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Cited by 380Dietary Effects on HealthGenetics, Aging, and Longevity in Model OrganismsMetabolism, Diabetes, and Cancer

Calorie restriction and cancer prevention: metabolic and molecular mechanisms

Open access
Longo, Valter D., Fontana, Luigi·2010·Trends in Pharmacological Sciences
DOI 10.1016/j.tips.2009.11.004PMC PMC2829867
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Abstract

An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer-prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the anti-tumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that may be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that calorie restriction without undernutrition is a broad cancer-preventive intervention in animal models, acting through reduced growth-factor and anabolic-hormone signaling, less inflammation and oxidative stress, and enhanced repair, apoptosis, and autophagy. It concludes that human cancer-prevention benefit remains unproven and calls for more mechanistic and controlled studies.

Key findings

  • In nonhuman primates, adult-onset moderate 30% calorie restriction lowered cancer incidence by 50%, mainly gastrointestinal adenocarcinoma; in rodents, 15–53% restriction below ad libitum intake produced a proportional 20–62% reduction in tumor incidence, although some tumors are resistant and responses vary by cancer type, timing, severity, and genetic background.
  • Calorie restriction reduces circulating IGF-1 by roughly 30–40% in rodents; GH/IGF-1 axis changes alter tumors, with GHR knockout mice showing about 50% less tumor burden and lethal cancer, GH overexpression increasing tumors and shortening lifespan, and IGF-1 infusion reversing calorie-restriction protection.
  • Human evidence links high IGF-1 to prostate, breast, and colon cancer; protein intake affects IGF-1. In severe calorie restriction with high protein, reducing protein lowered serum IGF-1 by 25% (194 to 152 ng/ml), and strict vegetarians with moderate protein intake had lower total and free IGF-1. Preliminary Laron dwarf data suggest protection but are inconclusive.
  • Mechanistic pathways include insulin/IGF-1, PI3K/Akt/TOR/S6K, Ras/AC/PKA, Nrf2, oxidative stress, DNA repair, apoptosis, and autophagy; PI3K-activated tumors are calorie-restriction-resistant, and restoring PTEN restores sensitivity.

Methods

  • Narrative review, not a primary study; it synthesizes epidemiological, clinical, rodent, nonhuman primate, yeast, worm/fly, and mouse genetic studies.
  • The main analysis is a conceptual synthesis of metabolic, endocrine, and molecular pathways linking calorie restriction to cancer prevention; no systematic search or meta-analysis is described.

Limitations

  • The paper states that whether calorie restriction reduces cancer in humans is unknown and that more controlled studies are needed, including studies of calorie restriction and Laron dwarf or similar populations.
  • Laron dwarf evidence is described as preliminary and inconclusive because the mean age of those patients was much lower than controls; human IGF-1 and protein-intake findings also require further study.
  • Evident from the text: as a review, it provides no new experimental data, and mechanisms are largely inferred from model organisms and animal studies; calorie restriction effects on cancer are heterogeneous, with some tumors resistant.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.tips.2009.11.004

Cites

144 of 144 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 229 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Environmental factors have profound effects on the initiation, promotion, and progression of common cancers in Western countries.

    “lifestyle and environmental factors affect cancer initiation, promotion and progression”
    • Also stated in: § NUTRITION AND CANCER · plain
      “environmental factors have profound effects in the initiation, promotion and progression of some of the most common cancers in Western countries (15, 16).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Kolonel LN Altshuler D Henderson BE The multiethnic cohort study: exploring genes, lifestyle and cancer risk Nat Rev Cancer 2004 4 7 519 27 15229477

      Not checked in the free run.

    • cites [16] Baade PD Youlden DR Krnjacki LJ International epidemiology of prostate cancer: geographical distribution and secular trends Mol Nutr Food Res 2009 53 2 171 84 19101947

      Not checked in the free run.

  • Premisecitation

    Adult-onset moderate calorie restriction reduces cancer incidence by 50% in monkeys.

    “Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys.”
    • Also stated in: § Calorie restriction and cancer · plain
      “The incidence of cancer (mainly gastrointestinal adenocarcinoma) was reduced by 50% in the CR monkeys as compared to that in controls (61).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Colman RJ Anderson RM Johnson SC Kastman EK Kosmatka KJ Beasley TM Allison DB Cruzen C Simmons HA Kemnitz JW Weindruch R Caloric restriction delays disease onset and mortality in rhesus monkeys Science 2009 325 5937 201 4 19590001 PMC2812811

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  • Interpretationreasoning

    Many malignancies are preventable.

    “suggesting that many malignancies are preventable.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Long-term cancer mortality after weight loss induced by gastric bypass surgery is significantly reduced.

    “Recent data indicate that long-term cancer mortality after weight loss induced by gastric bypass surgery is significantly reduced (40, 41).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Adams TD Gress RE Smith SC Halverson RC Simper SC Rosamond WD LaMonte MJ Stroup AM Hunt SC Long-Term Mortality after Gastric Bypass Surgery N Engl J Med 2007 357 753 61 17715409

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    • cites [41] Sjostrom L Narbro K Sjostrom CD Karason K Larsson B Wedel H Lystig T Sullivan M Bouchard C Carlsson B Bengtsson C Dahlgren S Gummesson A Jacobson P Karlsson J Lindroos AK Lonroth H Naslund I Olbers T Stenlof K Torgerson J Agren G Carlsson LM Swedish Obese Subjects Study Effects of bariatric surgery on mortality in Swedish obese subjects N Engl J Med 2007 357 8 741 52 17715408

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  • Premisecitation

    Excessive adiposity due to chronic energy imbalance is associated with increased oxidative stress, insulin resistance, inflammation, and changes in hormone and growth factor concentrations that play a key role in the pathogenesis of many cancers.

