title: The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice.
abstract: The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; Centre for Education and Research on Aging, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; School of Biological Sciences, The University of Sydney, NSW 2006, Australia.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Solon-Biet
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; Centre for Education and Research on Aging, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia.
authors.forename: Aisling C
authors.initials: AC
authors.lastname: McMahon
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: J William O
authors.initials: JW
authors.lastname: Ballard
authors.affiliation: EWOS Innovation, Dirdal 4335, Norway.
authors.forename: Kari
authors.initials: K
authors.lastname: Ruohonen
authors.affiliation: Laboratory for Aging Research, School of Medical Sciences, University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Wu
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; Centre for Education and Research on Aging, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; Centre for Education and Research on Aging, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Warren
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; Centre for Education and Research on Aging, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pichaud
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Melvin
authors.affiliation: Centre for Education and Research on Aging, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia.
authors.forename: Rahul
authors.initials: R
authors.lastname: Gokarn
authors.affiliation: ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia.
authors.forename: Mamdouh
authors.initials: M
authors.lastname: Khalil
authors.affiliation: Garvan Institute of Medical Research, University of New South Wales, Darlinghurst NSW 2010, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.affiliation: Garvan Institute of Medical Research, University of New South Wales, Darlinghurst NSW 2010, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.affiliation: Laboratory for Aging Research, School of Medical Sciences, University of New South Wales, Sydney NSW 2052, Australia; The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; School of Biological Sciences, The University of Sydney, NSW 2006, Australia; Institute of Natural Sciences, Massey University, Auckland 0632, New Zealand; Faculty of Veterinary Science, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Raubenheimer
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; Centre for Education and Research on Aging, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia; ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia. Electronic address: david.lecouteur@sydney.edu.au.
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney NSW 2006, Australia; School of Biological Sciences, The University of Sydney, NSW 2006, Australia. Electronic address: stephen.simpson@sydney.edu.au.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Simpson
mesh_terms: D000375:Aging; D000597:Amino Acids, Branched-Chain / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D004032:Diet; D002149:Energy Intake / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance; D007328:Insulin / Q000097:blood; D053208:Kaplan-Meier Estimate; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D007328:Insulin; D020738:Leptin; D058570:TOR Serine-Threonine Kinases; D005947:Glucose