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 Hine; Filomena 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

doi:10.1016/j.cmet.2016.05.027

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

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Abstract

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 language	English
Pages (from-to)	1093-1112
Number of pages	20
Journal	Cell Metabolism
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2016.05.027
State	Published - 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

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10.1016/j.cmet.2016.05.027

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Mitchell, S. J., Madrigal-Matute, J., Scheibye-Knudsen, M., Fang, E., Aon, M., González-Reyes, J. A., Cortassa, S., Kaushik, S., Gonzalez-Freire, M., Patel, B., Wahl, D., Ali, A., Calvo-Rubio, M., Burón, M. I., Guiterrez, V., Ward, T. M., Palacios, H. H., Cai, H., Frederick, D. W., ... De Cabo, R. (2016). Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metabolism, 23(6), 1093-1112. https://doi.org/10.1016/j.cmet.2016.05.027

@article{f62edf6d1a104c2a873b0fa7deca87ec,

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

abstract = "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.",

author = "Mitchell, {Sarah J.} and Julio Madrigal-Matute and Morten Scheibye-Knudsen and Evandro Fang and Miguel Aon and Gonz{\'a}lez-Reyes, {Jos{\'e} A.} and Sonia Cortassa and Susmita Kaushik and Marta Gonzalez-Freire and Bindi Patel and Devin Wahl and Ahmed Ali and Miguel Calvo-Rubio and Bur{\'o}n, {Mar{\'i}a I.} and Vincent Guiterrez and Ward, {Theresa M.} and Palacios, {Hector H.} and Huan Cai and Frederick, {David W.} and Christopher Hine and Filomena Broeskamp and Lukas Habering and John Dawson and Beasley, {T. Mark} and Junxiang Wan and Yuji Ikeno and Gene Hubbard and Becker, {Kevin G.} and Yongqing Zhang and Bohr, {Vilhelm A.} and Longo, {Dan L.} and Placido Navas and Luigi Ferrucci and Sinclair, {David A.} and Pinchas Cohen and Egan, {Josephine M.} and Mitchell, {James R.} and Baur, {Joseph A.} and Allison, {David B.} and Anson, {R. Michael} and Villalba, {Jos{\'e} M.} and Frank Madeo and Cuervo, {Ana Maria} and Pearson, {Kevin J.} and Ingram, {Donald K.} and Michel Bernier and {De Cabo}, Rafael",

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 Econom{\'i}a y Competitividad (grants BFU2011-23578 and BFU2015-64630-R). The authors thank the personnel from the Servicio Centralizado de Apoyo a la Investigaci{\'o}n (SCAI; University of C{\'o}rdoba) 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: {\textcopyright} 2016 Published by Elsevier Inc.",

year = "2016",

month = jun,

day = "14",

doi = "10.1016/j.cmet.2016.05.027",

language = "English",

volume = "23",

pages = "1093--1112",

number = "6",

}

Mitchell, SJ, Madrigal-Matute, J, Scheibye-Knudsen, M, Fang, E, Aon, M, González-Reyes, JA, Cortassa, S, Kaushik, S, Gonzalez-Freire, M, Patel, B, Wahl, D, Ali, A, Calvo-Rubio, M, Burón, MI, Guiterrez, V, Ward, TM, Palacios, HH, Cai, H, Frederick, DW, Hine, C, Broeskamp, F, Habering, L, Dawson, J, Beasley, TM, Wan, J, Ikeno, Y, Hubbard, G, Becker, KG, Zhang, Y, Bohr, VA, Longo, DL, Navas, P, Ferrucci, L, Sinclair, DA, Cohen, P, Egan, JM, Mitchell, JR, Baur, JA, Allison, DB, Anson, RM, Villalba, JM, Madeo, F, Cuervo, AM, Pearson, KJ, Ingram, DK, Bernier, M & De Cabo, R 2016, 'Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice', Cell Metabolism, vol. 23, no. 6, pp. 1093-1112. https://doi.org/10.1016/j.cmet.2016.05.027

TY - JOUR

T1 - Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice

AU - Mitchell, Sarah J.

AU - Madrigal-Matute, Julio

AU - Scheibye-Knudsen, Morten

AU - Fang, Evandro

AU - Aon, Miguel

AU - González-Reyes, José A.

AU - Cortassa, Sonia

AU - Kaushik, Susmita

AU - Gonzalez-Freire, Marta

AU - Patel, Bindi

AU - Wahl, Devin

AU - Ali, Ahmed

AU - Calvo-Rubio, Miguel

AU - Burón, María I.

AU - Guiterrez, Vincent

AU - Ward, Theresa M.

AU - Palacios, Hector H.

AU - Cai, Huan

AU - Frederick, David W.

AU - Hine, Christopher

AU - Broeskamp, Filomena

AU - Habering, Lukas

AU - Dawson, John

AU - Beasley, T. Mark

AU - Wan, Junxiang

AU - Ikeno, Yuji

AU - Hubbard, Gene

AU - Becker, Kevin G.

AU - Zhang, Yongqing

AU - Bohr, Vilhelm A.

AU - Longo, Dan L.

AU - Navas, Placido

AU - Ferrucci, Luigi

AU - Sinclair, David A.

AU - Cohen, Pinchas

AU - Egan, Josephine M.

AU - Mitchell, James R.

AU - Baur, Joseph A.

AU - Allison, David B.

AU - Anson, R. Michael

AU - Villalba, José M.

AU - Madeo, Frank

AU - Cuervo, Ana Maria

AU - Pearson, Kevin J.

AU - Ingram, Donald K.

AU - Bernier, Michel

AU - De Cabo, Rafael

N1 - 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.

PY - 2016/6/14

Y1 - 2016/6/14

N2 - 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.

AB - 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.

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DO - 10.1016/j.cmet.2016.05.027

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AN - SCOPUS:84975455180

VL - 23

SP - 1093

EP - 1112

IS - 6

ER -

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

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