    “Excessive adiposity due to chronic energy imbalance is associated with increased oxidative stress, insulin resistance, inflammation, and changes in hormone and growth factor concentrations that play a key role in the pathogenesis of many cancers (Figure 1) (10, 21, 23, 24).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Calle EE Kaaks R Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms Nat Rev Cancer 2004 4 579 591 15286738

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    • cites [21] World Cancer Research Fund/American Institute for Cancer Research 2007 Food, Nutrition, and Physical Activity, and the Prevention of Cancer: A Global Perspective Washington, DC AICR

      Not checked in the free run.

    • cites [23] Kaaks R Lukanova A Effects of weight control and physical activity in cancer prevention: role of endogenous hormone metabolism Ann N Y Acad Sci 2002 963 268 81 12095952

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    Premisecitation

    Detoxification and repair systems may fail, especially in environments that promote cell proliferation and inhibit apoptosis, and in non-dividing cells where repair opportunity may be limited.

    “However, these detoxification and repair systems may fail, especially in environments that promote cell proliferation and inhibit cell apoptosis, but also in non-dividing cells in which the opportunity for repair may be limited (5, 6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Lengauer C Kinzler KW Vogelstein B Genetic instabilities in human cancers Nature 1998 396 6712 643 649 9872311

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    • cites [6] Bishop JM Weinberg RA Molecular oncology New York Scientific American Inc 1996

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  • May combine two claims.

    Premisecitation

    Persistent positive energy balance promotes hypertrophy of adipose tissue, reduced adiponectin production, insulin resistance, and compensatory hyperinsulinemia.

    “Persistent positive energy balance promotes hypertrophy of adipose tissue, reduced adiponectin production, insulin resistance, and compensatory hyperinsulinemia (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Kershaw EE Flier JS Adipose tissue as an endocrine organ J Clin Endocrinol Metab 2004 89 2548 56 15181022

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cancer is a complex multistage disease associated with accumulation of multiple DNA mutations that cause deregulation of cell proliferation and differentiation, loss of normal tissue organization, and tissue invasion.

    “Cancer is a complex multistage disease associated with accumulation of multiple DNA mutations that cause a deregulation of cell proliferation and differentiation, loss of normal tissue organization, and eventually tissue invasion and dislocation to distant sites (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Hanahan D Weinberg RA The hallmarks of cancer Cell 2000 100 1 57 70 10647931

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    Premisecitation

    No association is seen between adiposity and risk of developing lung and prostate cancer, whereas premenopausal breast cancer is inversely correlated with body mass index.

    “No association is seen between adiposity and the risk of developing lung and prostate cancer, whereas premenopausal breast cancer is inversely correlated with body mass index (10, 21).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Calle EE Kaaks R Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms Nat Rev Cancer 2004 4 579 591 15286738

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    • cites [21] World Cancer Research Fund/American Institute for Cancer Research 2007 Food, Nutrition, and Physical Activity, and the Prevention of Cancer: A Global Perspective Washington, DC AICR

      Not checked in the free run.

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    Premisecitation

    Calorie restriction reduces levels of anabolic hormones, growth factors, and inflammatory cytokines, reduces oxidative stress and cell proliferation, and enhances autophagy and several DNA repair processes.

    “CR reduces the levels of a number of anabolic hormones, growth factors and inflammatory cytokines, reduces oxidative stress and cell proliferation, enhances autophagy and several DNA repair processes (13, 14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Fontana L Klein S Aging, adiposity, and calorie restriction JAMA 2007 297 9 986 94 17341713

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    • cites [14] Hursting SD Lavigne JA Berrigan D Perkins SN Barrett JC Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans Annu Rev Med 2003 54 131 52 12525670

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DNA damage occurs continuously in dividing and non-dividing cells of the human body and can increase after exposure to exogenous genotoxic carcinogens.

    “DNA damage, which occurs continuously in both the dividing and non-dividing cells of the human body, and can increase after exposure to exogenous genotoxic carcinogens”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Ames BN Gold LS Endogenous mutagens and the causes of aging and cancer Mutat Res 1991 250 1–2 3 16 1944345

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    • cites [3] Luch A Nature and nurture - lessons from chemical carcinogenesis Nat Rev Cancer 2005 5 2 113 25 15660110

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    • cites [4] Sancar A Lindsey-Boltz LA Unsal-Kaçmaz K Linn S Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints Annu Rev Biochem 2004 73 39 85 15189136

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  • May combine two claims.

    Premisecitation

    Calorie restriction without malnutrition is the most potent and reproducible physiological intervention for increasing lifespan and protecting against cancer in mammals.

    “Calorie restriction (CR) without malnutrition is the most potent and reproducible physiological intervention for increasing lifespan and protecting against cancer in mammals (13, 14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Fontana L Klein S Aging, adiposity, and calorie restriction JAMA 2007 297 9 986 94 17341713

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    • cites [14] Hursting SD Lavigne JA Berrigan D Perkins SN Barrett JC Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans Annu Rev Med 2003 54 131 52 12525670

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    Premisecitation

    Estrogens, androgens, and IGF-1 are strong mitogens for cells and stimulate the development and growth of several tumors.

