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

Sarah J. Mitchell, Julio Madrigal-Matute, Morten Scheibye-Knudsen, Evandro Fang, Miguel Aon, José A. González-Reyes, Sonia Cortassa, Susmita Kaushik, Marta Gonzalez-Freire, Bindi Patel, Devin Wahl, Ahmed Ali, Miguel Calvo-Rubio, María I. Burón, Vincent Guiterrez, Theresa M. Ward, Hector H. Palacios, Huan Cai, David W. Frederick, Christopher HineFilomena Broeskamp, Lukas Habering, John Dawson, T. Mark Beasley, Junxiang Wan, Yuji Ikeno, Gene Hubbard, Kevin G. Becker, Yongqing Zhang, Vilhelm A. Bohr, Dan L. Longo, Placido Navas, Luigi Ferrucci, David A. Sinclair, Pinchas Cohen, Josephine M. Egan, James R. Mitchell, Joseph A. Baur, David B. Allison, R. Michael Anson, José M. Villalba, Frank Madeo, Ana Maria Cuervo, Kevin J. Pearson, Donald K. Ingram, Michel Bernier, Rafael De Cabo

Research output: Contribution to journalArticlepeer-review

262 Scopus citations


Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.

Original languageEnglish
Pages (from-to)1093-1112
Number of pages20
JournalCell Metabolism
Issue number6
StatePublished - Jun 14 2016

Bibliographical note

Funding Information:
This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, and by NIH grants R01 AG043483 and R01 DK098656 (J.A.B.), NIH grant AG031782 (A.M.C.), and the Proteostasis of Aging Core AG038072 (A.M.C.). J.M.M. was supported by a postdoctoral fellowship from the American Diabetes Association, grant 1-15-MI-03. P.C. was supported by NIH grants (1P01AG034906, 1R01GM090311, and 1R01ES 020812). F.M. is grateful to the FWF for grants LIPOTOX, I1000, P27893, P29203, and P24381-B20 and the BMWFW for grants “Unconventional Research” and “Flysleep” (80.109/0001-WF/V/3b/2015). J.M.V. was supported by the Spanish Ministerio de Economía y Competitividad (grants BFU2011-23578 and BFU2015-64630-R). The authors thank the personnel from the Servicio Centralizado de Apoyo a la Investigación (SCAI; University of Córdoba) for technical support. Special thanks to the members of the Translational Gerontology Branch and the Comparative Medicine Section of the National Institute on Aging. In particular we acknowledge Paul Bastian, Elin Lehrmann, Frances Fan, Robin Minor, Dawn Nines, and Dawn Boyer.

Publisher Copyright:
© 2016 Published by Elsevier Inc.

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice'. Together they form a unique fingerprint.

Cite this