Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans

doi:10.1016/j.cmet.2019.07.016

Randomized Controlled Trial

. 2019 Sep 3;30(3):462-476.e6.

doi: 10.1016/j.cmet.2019.07.016. Epub 2019 Aug 27.

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans

Slaven Stekovic¹, Sebastian J Hofer², Norbert Tripolt³, Miguel A Aon⁴, Philipp Royer¹, Lukas Pein⁵, Julia T Stadler⁶, Tobias Pendl¹, Barbara Prietl⁷, Jasmin Url⁷, Sabrina Schroeder², Jelena Tadic¹, Tobias Eisenberg⁸, Christoph Magnes⁹, Michael Stumpe¹⁰, Elmar Zuegner⁹, Natalie Bordag⁹, Regina Riedl¹¹, Albrecht Schmidt¹², Ewald Kolesnik¹², Nicolas Verheyen¹², Anna Springer¹³, Tobias Madl¹⁴, Frank Sinner¹⁵, Rafael de Cabo¹⁶, Guido Kroemer¹⁷, Barbara Obermayer-Pietsch⁷, Jörn Dengjel¹⁸, Harald Sourij⁷, Thomas R Pieber¹⁹, Frank Madeo²⁰

Affiliations

¹ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria.
² Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; BioTechMed Graz, Graz 8010, Austria.
³ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria.
⁴ Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
⁵ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria.
⁶ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
⁷ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria.
⁸ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; BioTechMed Graz, Graz 8010, Austria; NAWI Graz Central Lab Gracia, NAWI Graz, Graz, Austria.
⁹ HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.
¹⁰ Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
¹¹ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria.
¹² Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Austria.
¹³ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/, VI 8010 Graz, Austria.
¹⁴ BioTechMed Graz, Graz 8010, Austria; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/, VI 8010 Graz, Austria.
¹⁵ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.
¹⁶ Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
¹⁷ Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM U1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden; Center of Systems Medicine, Chinese Academy of Science Sciences, Suzhou, China.
¹⁸ Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland; Department of Dermatology, Medical Center, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany.
¹⁹ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria; HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.
²⁰ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; BioTechMed Graz, Graz 8010, Austria. Electronic address: frank.madeo@uni-graz.at.

PMID: 31471173
DOI: 10.1016/j.cmet.2019.07.016

Free article

Randomized Controlled Trial

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans

Slaven Stekovic et al. Cell Metab. 2019.

Free article

. 2019 Sep 3;30(3):462-476.e6.

doi: 10.1016/j.cmet.2019.07.016. Epub 2019 Aug 27.

Authors

Affiliations

¹ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria.
² Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; BioTechMed Graz, Graz 8010, Austria.
³ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria.
⁴ Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
⁵ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria.
⁶ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
⁷ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria.
⁸ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; BioTechMed Graz, Graz 8010, Austria; NAWI Graz Central Lab Gracia, NAWI Graz, Graz, Austria.
⁹ HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.
¹⁰ Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland.
¹¹ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria.
¹² Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Austria.
¹³ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/, VI 8010 Graz, Austria.
¹⁴ BioTechMed Graz, Graz 8010, Austria; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/, VI 8010 Graz, Austria.
¹⁵ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.
¹⁶ Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
¹⁷ Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Cell Biology and Metabolomics platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM U1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden; Center of Systems Medicine, Chinese Academy of Science Sciences, Suzhou, China.
¹⁸ Department of Biology, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland; Department of Dermatology, Medical Center, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany.
¹⁹ Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria; HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.
²⁰ Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, Graz 8010, Austria; BioTechMed Graz, Graz 8010, Austria. Electronic address: frank.madeo@uni-graz.at.

PMID: 31471173
DOI: 10.1016/j.cmet.2019.07.016

Erratum in

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.
Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, Stadler JT, Pendl T, Prietl B, Url J, Schroeder S, Tadic J, Eisenberg T, Magnes C, Stumpe M, Zuegner E, Bordag N, Riedl R, Schmidt A, Kolesnik E, Verheyen N, Springer A, Madl T, Sinner F, de Cabo R, Kroemer G, Obermayer-Pietsch B, Dengjel J, Sourij H, Pieber TR, Madeo F. Stekovic S, et al. Cell Metab. 2020 Apr 7;31(4):878-881. doi: 10.1016/j.cmet.2020.02.011. Cell Metab. 2020. PMID: 32268118 No abstract available.

Abstract

Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.

Keywords: RCT; aging; body shape; caloric restriction; cardiovascular disease risk; clinical trial; fasting; fat distribution; intermittent fasting; triiodothyronine.

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Comment in

Alternate-Day Fasting Gets a Safe Bill of Health.
Heilbronn LK, Panda S. Heilbronn LK, et al. Cell Metab. 2019 Sep 3;30(3):411-413. doi: 10.1016/j.cmet.2019.08.006. Cell Metab. 2019. PMID: 31484053
Safety and efficacy of alternate day fasting.
Varady KA, Gabel K. Varady KA, et al. Nat Rev Endocrinol. 2019 Dec;15(12):686-687. doi: 10.1038/s41574-019-0270-y. Nat Rev Endocrinol. 2019. PMID: 31558778 No abstract available.
Cardiovascular benefits of intermittent fasting.
Abdellatif M, Sedej S. Abdellatif M, et al. Cardiovasc Res. 2020 Mar 1;116(3):e36-e38. doi: 10.1093/cvr/cvaa022. Cardiovasc Res. 2020. PMID: 32077476 No abstract available.

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Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans

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Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans

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