    “Estrogens, androgens and IGF-1 are strong mitogens for cells, and stimulate the development and growth of several tumors (31, 35, 36).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Prisco M Romano G Peruzzi F Valentinis B Baserga R Insulin and IGF-I receptors signaling in protection from apoptosis Horm Metab Res 1999 31 2–3 80 9 10226786

      Not checked in the free run.

    • cites [35] Flötotto T Djahansouzi S Gläser M Hanstein B Niederacher D Brumm C Beckmann MW Hormones and hormone antagonists: mechanisms of action in carcinogenesis of endometrial and breast cancer Horm Metab Res 2001 33 451 457 11544557

      Not checked in the free run.

    • cites [36] Yu H Shu XO Li BD Dai Q Gao YT Jin F Zheng W Joint effect of insulin-like growth factors and sex steroids on breast cancer risk Cancer Epidemiol Biomarkers Prev 2003 12 1067 73 14578144

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  • May combine two claims.

    Interpretationcitation

    Calorie restriction may contribute to prevention of telomere shortening, which may be important in modulating the pathogenesis of cancer and the biology of aging.

    “suggesting that CR may contribute to the prevention of telomere shortening, which may also be important in modulating the pathogenesis of cancer and biology of aging (52).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Rudolph KL Chang S Lee HW Blasco M Gottlieb GJ Greider C DePinho RA Longevity, stress response, and cancer in aging telomerase-deficient mice Cell 1999 96 5 701 12 10089885

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    Interpretationcitation

    Many effects of calorie restriction are likely mediated by regulating gene expression, including up-regulation of tumor-suppressor genes, genes promoting DNA and cellular repair, protein turnover, stress resistance, and antioxidant genes, and down-regulation of pro-inflammatory genes and modulation of energy metabolism pathways.

    “Many of the effects of CR are likely mediated by regulating gene expression including the up-regulation of tumor-suppressor genes, of genes promoting DNA and cellular repair, protein turnover, stress resistance, and anti-oxidant genes, and the down-regulation of pro-inflammatory genes and modulation of energy metabolism pathways (82, 83).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [82] Park SK Prolla TA Gene expression profiling studies of aging in cardiac and skeletal muscles Cardiovasc Res 2005 66 205 12 15820189

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    • cites [83] Dhahbi JM Kim HJ Mote PL Beaver RJ Spindler SR Temporal linkage between the phenotypic and genomic responses to caloric restriction Proc Natl Acad Sci U S A 2004 101 5524 9 15044709 PMC397416

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  • May combine two claims.

    Interpretationcitation

    Calorie restriction simultaneously affects multiple processes involved in the pathogenesis of cancer, including enhanced DNA repair, increased removal of damaged cells through apoptosis, enhanced autophagy, and protection from the damaging effects of toxic and genotoxic compounds.

    “In addition, CR simultaneously affects multiple processes that are involved in the pathogenesis of cancer, including enhanced DNA repair processes, increased removal of damaged cells through apoptosis, enhanced autophagy and protection from the damaging effects of a range of damaging agents (e.g., toxic and genotoxic compounds) (78–81).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [78] Weraarchakul N Strong R Wood WG Richardson A Effect of aging and dietary restriction on DNA repair Exp Cell Res 1989 181 197 204 2917602

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    • cites [79] Wachsman JT The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis Mutat Res 1996 350 1 25 34 8657188

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    • cites [80] Leeuwenburgh C Wagner P Holloszy JO Sohal RS Heinecke JW Caloric restriction attenuates dityrosine cross-linking of cardiac and skeletal muscle proteins in aging mice Arch Biochem Biophys 1997 346 74 80 9328286

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    • cites [81] Cuervo AM Bergamini E Brunk UT Dröge W Ffrench M Terman A Autophagy and aging: the importance of maintaining “clean” cells Autophagy 2005 1 3 131 40 16874025

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    Premisecitation

    Reduction in insulin levels is associated with increased SHBG and reduced free estrogens and testosterone, and with increased IGFBP-1 and reduced free IGF-1.

    “The reduction in insulin levels is associated with: (1) increased SHBG and reduced free estrogens and testosterone, (2) increased IGFBP-1 and reduced free IGF-1 (10, 21, 23, 32, 34, 37, 42).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Calle EE Kaaks R Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms Nat Rev Cancer 2004 4 579 591 15286738

      Not checked in the free run.

    • cites [21] World Cancer Research Fund/American Institute for Cancer Research 2007 Food, Nutrition, and Physical Activity, and the Prevention of Cancer: A Global Perspective Washington, DC AICR

      Not checked in the free run.

    • cites [23] Kaaks R Lukanova A Effects of weight control and physical activity in cancer prevention: role of endogenous hormone metabolism Ann N Y Acad Sci 2002 963 268 81 12095952

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Whether calorie restriction with adequate nutrition will reduce cancer incidence in humans is unknown.

    “Whether CR with adequate nutrition will reduce cancer incidence in humans is unknown”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Weight loss is associated with a reduction in inflammatory cytokines and prostaglandins, and in several markers of oxidative stress and DNA damage.

