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

Research output: Contribution to journalArticlepeer-review

683 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)418-430
Number of pages13
JournalCell Metabolism
Issue number3
StatePublished - Mar 4 2014
Externally publishedYes

Bibliographical note

Funding Information:
Funding was obtained from the Australian National Health and Medical Research Council (NHMRC project grant 571328), the Ageing and Alzheimers Research Fund of Concord RG Hospital, and the Sydney Medical School Foundation. Additionally, S.J.S. was supported by an Australian Research Council Laureate Fellowship; D.R. was part funded by Gravida, the National Research Centre for Growth and Development, New Zealand; and L.E.W. was supported by an early career fellowship from the Cancer Institute NSW (CINSW), Australia. We acknowledge the assistance of the Departments of Biochemistry and Anatomical Pathology, Concord RG Hospital. We thank Leon McQuade for amino acid analyses and Andrew Holmes, Arthur Conigrave, and Patrick Bertolino for their contribution to other aspects of the study protocol. We are extremely grateful to John Speakman and Linda Partridge for their detailed review of earlier versions of the manuscript. There are no conflicts of interest to declare.


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