Ahmed Ali, Miguel Calvo-Rubio, R. Michael Anson, T. Mark Beasley, Vincent Guiterrez, John Dawson, Vilhelm A. Bohr, Pinchas Cohen, Devin Wahl, Dan L. Longo, Ana Maria Cuervo, David W. Frederick, Rafael de Cabo, M. I. Burón, Yongqing Zhang, Joseph A. Baur, Donald K. Ingram, Kevin J. Pearson, James R. Mitchell, José A. González-Reyes, Evandro Fei Fang, José M. Villalba, Christopher Hine, Julio Madrigal-Matute, Kevin G. Becker, Morten Scheibye-Knudsen, Gene B. Hubbard, Yuji Ikeno, Marta Gonzalez-Freire, Michel Bernier, Sarah J. Mitchell, Frank Madeo, Lukas Habering, David B. Allison, Susmita Kaushik, Junxiang Wan, Theresa M. Ward, Josephine M. Egan, Bindi Patel, Miguel A. Aon, Sonia Cortassa, Huan Cai, Plácido Navas, Luigi Ferrucci, David A. Sinclair, Hector H. Palacios, Filomena Broeskamp, Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), National Institutes of Health (US), American Diabetes Association, Research Foundation - Flanders, Federal Ministry of Education and Research (Germany), and Universidad de Córdoba (España)
Author manuscript; available in PMC 2017 June 14.-- et al., 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., 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.), 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, 1R01ES 020812). F.M. is grateful to the FWF for grants LIPOTOX, I1000, P 27893, P 29203 and P24381-B20 and the BMWFW for grants “Unconventional research” and «Flysleep (80.109/0001 -WF/V/3b/2015). JMV 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.