    “Weight loss is also associated with a reduction in inflammatory cytokines and prostaglandins, and in several markers of oxidative stress and DNA damage (47–50).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [47] Esposito K Pontillo A Di Palo C Giugliano G Masella M Marfella R Giugliano D Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial JAMA 2003 289 14 1799 804 12684358

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    • cites [48] Fontana L Villareal DT Weiss EP Racette SB Steger-May K Klein S Holloszy JO the Washington University School of Medicine CALERIE Group Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial Am J Physiol Endocrinol Metab 2007 293 1 E197 202 17389710

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    • cites [49] Hofer T Fontana L Weiss EP Anton S Malayappan B Holloszy JO Leeuwenburgh C One year of caloric restriction and exercise in humans and the effects on DNA and RNA oxidation levels in white blood cells and urine Rejuvenation Research 2008 11 4 793 799 18729811 PMC2724865

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    • cites [50] Heilbronn LK de Jonge L Frisard MI Pennington CALERIE Team Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial JAMA 2006 295 1539 48 16595757 PMC2692623

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  • May combine two claims.

    Premisecitation

    The effects of calorie restriction on cancer are not homogeneous; some cancers show a greater response than others, and a small portion of tumors is resistant to calorie restriction.

    “Nonetheless, the effects of CR on cancer are not homogeneous. Some cancers show a greater response to CR than others, and a small portion of tumors is resistant to the effects of CR (54, 56, 57, 60, 62).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [54] Tannenbaum A Silverstone H The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice Cancer Res 1949 9 12 724 7 15395906

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    • cites [56] Cheney KE Liu RK Smith GS Meredith PJ Mickey MR Walford RL The effect of dietary restriction of varying duration on survival, tumor patterns, immune function, and body temperature in B10C3F1 female mice J Gerontol 1983 38 4 420 30 6306089

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    • cites [57] Weindruch R Walford RL The retardation of aging and disease by dietary restriction Springfield, IL Charles C Thomas Publisher 1988

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  • May combine two claims.

    Premisecitation

    Weight loss induced by negative energy balance is associated with decreased fat cell size, reduction in visceral, hepatic, and skeletal muscle fat, improved adipokine profile and insulin sensitivity, and reduced circulating insulin levels.

    “Weight loss induced by a negative energy balance is associated with decreased fat cell size, a reduction in visceral, hepatic and skeletal muscle fat, improved adipokine profile and insulin sensitivity, and reduced circulating insulin levels (25, 43–45).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [25] Kershaw EE Flier JS Adipose tissue as an endocrine organ J Clin Endocrinol Metab 2004 89 2548 56 15181022

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    • cites [43] Racette SB Weiss EP Villareal DT The Washington University School of Medicine CALERIE Group One Year of Caloric Restriction in Humans: Feasibility and Effects on Body Composition and Abdominal Adipose Tissue J Gerontol A Biol Sci Med Sci 2006 61 943 950 16960025 PMC4376245

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    • cites [44] Weiss EP Racette SB Villareal DT Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial Am J Clin Nutr 2006 84 5 1033 42 17093155 PMC1941677

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    • cites [45] Larson-Meyer DE Heilbronn LK Redman LM Newcomer BR Frisard MI Anton S Smith SR Alfonso A Ravussin E Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects Diabetes Care 2006 29 6 1337 44 16732018 PMC2677812

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  • May combine two claims.

    Premisecitation

    Severe calorie restriction, when protein intake is normal, causes a reduction in IGF-I without leading to obesity, while concomitantly reducing many markers of heart disease.

    “severe CR (when protein intake is normal) causes a reduction in IGF-I without leading to obesity, and while concomitantly reducing many of the markers of heart diseases (84).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Fontana L Meyer TE Klein S Holloszy JO Long-Term Calorie Restriction Is Highly Effective In Reducing The Risk For Atherosclerosis In Humans Procedings of the National Academy of Science USA 2004 101 17 6659 6663 PMC404101 15096581

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    Premisecitation

    When growth hormone and IGF-I deficient dwarf mice are calorie restricted, they no longer become obese and can live up to 100% longer than wild type and ad lib fed mice.

    “when these mice are calorie restricted, they no longer become obese and can live up to 100% longer than wild type and ad lib fed mice (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Bartke A Bonkowski M Masternak M THow diet interacts with longevity genes Hormones (Athens) 2008 7 1 17 23 18359740

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    Premisecitation

    Growth hormone overexpressing mice have very high concentrations of IGF-1, increased body size up to 100%, increased incidence and early onset of tumors, and a marked reduction in lifespan compared to their normal siblings.

    “GH overexpressing mice have very high concentrations of IGF-1, increased body size up to 100%, increased incidence and early on-set of tumors, and a marked reduction in lifespan compared to their normal siblings (97).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Bartke A Chandrashekar V Bailey B Zaczek D Turyn D Consequences of growth hormone (GH) overexpression and GH resistance Neuropeptides 2002 36 2–3 201 8 12359510

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    Premisecitation

    In men, animal and vegetable protein consumption was associated with an increase in serum IGF-1 concentrations, whereas calorie intake was associated with an increase in serum IGF-I concentration only in lean men with a BMI <25 kg/m2.

