The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice

Samantha M Solon-Biet; Aisling C McMahon; J William O Ballard; Kari Ruohonen; Lindsay E Wu; Victoria C Cogger; Alessandra Warren; Xin Huang; Nicolas Pichaud; Richard G Melvin; Rahul Gokarn; Mamdouh Khalil; Nigel Turner; Gregory J Cooney; David A Sinclair; David Raubenheimer; David G Le Couteur; Stephen J Simpson

doi:10.1016/j.cmet.2014.02.009

The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice

Cell Metab. 2014 Mar 4;19(3):418-30. doi: 10.1016/j.cmet.2014.02.009.

Authors

Samantha M Solon-Biet¹, Aisling C McMahon², J William O Ballard³, Kari Ruohonen⁴, Lindsay E Wu⁵, Victoria C Cogger², Alessandra Warren², Xin Huang², Nicolas Pichaud³, Richard G Melvin⁶, Rahul Gokarn⁷, Mamdouh Khalil⁸, Nigel Turner⁹, Gregory J Cooney⁹, David A Sinclair¹⁰, David Raubenheimer¹¹, David G Le Couteur¹², Stephen J Simpson¹³

Affiliations

¹ 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.
² 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.
³ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia.
⁴ EWOS Innovation, Dirdal 4335, Norway.
⁵ Laboratory for Aging Research, School of Medical Sciences, University of New South Wales, Sydney NSW 2052, Australia.
⁶ Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
⁷ 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.
⁸ ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney NSW 2139, Australia.
⁹ Garvan Institute of Medical Research, University of New South Wales, Darlinghurst NSW 2010, Australia.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging*
Amino Acids, Branched-Chain / pharmacology
Animals
Blood Pressure / drug effects
Body Composition / drug effects
Cardiovascular Physiological Phenomena / drug effects
Diet*
Energy Intake / drug effects
Glucose / pharmacology
Glucose Intolerance
Insulin / blood
Kaplan-Meier Estimate
Leptin / blood
Liver / metabolism
Longevity* / drug effects
Male
Mice
Mice, Inbred C57BL
Phosphorylation
TOR Serine-Threonine Kinases / metabolism

Substances

Amino Acids, Branched-Chain
Insulin
Leptin
TOR Serine-Threonine Kinases
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding