Calorie Restriction (CR) Diet

CR & Disease: Cardiovascular Research

February 15, 2011

CR May Provide Some Protection Against Heart Disease

Following are excerpts and references from animal and human studies of the effects of CR on the cardiovascular system. In all cases the original paper should be read for a full understanding of what was being studied and what could be concluded. Before getting to the individual human and animal studies, here is a review.


Title: "Mechanisms Underlying Caloric Restriction and Lifespan Regulation - Implications for Vascular Aging ."

Zoltan Ungvari, Cristina Parrado-Fernandez, Anna Csiszar, Rafael de Cabo

From the Department of Physiology (Z.U., A.C.), New York Medical College, Valhalla; Laboratory of Experimental Gerontology (C.P.-F., R.d.C.), National Institute on Aging, National Institutes of Health, Baltimore, Md; and Laboratorio de Biología Celular (C.P.-F.), Universidad de Córdoba, Spain.

Correspondence to Dr Rafael de Cabo, Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail

Full Text: Circulation Research

"ABSTRACT: This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species and inhibition of inflammatory pathways play a central role in the antiaging cardiovascular effects of caloric restriction. .... We propose that caloric restriction ....suppresses initiation/progression of vascular disease that accompany aging.

INTRODUCTION: ...CR decreases the incidence of cardiovascular disease and has been shown to alter neuroendocrine and sympathetic nervous system in laboratory animals, and some of these are replicating now in ongoing human studies. In particular, the National Institute on Aging, through its program, CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy, initiated in 2002) endeavors to fund clinical trials that address the feasibility of using CR as a therapeutic tool as well as its effects and mechanisms in disease prevention...."

CONCLUSIONS AND PERSPECTIVES: Oxidative stress plays an important role in the pathogenesis of coronary artery disease by mediating expression of inflammatory genes and eliciting oxidative modification of lipoprotein particles. CR seems to attenuate both vascular oxidative stress and exert antiinflammatory effects in aged animals......In addition, CR exerts beneficial effects on a range of systemic cardiovascular risk factors. There is a great deal of effort to dissect the pathways that invoke CR benefits to develop pharmacological agents that would act as CR mimetics."

Human Studies

  1. Title: "Caloric restriction and heart function: is there a sensible link?"

    Acta Pharmacol Sin. 2010 Sep;31(9):1111-7. Epub 2010 Aug 23.; Han X, Ren J.

    PMID: 20729873

    Calorie restriction (CR) is defined as a reduction in calorie intake below the usual ad libitum intake without malnutrition. Ample of clinical and experimental evidence has demonstrated that CR is capable of retarding aging process and development of cardiovascular disease. Although suppression of reactive oxygen species production and inflammation plays a central role in the favorable cardiovascular effects of CR, the health benefit of CR is believed to be ultimately mediated through a cadre of biochemical and cellular adaptations including redox homeostasis, mitochondrial function, inflammation, apoptosis and autophagy. Despite the apparent beneficial cardiovascular effects of CR, implementation of CR in the health care management is still hampered by apparent applicability issues and health concerns. Here we briefly review the cardiac consequence of CR and discuss whether CR may represent a safe and effective strategy in the management of cardiovascular health."

  2. Title: "Long-Term Caloric Restriction Ameliorates the Decline in Diastolic Function in Humans."

    J Am Coll Cardiol, 2006; 47:398-402, doi:10.1016/j.jacc.2005.08.069 (Published online 22 December 2005).; Timothy E. Meyer, PhD*,{dagger}, Sándor J. Kovács, PhD, MD{dagger}, Ali A. Ehsani, MD*,{dagger}, Samuel Klein, MD*, John O. Holloszy, MD* and Luigi Fontana, MD, PhD.

    PMID: 16412867

    "OBJECTIVES: We determined whether caloric restriction (CR) has cardiac-specific effects that attenuate the established aging-associated impairments in diastolic function (DF).

    BACKGROUND: Caloric restriction retards the aging process in small mammals; however, no information is available on the effects of long-term CR on human aging. In healthy individuals, Doppler echocardiography has established the pattern of aging-associated DF impairment, whereas little change is observed in systolic function (SF). .."

    CONCLUSIONS: Caloric restriction has cardiac-specific effects that ameliorate aging-associated changes in DF. These beneficial effects on cardiac function might be mediated by the effect of CR on blood pressure, systemic inflammation, and myocardial fibrosis. .."

  3. Title: "[Potential and unsolved problems concerning caloric restriction in nutritional therapeutics for the purpose of promoting health and controlling aging]. [Japanese]."

    Nippon Ronen Igakkai Zasshi - Japanese Journal of Geriatrics. 43(1):89-91, 2006 Jan.; Shinmura, Ken.

