Calorie restriction combined with resveratrol induces autophagy and protects 26-month-old rat hearts from doxorubicin-induced toxicity

Free Radic Biol Med. 2014 Sep;74:252-62. doi: 10.1016/j.freeradbiomed.2014.06.011. Epub 2014 Jun 26.


The multiple beneficial effects of calorie restriction (CR) on several organs, including the heart, are widely known. Recently, the plant polyphenol resveratrol has been shown to possess several beneficial effects similar to those of CR. Among the host of effects on cardiac muscle, a cellular self-eating process called autophagy has been shown to be induced by both CR and resveratrol. Autophagy is vital in removing dysfunctional organelles and damaged proteins from the cell, thereby maintaining cellular quality control. In this study, we explored whether short-term moderate CR (20%), either alone or in combination with resveratrol, can induce autophagy in the hearts of 26-month-old Fischer 344 × Brown Norway rats. Autophagy stimulation was investigated by measuring the protein expression levels of the autophagy proteins beclin-1, Atg5, and p62 and the LC3-II/LC3-I ratio. We found that 20% CR or resveratrol alone for 6 weeks could not induce autophagy, but 20% CR in combination with 50 mg/kg/day resveratrol resulted in an induction of autophagy in the hearts of 26-month-old rats. Although oxidative stress has been proposed to be an inducer of autophagy, treatment with the chemotherapeutic drug doxorubicin was unable to stimulate autophagy. The enhanced autophagy due to CR + resveratrol was associated with protection from doxorubicin-induced damage, as measured by cardiac apoptotic levels and serum creatine kinase and lactate dehydrogenase activity. We propose that a combinatorial approach of low-dose CR and resveratrol has the potential to be used therapeutically to induce autophagy and provides protection against doxorubicin-mediated toxicity.

Keywords: Autophagy; Calorie restriction; Doxorubicin; Free radicals; Heart; Oxidative stress; Resveratrol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects
  • Autophagy-Related Protein 5
  • Beclin-1
  • Caloric Restriction*
  • Creatine Kinase / blood
  • Doxorubicin / administration & dosage
  • Doxorubicin / toxicity*
  • Heart / drug effects*
  • Heart / physiology
  • Heat-Shock Proteins / metabolism
  • L-Lactate Dehydrogenase / blood
  • Male
  • Proteins / metabolism
  • Rats
  • Rats, Inbred Strains
  • Resveratrol
  • Sequestosome-1 Protein
  • Stilbenes / administration & dosage*


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Atg5 protein, rat
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, rat
  • Heat-Shock Proteins
  • Proteins
  • Sequestosome-1 Protein
  • Sqstm1 protein, rat
  • Stilbenes
  • Doxorubicin
  • L-Lactate Dehydrogenase
  • Creatine Kinase
  • Resveratrol