Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice

  • Julio Madrigal-Matute (Contributor)
  • Morten Scheibye-Knudsen (Contributor)
  • Evandro Fang (Contributor)
  • Miguel Aon (Contributor)
  • Sonia Cortassa (Contributor)
  • Susmita Kaushik (Contributor)
  • Marta Gonzalez-Freire (Contributor)
  • Bindi Patel (Contributor)
  • Devin Wahl (Contributor)
  • Ahmed Ali (Contributor)
  • Miguel Calvo-Rubio (Contributor)
  • Vincent Guiterrez (Contributor)
  • Huan Cai (Contributor)
  • Christopher Hine (Contributor)
  • Filomena Broeskamp (Contributor)
  • Lukas Habering (Contributor)
  • John Dawson (Contributor)
  • Junxiang Wan (Contributor)
  • Yuji Ikeno (Contributor)
  • Gene Hubbard (Contributor)
  • Yongqing Zhang (Contributor)
  • Placido Navas (Contributor)
  • L. Ferrucci (Contributor)
  • Pinchas Cohen (Contributor)
  • Frank Madeo (Contributor)
  • Michel Bernier (Contributor)
  • Rafael De Cabo (Contributor)



Calorie restriction (CR) is the most robust non-genetic intervention to universally delay the onset of age-related diseases and extend mean and maximum lifespan. However, species, strain, sex, diet, age of onset, and level of CR are emerging as important variables to consider for a successful CR response. Here, we investigated the role of strain, sex and level of CR on outcomes of health and survival in mice. Response to CR varied from lifespan extension to no effect on survival, while consistently delaying the onset and impact of diseases independently of strain, sex and level of dietary restriction. CR led to transcriptional and metabolomics changes in the liver indicating anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. Additionally, CR prevented the age-associated decline in the proteostasis network. Further, CR increased mitochondrial number and preserved their ultrastructure and function with age. Abrogation of mitochondrial function by deletion of fumarate hydratase or malate dehydrogenase 2 negated the life-prolonging effects of CR in yeast and worms. In F1 hybrid strains of mice, the lifespan response to CR tracked with the dam, indicating that the mitochondrial haplotype is an important regulator of CR. Our data illustrate the complexity of the CR responses within a single animal species in the context of aging, with a clear separation of outcomes related to health and survival, highlighting the complexities of translation of CR into human interventions. The study examines the effects of sex (male/female), mouse strain (DBA2/J versus C57BL/J), and diet (Ad libitum, 20% caloric restriction (20%CR), or 40%CR) using six biological replicate samples per group.
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