    “In men animal and vegetable protein consumption was associated with an increase in serum IGF-1 concentrations, whereas calorie intake was associated with an increase in serum IGF-I concentration only in lean men with a BMI <25 kg/m2 (105).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Giovannucci E Pollak M Liu Y Platz EA Majeed N Rimm EB Willett WC Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men Cancer Epidemiol Biomarkers Prev 2003 Feb 12 2 84 9 12582016

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    Premisecitation

    At least 50% of US males are eating ≥1.34 g of protein/kg of body weight/day, which is 40% or more protein than the RDA recommended intakes, and therefore associated with a positive nitrogen balance.

    “at least 50% of the US males are eating ≥ 1.34 g of protein/kg of body weight/day, which is 40% or more protein than the RDA recommended intakes, and therefore associated with a positive nitrogen balance (108, 109).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [108] Rand WM Pellett PL Young VR Meta-analysis of nitrogen balance studies for estimating protein requirements in healthy adults Am J Clin Nutr 2003 77 109 27 12499330

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    • cites [109] Moshfegh A Goldman J Cleveland L 2005 What we eat in America, NHANES 2001–2002: Usual nutrient intakes from food compared to Dietary Reference Intakes Available at: http://www.ars.usda.gov/SP2UserFiles/Place/12355000/pdf/usualintaketables2001-02.pdf Accessed Sep 20, 2009

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  • May combine two claims.

    Interpretationcitation

    The calorie-restriction-mediated increase in corticosterone may play an important role in preventing cancer, as adrenalectomy reverses the cancer-protective effects of calorie restriction and glucocorticoid supplementation restores inhibition.

    “The CR-mediated increase in corticosterone, for example, may also play an important role in preventing cancer, as adrenalectomy reverses the cancer-protective effects of CR, and glucocorticoid supplementation restores inhibition (98).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Stewart JW Koehler K Jackson W Hawley J Wang W Au A Myers R Birt DF Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition Carcinogenesis 2005 26 6 1077 84 15746164

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  • May combine two claims.

    Premisecitation

    IGF-1 is produced primarily in the liver and acts synergistically with other anabolic hormones, and in relation to calorie and protein availability, to regulate energy metabolism, cell proliferation, cell differentiation, body size, and longevity.

    “Insulin-like growth factor 1 (IGF-1), a growth factor produced primarily from the liver, acts synergistically with other anabolic hormones (e.g. insulin, sex steroids), and in relation to calorie and protein availability, to regulate energy metabolism, cell proliferation, cell differentiation, body size and longevity (31, 35, 36).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Prisco M Romano G Peruzzi F Valentinis B Baserga R Insulin and IGF-I receptors signaling in protection from apoptosis Horm Metab Res 1999 31 2–3 80 9 10226786

      Not checked in the free run.

    • cites [35] Flötotto T Djahansouzi S Gläser M Hanstein B Niederacher D Brumm C Beckmann MW Hormones and hormone antagonists: mechanisms of action in carcinogenesis of endometrial and breast cancer Horm Metab Res 2001 33 451 457 11544557

      Not checked in the free run.

    • cites [36] Yu H Shu XO Li BD Dai Q Gao YT Jin F Zheng W Joint effect of insulin-like growth factors and sex steroids on breast cancer risk Cancer Epidemiol Biomarkers Prev 2003 12 1067 73 14578144

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The calorie-restriction-mediated reduction in IGF-1 levels is believed to play a key role in protecting against cancer and slowing aging.

    “this CR-mediated reduction in IGF-1 levels is believed to play a key role in protecting against cancer and slowing aging (11, 64, 89–90).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Hursting SD Slaga TJ Fischer SM DiGiovanni J Phang JM Mechanism-based cancer prevention approaches: targets, examples, and the use of transgenic mice J Natl Cancer Inst 1999 91 3 215 25 10037099

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    • cites [64] Sonntag WE Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals J Gerontol A Biol Sci Med Sci 1999 54 B521 38 10647962

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    • cites [89] Colbert LH Westerlind KC Perkins SN Haines DC Berrigan D Donehower LA Fuchs-Young R Hursting SD Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer Med Sci Sports Exerc 2009 41 8 1597 605 19568200 PMC3040490

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    • cites [90] Colbert LH Mai V Perkins SN Berrigan D Lavigne JA Wimbrow HH Alvord WG Haines DC Srinivas P Hursting SD Exercise and intestinal polyp development in APCMin mice Med Sci Sports Exerc 2003 35 10 1662 9 14523302

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The recommended daily allowance for protein intake in healthy adults is 0.83 g/kg of body weight/day.

    “the recommended daily allowance for protein intake in healthy adults is 0.83 g/kg of body weight/day (108)”
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    • cites [108] Rand WM Pellett PL Young VR Meta-analysis of nitrogen balance studies for estimating protein requirements in healthy adults Am J Clin Nutr 2003 77 109 27 12499330

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Growth hormone and IGF-I deficient dwarf mice become obese at middle age and live approximately 40% longer.

    “GH and IGF-I deficient dwarf mice become obese at middle age and live approximately 40% longer (112)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Berryman DE List EO Coschigano KT Behar K Kim JK Kopchick JJ Comparing adiposity profiles in three mouse models with altered GH signaling Growth Horm IGF Res 2004 14 4 309 18 15231300

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations increase with age in S. cerevisiae by as much as 10-fold and are reduced by calorie restriction.

    “mutations, which increase with age in S. cerevisiae by as much as 10-fold, are reduced by CR (115–117).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [115] Longo VD Liou LL Valentine JS Gralla EB Mitochondrial superoxide decreases yeast survival in stationary phase Arch Biochem Biophys 1999 365 1 131 42 10222047

      Not checked in the free run.

