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The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice
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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.
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“Although density is only a rough proxy for fitness, our results are consistent with laboratory experiments, which demonstrated that generalists pay the cost of relying on unbalanced diets, suffering either high mortality rates and disease risk52,53 or low reproductive outputs12.”
From Nutritional ecology of a prototypical generalist predator, the red fox (Vulpes vulpes) (2024) · cites this paper as [53]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Several studies have shown that restriction of protein or specific restriction of either methionine or one or more of the branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) reduces mTORC1 activity and extends lifespan in preclinical species 24,150–152.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [24]
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“For example, Solon-Biet and colleagues [30] explored the contribution of 25 different diets to the overall health and longevity of over 800 mice.”
From Multi-omics approaches to disease (2017) · cites this paper as [30]
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“The ratio of protein to carbohydrate in the diet was shown to have profound effects on health parameters later in life, offering mechanistic insight into how this is achieved.”
From Multi-omics approaches to disease (2017) · cites this paper as [30]
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“The observation that protein is prioritized and regulated to a specific target suggests that small changes in the proportion of dietary protein can induce large changes in total food and energy intake, a concept termed protein leveraging”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [106]
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Metadata
- Authors
- Solon-Biet, S. M., McMahon, A. C., Ballard, J. W. O., Ruohonen, K., Wu, L. E., Cogger, V. C., Warren, A., Huang, X., Pichaud, N., Melvin, R. G., Gokarn, R., Khalil, M., Turner, N., Cooney, G. J., Sinclair, D. A., Raubenheimer, D., Le Couteur, D. G., & Simpson, S. J.
- Affiliations
- The University of Sydney (AU)
- UNSW Sydney (AU)
- Ewos Innovation (Norway) (NO)
- University of Helsinki (FI)
- Garvan Institute of Medical Research (AU)
- Harvard University (US)
- Corresponding author
- Simpson, Stephen J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 19
- Issue
- 3
- Pages
- 418-430
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5087279
- OpenAlex
- W2042438674
- Cited by
- 904
- References
- 39
- Citations by year
- 2026: 37 · 2025: 47 · 2024: 71 · 2023: 75 · 2022: 82 · 2021: 86 · 2020: 101 · 2019: 86 · 2018: 76 · 2017: 74 · 2016: 68 · 2015: 68 · 2014: 31
- FWCI
- 27.47
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-03-03)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Research Centre
- Cancer Institute NSW
- Australian Research Council
- National Health and Medical Research Council
- National Medical Research Council
- National Institute on Aging (DP1AG058605, R37AG028730, R01AG028730, R01AG019719)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100263)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- macronutrient ratio, dietary protein, dietary carbohydrates, dietary fat, ad libitum feeding, longevity, cardiometabolic health, aging, compensatory feeding, mTOR signaling, mitochondrial function, branched-chain amino acids, glucose, food intake regulation, caloric restriction, dietary dilution, geometric framework, mice
- MeSH terms
- Aging, Amino Acids, Branched-Chain, Animals, Blood Pressure, Body Composition, Energy Intake, Cardiovascular Physiological Phenomena, Diet, Glucose, Insulin, Liver, Longevity, Male, Mice, Inbred C57BL, Phosphorylation, Glucose Intolerance, Leptin, Mice, Kaplan-Meier Estimate, TOR Serine-Threonine Kinases
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