Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.
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.
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Sarah J
SJ
Mitchell
Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Julio
J
Madrigal-Matute
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA; Laboratory of Molecular Gerontology, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA; Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
Morten
M
Scheibye-Knudsen
Laboratory of Molecular Gerontology, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Evandro
E
Fang
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Miguel
M
Aon
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Agrifood Campus of International Excellence, ceiA3, 14071 Córdoba, Spain.
José A
JA
González-Reyes
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Sonia
S
Cortassa
Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Susmita
S
Kaushik
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Marta
M
Gonzalez-Freire
Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Bindi
B
Patel
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Devin
D
Wahl
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Ahmed
A
Ali
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Agrifood Campus of International Excellence, ceiA3, 14071 Córdoba, Spain.
Miguel
M
Calvo-Rubio
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Agrifood Campus of International Excellence, ceiA3, 14071 Córdoba, Spain.
María I
MI
Burón
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Vincent
V
Guiterrez
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Theresa M
TM
Ward
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Hector H
HH
Palacios
Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Huan
H
Cai
Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
David W
DW
Frederick
Department of Genetics and Complex Diseases, Harvard University, Boston, MA 02115, USA.
Christopher
C
Hine
Institute of Molecular Biosciences, NAWI Graz, University of Graz, and BioTechMed Graz, 8010 Graz, Austria.
Filomena
F
Broeskamp
Institute of Molecular Biosciences, NAWI Graz, University of Graz, and BioTechMed Graz, 8010 Graz, Austria.
Lukas
L
Habering
Department of Biostatistics, University of Alabama, Birmingham, AL 35294, USA; GRECC, Birmingham/Atlanta Veterans Administration Hospital, Birmingham, AL 35294, USA.
John
J
Dawson
Department of Biostatistics, University of Alabama, Birmingham, AL 35294, USA; GRECC, Birmingham/Atlanta Veterans Administration Hospital, Birmingham, AL 35294, USA.
T Mark
TM
Beasley
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Junxiang
J
Wan
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245-3207, USA.
Yuji
Y
Ikeno
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245-3207, USA.
Gene
G
Hubbard
Laboratory of Genetics, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Kevin G
KG
Becker
Laboratory of Genetics, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Yongqing
Y
Zhang
Laboratory of Molecular Gerontology, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Vilhelm A
VA
Bohr
Laboratory of Genetics, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Dan L
DL
Longo
Centro Andaluz de Biologia del Desarrollo, and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC, 41013 Sevilla, Spain.
Placido
P
Navas
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Luigi
L
Ferrucci
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
David A
DA
Sinclair
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Pinchas
P
Cohen
Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Josephine M
JM
Egan
Department of Genetics and Complex Diseases, Harvard University, Boston, MA 02115, USA.
James R
JR
Mitchell
Department of Physiology, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
Joseph A
JA
Baur
Department of Biostatistics, University of Alabama, Birmingham, AL 35294, USA; GRECC, Birmingham/Atlanta Veterans Administration Hospital, Birmingham, AL 35294, USA.
David B
DB
Allison
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
R Michael
RM
Anson
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Agrifood Campus of International Excellence, ceiA3, 14071 Córdoba, Spain.
José M
JM
Villalba
Institute of Molecular Biosciences, NAWI Graz, University of Graz, and BioTechMed Graz, 8010 Graz, Austria.
Frank
F
Madeo
Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Ana Maria
AM
Cuervo
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA; Graduate Center for Nutritional Sciences, University of Kentucky, C.T. Wethington Building, Room 591, 900 South Limestone, Lexington, KY 40536, USA.
Kevin J
KJ
Pearson
Pennington Biomedical Research Center, Baton Rouge, LA 70809, USA.
Donald K
DK
Ingram
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA.
Michel
M
Bernier
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA. Electronic address: decabora@mail.nih.gov.
Rafael
R
de Cabo
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D031204:Caloric Restriction; D016000:Cluster Analysis; D002149:Energy Intake / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006862:Hydrogen Sulfide / Q000378:metabolism; D007515:Islets of Langerhans / Q000033:anatomy & histology; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008136:Longevity / Q000235:genetics / Q000502:physiology; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012727:Sex Characteristics; D025801:Ubiquitin / Q000378:metabolism
D015415:Biomarkers; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; D006862:Hydrogen Sulfide