    • cites [116] Fabrizio P Battistella L Vardavas R Gattazzo C Liou LL Diaspro A Dossen JW Gralla EB Longo VD Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae J Cell Biol 2004 166 7 1055 67 15452146 PMC2172019

      Not checked in the free run.

    • cites [117] Madia F Gattazzo C Fabrizio P Longo VD A simple model system for age-dependent DNA damage and cancer Mech Ageing Dev 2007 128 1 45 9 17118426 PMC1847572

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of TOR/SCH9 and/or AKT genes, and down-regulation of the Ras/AC/PKA pathway, postpone the age-dependent increase in spontaneous mutations.

    “The deletion of either the TOR/SCH9, the yeast homologues of mammalian target of rapamycin (mTOR), and S6 kinase (S6K) and/or AKT genes, respectively, and the down-regulation of the Ras/adenylyl cyclase (AC)/protein kinase A (PKA) pathway postpone this age-dependent increase in spontaneous mutations (118–120).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [118] Fabrizio P Gattazzo C Battistella L Wei M Cheng C McGrew K Longo VD Sir2 blocks extreme life-span extension Cell 2005 123 4 655 67 16286010

      Not checked in the free run.

    • cites [119] Madia F Wei M Yuan V Hu J Gattazzo C Pham P Goodman MF Longo VD Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism J Cell Biol 2009 186 4 509 23 19687253 PMC2733759

      Not checked in the free run.

    • cites [120] Madia F Gattazzo C Wei M Fabrizio P Burhans WC Weinberger M Galbani A Smith JR Nguyen C Huey S Comai L Longo VD Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system J Cell Biol 2008 180 1 67 81 18195102 PMC2213615

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The Tor/Sch9 pathway promotes superoxide generation and reduces antioxidant protection by down-regulating Msn2/4 and Gis1.

    “The evidence suggests that the Tor/Sch9 pathway promotes superoxide generation and reduces the anti-oxidant protection by down-regulating Msn2/4 and Gis1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The generation of oxidants is elevated and resistance to oxidants and life span are decreased in S. cerevisiae expressing an oncogene-like constitutively active RAS2val19 or overexpressing SCH9.

    “the generation of oxidants is elevated and resistance to oxidants and life span are decreased in S. cerevisiae expressing an oncogene-like constitutively active RAS2val19 (121, 122) or overexpressing SCH9.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] Fabrizio P Liou LL Moy VN Diaspro A Valentine JS Gralla EB Longo VD SOD2 functions downstream of Sch9 to extend longevity in yeast Genetics 2003 163 1 35 46 12586694 PMC1462415

      Not checked in the free run.

    • cites [122] Hlavatá L Aguilaniu H Pichová A Nyström T The oncogenic RAS2(val19) mutation locks respiration, independently of PKA, in a mode prone to generate ROS EMBO J 2003 22 13 3337 45 12839995 PMC165639

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These deficiencies appear to mediate the effects of Prop-1 and Pit-1 mutations on longevity, since mice that cannot release growth hormone in response to growth hormone releasing hormone also live longer.

    “These deficiencies appear to mediate the effects of Prop-1 and Pit-1 mutations on longevity, since the mice that cannot release GH in response to growth hormone releasing hormone also live longer (128).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Flurkey K Papaconstantinou J Miller RA Harrison DE Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production Proc Natl Acad Sci U S A 2001 98 12 6736 41 11371619 PMC34422

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-dependent regrowth frequency doubles in cells lacking cytosolic superoxide dismutase but is reduced in cells overexpressing antioxidant enzymes.

    “age-dependent regrowth frequency doubles in cells lacking cytosolic superoxide dismutase but is reduced in cells overexpressing antioxidant enzymes (116, 119, 121).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [116] Fabrizio P Battistella L Vardavas R Gattazzo C Liou LL Diaspro A Dossen JW Gralla EB Longo VD Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae J Cell Biol 2004 166 7 1055 67 15452146 PMC2172019

      Not checked in the free run.

    • cites [119] Madia F Wei M Yuan V Hu J Gattazzo C Pham P Goodman MF Longo VD Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism J Cell Biol 2009 186 4 509 23 19687253 PMC2733759

      Not checked in the free run.

    • cites [121] Fabrizio P Liou LL Moy VN Diaspro A Valentine JS Gralla EB Longo VD SOD2 functions downstream of Sch9 to extend longevity in yeast Genetics 2003 163 1 35 46 12586694 PMC1462415

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dwarf mice with high plasma growth hormone but 90% lower IGF-I (GHR/BP null mice) and heterozygous female IGF-I receptor knockout mice live longer than wild type controls.

    “dwarf mice with high plasma GH, but a 90% lower IGF-I (GHR/BP null mice) and heterozygous female IGF-I receptor knockout mice live longer than the wild type controls (129, 130).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [129] Holzenberger M Dupont J Ducos B Leneuve P Géloën A Even PC Cervera P Le Bouc Y IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice Nature 2003 421 6919 182 7 12483226

      Not checked in the free run.

    • cites [130] Coschigano KT Clemmons D Bellush LL Kopchick JJ Assessment of growth parameters and life span of GHR/BP gene-disrupted mice Endocrinology 2000 141 7 2608 13 10875265

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced insulin/IGF-1 signaling in mice not only increases life span, but also delays or reduces aging-related pathology, most notably spontaneous tumors.