    "Overeating and obesity are major health problems even in the elderly since they lead to the metabolic syndrome, resulting in an increase in cardiovascular disease. The development of novel nutritional therapeutics for the purpose of promoting health and controlling ageing process aims at the self-helping elderly. Caloric restriction (CR) has been widely investigated as a powerful method that can prevent and reverse senescent changes. CR might counteract the deleterious aspects of metabolic syndrome and may prolong lifespan even in humans. However, we should keep in mind that several fundamental issues about CR still remain unsolved. In addition, malnutrition and nutritional troubles are emerging problems in the elderly in care. Thus, we emphasize that nutritional intervention aiming at ageing control should be established and be developed as a custom-made therapeutics for the elderly, who show great individual variation. .."

    PMID: 16521813

  4. Title: "Intermittent versus on-demand use of a very low calorie diet: a randomized 2-year clinical trial."

    Journal of Internal Medicine. 253(4):463-71, 2003 Apr.; Lantz, H. Peltonen, M. Agren, L. Torgerson, J S.

    "OBJECTIVES: To compare two different very low calorie diet (VLCD)-based weight maintenance strategies. DESIGN AND SETTING: A randomized 2-year clinical trial performed at the Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Sweden. SUBJECTS: A total of 334 patients, body mass index (BMI) >30 kg m-2, aged 18-60 years. ..."

    "Most cardiovascular risk factors improved during the first year, whilst anthropometric measures, insulin, HDL- and LDL-cholesterol were also significantly improved after 2 years of treatment. "

Animal Studies - Primate

  1. Title: "Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys"

    Ricki J. Colman, Rozalyn M. Anderson, Sterling C. Johnson, Erik K. Kastman, Kristopher J. Kosmatka, T. Mark Beasley, David B. Allison, Christina Cruzen, Heather A. Simmons, Joseph W. Kemnitz, and Richard Weindruch
    Science 10 July 2009: 201-204


    "As it is in humans, cardiovascular disease is a prevalent age-associated disorder in rhesus monkeys. The methods used to diagnose cardiovascular disease are described (7). The most common diagnosis in living monkeys was leak of the mitral valve. The most frequently observed lesions at necropsy were valvular endocardiosis, cardiomyopathy, and myocardial fibrosis. The incidence of cardiovascular disease was reduced by 50% in the animals subjected to CR as compared to that in controls (Fig. 3A)."

  2. Title: "Caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): metabolic, physiologic, and atherosclerotic measures from a 4-year intervention trial."

    Journals of Gerontology Series A-Biological Sciences & Medical Sciences. 59(10):1007-14, 2004 Oct.; Cefalu, William T. Wang, Zhong Q. Bell-Farrow, Audrey D. Collins, Joel. Morgan, Timothy. Wagner, Janice D.

    PMID: 15528768

    "Caloric restriction (CR) retards aging processes, extends maximal life span, and consistently improves insulin resistance in lower species. Insulin resistance is associated with cardiovascular disease, but data is lacking demonstrating that increased insulin sensitivity reduces atherosclerosis progression. We initiated a study in 32 adult cynomolgus monkeys to evaluate increased insulin sensitivity secondary to CR on atherosclerosis extent..."

    "These studies demonstrate that CR significantly improves insulin sensitivity, but when elevated plasma cholesterol concentrations were held similar, there was no effect on atherosclerosis extent. However, the composition of these lesions and changes in endothelial function may have been improved but were not evaluated in this study. Thus, further studies are needed to determine if improved insulin sensitivity might decrease arterial inflammation and improve endothelial function, despite no changes in atherosclerosis extent. ."

Animal Studies - Non-Primate

  1. Title: "Aging and dietary restriction effects on ubiquitination, sumoylation, and the proteasome in the heart."

    Mechanisms of Ageing & Development. 129(9):515-21, 2008 Sep.; Li, Feng. Zhang, Le. Craddock, Jeffrey. Bruce-Keller, Annadora J. Dasuri, Kalavathi. Nguyen, AnhThao. Keller, Jeffrey N.

    PMID: 18533226

    "Dietary restriction (DR), in the absence of malnutrition, is the only intervention known to reliably increase average and maximal lifespan in a variety of organisms including mammals. Because the effects of DR on the heart are poorly understood, in the present study we examined the effects of DR on the ubiquitin-proteasome pathway (UPP) in the heart.... "

    "These data demonstrate for the first time the effects of aging and DR on proteasome biogenesis and sumoylation in the heart. Cumulatively, our data indicate that DR has many beneficial effects towards the UPP in the heart, and suggests that a preservation of the UPP may be a potential mechanism by which DR mediates beneficial effects on the cardiovascular system..."

