Calorie restriction in humans inhibits the PI 3 K/AKT pathway and induces a younger transcription profile
Open accessAbstract
Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.
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Exercise and CR reveal distinct molecular signatures.
“Because exercise and CR do reveal distinct molecular signatures (Mercken et al., 2013), it is likely that the integration of regular exercise with CR results in synergistic health-promoting effects.”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Mercken et al., 2013
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“…were suppressed, and Foxo3a was up-regulated transiently in the cerebral cortex in response to DNP. Down-regulation of insulin receptor signaling may contribute to the mechanism whereby caloric restriction extends longevity in animal models of aging (Bl€uher et al. 2003; Mercken et al. 2013).”
BackgroundGarcía‐Matas, S., Paul, R. K., Molina‐Martínez, P., Palacios, H., Gutierrez, V. M., Corpas, R., Pallas, M., Cristòfol, R., de Cabo, R., & Sanfeliu, C. (2015) · Aging Cell · doi:10.1111/acel.12259 · Cited by 22 · see citing works
- Authors
- Mercken, E. M., Crosby, S. D., Lamming, D. W., JeBailey, L., Krzysik‐Walker, S., Villareal, D. T., Capri, M., Franceschi, C., Zhang, Y., Becker, K., Sabatini, D. M., de Cabo, R., & Fontana, L.
- Affiliations
- National Institutes of Health (US)
- Washington University in St. Louis (US)
- Broad Institute (US)
- GeneGo Inc. St. Joseph MI 49085 USA
- Laboratory of Clinical Investigation National Institute on Aging National Institutes of Health Baltimore MD 21224 USA
- University of Bologna (IT)
- Laboratory of Experimental Gerontology National Institute on Aging National Institutes of Health Baltimore MD 21224 USA
- University of Salerno (IT)
- Corresponding author
- Fontana, Luigi
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2013-06-05
- Volume
- 12
- Issue
- 4
- Pages
- 645-651
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3714316
- OpenAlex
- W2125881727
- Cited by
- 261
- References
- 27
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 14 · 2023: 8 · 2022: 17 · 2021: 30 · 2020: 18 · 2019: 20 · 2018: 23 · 2017: 21 · 2016: 21 · 2015: 33 · 2014: 20 · 2013: 6
- FWCI
- 9.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- AFAR (UL1 RR024992, P30DK056341, P30 CA91842, UL1RR024992)
- National Institutes of Health
- NIH Roadmap for Medical Research (UL1 RR024992, P30DK056341, P30 CA91842, UL1RR024992)
- National Center for Research Resources (UL1 RR024992)
- National Institute of Diabetes And Digestive And Kidney Diseases (P30DK056341)
- National Institute on Aging-Intramural Research Program
- Longer Life Foundation
- Bakewell Foundation
- Calorie Restriction Society and the Scott and Annie Appleby Charitable Trust
- NCI Cancer Center (P30 CA91842, UL1RR024992)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- caloric restriction, PI3K/Akt signaling, skeletal muscle, gene expression profiling, longevity, mitochondrial biogenesis, inflammation, age-related diseases, therapeutic target
- MeSH terms
- Forkhead Box Protein O3, Adipose Tissue, Adult, Aging, Animals, Female, Humans, Insulin-Like Growth Factor I, Male, Transcription, Genetic, Signal Transduction, Phosphatidylinositol 3-Kinases, Principal Component Analysis, Caloric Restriction, Rats, Forkhead Transcription Factors, Quadriceps Muscle, Kaplan-Meier Estimate, Transcriptome, Mitochondrial Turnover
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