    “Reduced insulin/IGF-1 signaling in mice not only increases life span, but also delays or reduces aging-related pathology, most notably spontaneous tumors (94, 131)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Ikeno Y Hubbard GB Lee S Cortez LA Lew CM Webb CR Berryman DE List EO Kopchick JJ Bartke A Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice J Gerontol A Biol Sci Med Sci 2009 64 5 522 9 19228785 PMC2667132

      Not checked in the free run.

    • cites [131] Ikeno Y Bronson RT Hubbard GB Lee S Bartke A Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity J Gerontol A Biol Sci Med Sci 2003 58 4 291 6 12663691

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These changes result in increased oxidative damage to DNA and increased expression of the REV1 gene, which together promote age-dependent point mutations.

    “These changes result in increased oxidative damage to the DNA but also in increased expression of the REV1 gene, which, together, promote age-dependent point mutations (119).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Madia F Wei M Yuan V Hu J Gattazzo C Pham P Goodman MF Longo VD Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism J Cell Biol 2009 186 4 509 23 19687253 PMC2733759

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mn-superoxide dismutase heterozygous knockout mice have reduced MnSOD activity, increased levels of oxidative damage to DNA in all tissues, a 100% increase in cancer incidence, but average and maximal lifespan is not affected.

    “Mn-superoxide dismutase (MnSOD) heterozygous knockout mice, that have reduced MnSOD activity, have increased levels of oxidative damage to DNA in all tissues, a 100% increase in cancer incidence, but average and maximal lifespan is not affected (136).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Van Remmen H Ikeno Y Hamilton M Pahlavani M Wolf N Thorpe SR Alderson NL Baynes JW Epstein CJ Huang TT Nelson J Strong R Richardson A Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging Physiol Genomics 2003 16 1 29 37 14679299

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Calorie restriction likely regulates pro- and anti-oxidant systems by similar mechanisms, since life span extension caused by calorie restriction is largely reversed in cells lacking the three stress resistance transcription factors Msn2/4 and Gis1.

    “CR is likely to regulate pro- and anti-oxidant systems by similar mechanisms since life span extension caused by CR is largely reversed in cells lacking these 3 stress resistance transcription factors (i.e. Msn2/4 and Gis1) (124).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Wei M Fabrizio P Hu J Ge H Cheng C Li L Longo VD Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9 PLoS Genet 2008 4 1 e13 18225956 PMC2213705

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, mutations in the Prop-1 or Pit-1 genes cause severe deficiencies in growth hormone and IGF-I, extend life span by 25 to 65%, and cause dwarfism.

    “In mice, mutations in the Prop-1 or Pit-1 genes, which cause severe deficiencies in GH and IGF-I, extend life span by 25 to 65% and cause dwarfism (126, 127).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [126] Brown-Borg HM Borg KE Meliska CJ Bartke A Dwarf mice and the ageing process Nature 1996 384 6604 33 8900272

      Not checked in the free run.

    • cites [127] Flurkey K Papaconstantinou J Harrison DE The Snell dwarf mutation Pit1(dw) can increase life span in mice Mech Ageing Dev 2002 123 2–3 121 30 11718806

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IGF-I and age-dependent cancer are both decreased in calorie-restricted mice.

    “Notably, IGF-I and age-dependent cancer are both decreased in CR mice (14, 54–60).”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [14] Hursting SD Lavigne JA Berrigan D Perkins SN Barrett JC Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans Annu Rev Med 2003 54 131 52 12525670

      Not checked in the free run.

    • cites [54] Tannenbaum A Silverstone H The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice Cancer Res 1949 9 12 724 7 15395906

      Not checked in the free run.

    • cites [55] Cheney KE Liu RK Smith GS Leung RE Mickey MR Walford RL Survival and disease patterns in C57BL/6J mice subjected to undernutrition Exp Gerontol 1980 15 4 237 58 7409023

      Not checked in the free run.

    • cites [56] Cheney KE Liu RK Smith GS Meredith PJ Mickey MR Walford RL The effect of dietary restriction of varying duration on survival, tumor patterns, immune function, and body temperature in B10C3F1 female mice J Gerontol 1983 38 4 420 30 6306089

      Not checked in the free run.

    • cites [57] Weindruch R Walford RL The retardation of aging and disease by dietary restriction Springfield, IL Charles C Thomas Publisher 1988

      Not checked in the free run.

    • cites [58] Shimokawa I Higami Y Yu BP Masoro EJ Ikeda T Influence of dietary components on occurrence of and mortality due to neoplasms in male F344 rats Aging (Milano) 1996 8 4 254 62 8904955

      Not checked in the free run.

    • cites [59] Klurfeld DM Welch CB Davis MJ Kritchevsky D Determination of degree of energy restriction necessary to reduce DMBA-induced mammary tumorigenesis in rats during the promotion phase J Nutr 1989 119 2 286 91 2493082

      Not checked in the free run.

    • cites [60] Thompson HJ Zhu Z Jiang W Dietary energy restriction in breast cancer prevention J Mammary Gland Biol Neoplasia 2003 8 1 133 42 14587868

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The frequency of the cancer-like regrowth phenotype is greatly reduced in calorie-restricted yeast and yeast with mutations in the Tor/Sch9 and Ras/AC/PKA pathways.