  2. Title: "Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats."

    FASEB Journal. 20(6):631-7, 2006 Apr.; Mager, Donald E. Wan, Ruiqian. Brown, Martin. Cheng, Aiwu. Wareski, Przemyslaw. Abernethy, Darrell R. Mattson, Mark P.

    PMID: unknown, but abstract available

    "Dietary restriction (DR) has been shown to increase life span, delay or prevent age-associated diseases, and improve functional and metabolic cardiovascular risk factors in rodents and other species. To investigate the effects of DR on beat-to-beat heart rate and diastolic blood pressure variability (HRV and DPV) in male Sprague-Dawley rats, we implanted telemetric transmitters and animals were maintained on either intermittent fasting (every other day feeding) or calorie-restricted (40% caloric reduction) diets. .."

    "Both methods of DR produced decreases in the low-frequency component of DPV spectra, a marker for sympathetic tone, and the high-frequency component of HRV spectra, a marker for parasympathetic activity, was increased. .."

    "These results suggest an additional cardiovascular benefit of DR that merits further studies of this potential effect in humans. .."

  3. Title: "Gene expression and physiologic responses of the heart to the initiation and withdrawal of caloric restriction."

    Journals of Gerontology Series A-Biological Sciences & Medical Sciences. 61(3):218-31, 2006 Mar.; Dhahbi, Joseph M. Tsuchiya, Tomoshi. Kim, Hyon-Jeen. Mote, Patricia L. Spindler, Stephen R.

    PMID: unknown, but abstract available

    "Aging increases and caloric restriction (CR) decreases morbidity and mortality associated with the cardiovascular system. Using Affymetrix microarrays, we identified changes in heart gene expression induced by aging and CR in male mice. .."

    "Thus, key CR-induced effects are rapidly responsive to diet, suggesting reduced caloric intake has rapid, positive effects on the heart. .."

  4. Title: "Effects of aging and anti-aging caloric restrictions on carbonyl and heat shock protein levels and expression."

    Biogerontology. 6(6):397-406, 2005 Dec.; Colotti, C. Cavallini, G. Vitale, R L. Donati, A. Maltinti, M. Del Ry, S. Bergamini, E. Giannessi, D.

    PMID: 16518701

    "Heat shock proteins (Hsps) are induced by stressful stimuli and have been shown to protect cells and organs from such stresses both in vitro and in vivo, and play a positive role in lifespan determination. .."

    "Two different caloric restriction regimens have been found to counteract in part the decrease in the levels of Hsp expression in the aged heart tissue as well as the tendency to an increase of the levels of carbonyl in cardiac proteins. Our data suggest that cardiac Hsp levels may be a determinant of longevity in rodents, and that generation of new regimens of caloric restriction may eventually show how to improve modulation of cardiac aging. .."

  5. Title: "Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity."

    Journals of Gerontology Series A-Biological Sciences & Medical Sciences. 60(12):1494-509, 2005 Dec.; Corton, J Christopher. Brown-Borg, Holly M.

    PMID: 16424281

    "CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC-1) alpha and beta, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. .."

    "CR reverses age-dependent decreases in PGC-1alpha, PPARalpha, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity. .."

  6. Title: "Synergistic action of olive oil supplementation and dietary restriction on serum lipids and cardiac antioxidant defences."

    Canadian Journal of Physiology & Pharmacology. 82(11):969-75, 2004 Nov.

    PMID: 15644936

    "The purpose of the present study was to analyse the association of olive oil and dietary restriction on lipid profile and myocardial antioxidant defences. Male Wistar rats (180-200 g, n = 6) were divided into 4 groups: control ad libitum diet (C), 50% restricted diet (DR), fed ad libitum and supplemented with olive oil (3 mL/(kg x day)) (OO), and 50% restricted diet and supplemented with olive oil (DROO). .."

    "There was a synergistic beneficial action of dietary restriction and olive oil on serum lipids and myocardial antioxidant defences."

  7. Title: "Vascular aging: molecular modulation of the prostanoid cascade by calorie restriction."

    Journals of Gerontology Series A-Biological Sciences & Medical Sciences. 59(9):B876-85, 2004 Sep.; Kim, Jung Won. Zou, Yani. Yoon, Sik. Lee, Ji Hyeon. Kim, Yoon Kyung. Yu, Byung Pal. Chung, Hae Young.

    PMID: 15472149

    "The relevance of prostanoids to inflammation, thrombosis, and cardiovascular diseases is well known. The present study attempts to explore age effects on prostanoids and their biosynthesis cascade.. .."

    "Moreover, calorie restriction (CR) was found to attenuate age-related prostanoid changes by suppressing inflammatory activities. In conclusion, the data from this study indicated that age-related increases in prostanoids and their biosynthesis might be closely associated with a weakened antioxidant capacity."

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