increased risk.
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Comparing caloric restriction regimens for effective weight ...
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Caloric restriction improves health and survival of rhesus monkeys
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Caloric restriction improves health and survival of rhesus monkeys
Jan 17, 2017 · With the launch of the NIA rhesus monkey study in 1987, the implementation of CR was such that the control monkeys were not free-fed. Food ...
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Caloric restriction reduces age-related and all-cause mortality in ...
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Monkey caloric restriction study shows big benefit; contradicts earlier ...
Apr 1, 2014 · Monkey caloric restriction study shows big benefit; contradicts earlier study ... Rhesus monkeys 27-year-old Canto, on a restricted diet (left), ...
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Caloric Restriction and Aging: Studies in Mice and Monkeys - PMC
It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models.
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Oct 9, 2024 · We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction.
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Steroid signaling mediates longevity responses to the eat-2 genetic ...
Dietary restriction (DR) has been shown to extend the lifespan of many model organisms, including the nematode Caenorhabditis elegans [1,2]. The mechanisms by ...
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Dietary restriction and the transcription factor clock delay eye aging ...
Jun 7, 2022 · We demonstrate that dietary restriction extends lifespan in Drosophila melanogaster by promoting circadian homeostatic processes that protect the visual system.
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Effect of calorie restriction on spontaneous physical activity and ...
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Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism
The sirtuins are a family of highly conserved NAD+-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic ...<|separator|>
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Tissue-specific regulation of SIRT1 by calorie restriction
Jun 11, 2008 · Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life ...
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Calorie restriction extends yeast life span by lowering the level of ...
Previously, we showed that calorie restriction increases the replicative life span in yeast by activating Sir2, a highly conserved NAD-dependent deacetylase.
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Metabolic control of muscle mitochondrial function and fatty acid ...
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The sirtuins, oxidative stress and aging: an emerging link
Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several ...
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Jul 1, 2008 · Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life ...
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A Low Dose of Dietary Resveratrol Partially Mimics Caloric ...
Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet.<|control11|><|separator|>
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Autophagy in healthy aging and disease - Nature
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Calorie restriction and rapamycin distinctly mitigate aging ... - Nature
Aug 10, 2024 · Calorie restriction (CR) and treatment with rapamycin (RM), an inhibitor of the mTORC1 growth-promoting signaling pathway, are known to slow aging and promote ...
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Dietary regulation in health and disease - Nature
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Effects of 2-year Calorie Restriction on Circulating Levels of IGF-1 ...
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Effect of long-term caloric restriction on DNA methylation measures ...
Feb 9, 2023 · We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in ...
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Common environmental factors and their impact on epigenetic age
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Caloric restriction induced epigenetic effects on aging - PMC
Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to ...
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The Impact of Caloric Restriction on the Epigenetic Signatures of ...
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Effects of a Caloric Restriction Weight Loss Diet and Exercise on ...
May 1, 2012 · IL-6 decreased by 0.34 pg/mL (23.1%, P = 0.001 vs. control) in the diet group and by 0.32 pg/mL (24.3%, P < 0.001 vs. control) in the diet + ...
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Lithocholic acid phenocopies anti-ageing effects of calorie restriction
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Gut microbiome remodeling and metabolomic profile improves in ...
May 28, 2024 · Intermittent fasting - protein pacing (IF-P) significantly influences gut microbiome (GM) dynamics compared to calorie restriction (CR). We ...
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Permissive Underfeeding or Standard Enteral Feeding in Critically Ill ...
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Early moderate enteral underfeeding (60% of goal requirements) could improve the intestinal barrier function and nutritional and inflammatory status
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Effect of caloric restriction on organ size and its contribution to ...
Aug 19, 2025 · The CR group experienced reductions in adipose tissue and skeletal muscle mass compared to the control group. Sleeping energy expenditure ...
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Calorie Restriction and Intermittent Fasting: Impact on Glycemic ...
May 1, 2020 · This study showed that weight loss is the key component of treatment to reduce A1C in patients with type 2 diabetes. Given the strong ...
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Diagnosis and Management of the Metabolic Syndrome | Circulation
These recommendations are derived in large part from existing NHLBI, AHA, and ADA guidelines for management of specific risk factors. It is important to note ...
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Calorie restriction or dietary restriction: how far they can protect the ...
Jan 7, 2022 · In a Parkinson disease model, animals under calorie restriction for 6 months had better motor activity, higher basal ganglia response, and ...
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When less may be more: calorie restriction and response to cancer ...
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Fasting and Caloric Restriction in Cancer Prevention and Treatment
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Clinical implications of nutritional interventions reducing calories, a ...
The study showed that both types of restrictive diets resulted in weight loss, with the daily CR diet showing slightly greater weight loss. Both interventions ...
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Intermittent fasting strategies and their effects on body weight and ...
Jun 18, 2025 · The current evidence provides some indication that intermittent fasting diets have similar benefits to continuous energy restriction for weight loss and ...
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4:3 Intermittent Fasting Outperforms Daily Calorie Restriction in ...
Mar 31, 2025 · New study shows greater adherence and weight loss in a 4:3 intermittent fasting group compared with a traditional daily calorie restriction ...Missing: screening | Show results with:screening
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Time Restricted Eating: A Valuable Alternative to Calorie Restriction ...
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Metformin improves healthspan and lifespan in mice - Nature
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Caloric Restriction Mimetics against Age-Associated Disease
Mar 5, 2019 · However, resveratrol seems to only prolong the lifespan of mice on a high-fat diet (HFD) (Baur et al., 2006), but not on regular chow. Still, ...
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A ketogenic diet extends longevity and healthspan in adult mice - NIH
Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation.Missing: benefits 2025
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Calorie Restriction, Ketogenic Diets Reduce Biological Aging in RRMS
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The Effects of Calorie Restriction and Time-Restricted Feeding on ...
The serum concentration of IGF1 increased in response to a high-fat diet and weight gain, while there were no significant changes in the second phase groups.Missing: eating carb
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Intermittent fasting and time-restricted eating role in dietary ...
It is possible that both caloric-restriction diets and time-restriction protocols could work synergistically or additively to improve metabolic health outcomes.