    “The frequency of this cancer-like regrowth phenotype is greatly reduced in CR yeast and yeast with mutations in the Tor/Sch9 and Ras/AC/PKA pathways (117).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Madia F Gattazzo C Fabrizio P Longo VD A simple model system for age-dependent DNA damage and cancer Mech Ageing Dev 2007 128 1 45 9 17118426 PMC1847572

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Calorie restriction and other interventions might lower oncogene mutation frequency and alter how mutated cancer cells grow and invade, by dampening pro-aging pathways, reducing inflammation and growth in neighboring normal and pre-cancerous cells, and increasing apoptosis in damaged cells.

    “CR (and other interventions) by reducing the activity of pro-aging pathways, reducing growth and inflammation in the pre-cancerous and normal neighbor cells, and increasing apoptosis in damaged cells may reduce oncogene mutations frequency but also modulate the growth and invasiveness potentials of the mutated cancerous cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These data suggest that the relationship between oxidative stress, cancer, and aging is complex, and may also indicate that conditions that increase mutations and cancer are not necessarily accelerating aging.

    “These data suggest that the relationship between oxidative stress, cancer and aging is complex, and may also indicate that the conditions that increase mutations and cancer are not necessarily accelerating aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tumors that are calorie-restriction-resistant originate from cancer cells with constitutive activation of the PI3K pathway, which in culture proliferate in the absence of IGF-1 and insulin.

    “Tumors that are CR-resistant originate from cancer cells with constitutive activation of the PI3K pathway, which in culture proliferate in the absence of IGF-1 and insulin (137).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Kalaany NY Sabatini DM Tumours with PI3K activation are resistant to dietary restriction Nature 2009 458 7239 725 31 19279572 PMC2692085

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metastases account for 90% of human cancer deaths.

    “metastases are the cause of 90% of human cancer deaths (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Fidler IJ The pathogenesis of cancer metastasis: The “seed and soil” hypothesis revisited Nat Rev Cancer 2003 3 453 458 12778135

      Not checked in the free run.

44 of 44

  • The paper relies on this without support.

    Calorie restriction extends the life span of all the major model organisms used to study aging.

    “Because CR extends the life span of all the major model organisms used to study aging”

  • The paper relies on this without support.

    Worms and flies have a mostly non-dividing cellular network and rare tumor phenotypes, which limits their value for studying mechanisms of age-dependent tumorigenesis.

    “Although worms and flies are excellent model organisms to study aging, their mostly non-dividing cellular network and rare tumor phenotypes limit their value in studies of the mechanisms of age-dependent tumorigenesis.”

  • The paper relies on this without support.

    S. cerevisiae can provide evidence for fundamental molecular mechanisms of age-dependent genomic instability, and mice can be studied to determine whether similar mechanisms apply to mammals.

    “By contrast, the simple S. cerevisiae can provide evidence for the fundamental molecular mechanisms of age-dependent genomic instability whereas mice can be studied to determine whether similar mechanisms apply to mammals.”

  • The paper relies on this without support.

    The nutrient-response pathways that regulate aging and age-dependent genomic instability in model organisms can provide insights on the mechanisms linking calorie restriction and the reduction in cancer.

    “the nutrient-response pathways that regulate aging and age-dependent genomic instability in these organisms can provide insights on the mechanisms linking CR and the reduction in cancer.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Insulin, estrogens, androgens, and IGF-1 are powerful mitogens for cells, and stimulate the development and growth of several common tumors, including breast, colon, prostate, pancreatic, and endometrial cancer.

    “Insulin, estrogens, androgens, and IGF-1 are powerful mitogens for cells, and stimulate the development and growth of several common tumors, including breast, colon, prostate, pancreatic, and endometrial cancer (68).”

    From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [68]

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Authors
Longo, V. D., & Fontana, L.
Affiliations
  • University of Southern California (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Longo, Valter D.
  • Fontana, Luigi
ORCID
Venue
Trends in Pharmacological Sciences
Publisher
Elsevier BV
Published
2010-02
Volume
31
Issue
2
Pages
89-98
ISSN
0165-6147 (ISSN-L)
DOI
10.1016/j.tips.2009.11.004
PMC
PMC2829867
OpenAlex
W2068091527
Semantic Scholar
a252189f05696f14cf8a7fb1c5055dae88f3bdf4
Cited by
378
References
144
Citations by year
2026: 5 · 2025: 13 · 2024: 19 · 2023: 25 · 2022: 23 · 2021: 26 · 2020: 25 · 2019: 23 · 2018: 30 · 2017: 26 · 2016: 29 · 2015: 23 · 2014: 30 · 2013: 32 · 2012: 18
FWCI
16.90
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Pharmacological Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000448)
  • National Institute on Aging (R01AG020642)
  • National Center for Research Resources (UL1RR024992)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Physiology › Dietary Effects on Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
caloric restriction, cancer prevention, chemoprevention, metabolic mechanisms, molecular mechanisms, growth factors, anabolic hormones, inflammatory cytokines, oxidative stress, adiposity, physical activity, diet, dietary intervention, rodents, monkeys
MeSH terms
Animals, Humans, Insulin-Like Growth Factor I, Neoplasms, Nutritional Physiological Phenomena, Growth Hormone, Cyclic AMP-Dependent Protein Kinases, Phosphatidylinositol 3-Kinases, Caloric Restriction, Genomic Instability, Adiposity, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

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