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Cell Metab. 2014 Mar 4;19(3):418-30. 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.

Author information

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.

PMID:
24606899
PMCID:
PMC5087279
DOI:
10.1016/j.cmet.2014.02.009
[Indexed for MEDLINE]
Free PMC Article
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