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Impaired Insulin/IGF1 Signaling Extends Life Span by Promoting Mitochondrial L-Proline Catabolism to Induce a Transient ROS Signal
Open accessAbstract
Impaired insulin and IGF-1 signaling (iIIS) in C. elegans daf-2 mutants extends life span more than 2-fold. Constitutively, iIIS increases mitochondrial activity and reduces reactive oxygen species (ROS) levels. By contrast, acute impairment of daf-2 in adult C. elegans reduces glucose uptake and transiently increases ROS. Consistent with the concept of mitohormesis, this ROS signal causes an adaptive response by inducing ROS defense enzymes (SOD, catalase), culminating in ultimately reduced ROS levels despite increased mitochondrial activity. Inhibition of this ROS signal by antioxidants reduces iIIS-mediated longevity by up to 60%. Induction of the ROS signal requires AAK-2 (AMPK), while PMK-1 (p38) and SKN-1 (NRF-2) are needed for the retrograde response. IIIS upregulates mitochondrial L-proline catabolism, and impairment of the latter impairs the life span-extending capacity of iIIS while L-proline supplementation extends C. elegans life span. Taken together, iIIS promotes L-proline metabolism to generate a ROS signal for the adaptive induction of endogenous stress defense to extend life span.
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“Impaired insulin/IGF-1 signaling (IIS) extends lifespan by 2-fold in C. elegans daf-2 mutants, by promoting L-proline catabolism and endogenous stress defense response via a transient ROS signal”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Zarse et al. 2012
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“In addition, increased ROS levels induced expression of antioxidant enzymes, followed by a decrease in ROS levels20.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [20]
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Metadata
- Authors
- Zarse, K., Schmeisser, S., Groth, M., Priebe, S., Beuster, G., Kuhlow, D., Guthke, R., Platzer, M., Kahn, C. R., & Ristow, M.
- Affiliations
- Joslin Diabetes Center (US)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Friedrich Schiller University Jena (DE)
- German Institute of Human Nutrition (DE)
- Corresponding author
- Ristow, Michael
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 15
- Issue
- 4
- Pages
- 451-465
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4844853
- OpenAlex
- W2027977649
- Cited by
- 430
- References
- 73
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 28 · 2023: 17 · 2022: 28 · 2021: 36 · 2020: 26 · 2019: 31 · 2018: 27 · 2017: 31 · 2016: 40 · 2015: 41 · 2014: 50 · 2013: 28 · 2012: 12
- FWCI
- 13.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 472 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Center for Research Resources
- University of Minnesota
- Deutsche Forschungsgemeinschaft (RI 1976/3-1)
- Bundesministerium für Bildung und Forschung (0315581, DK31036, DK33201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- insulin/IGF-1 signaling, lifespan extension, reactive oxygen species, mitohormesis, daf-2, AMPK, p38 MAPK, SKN-1, antioxidant defense, antioxidants, glucose uptake, Caenorhabditis elegans, longevity
- MeSH terms
- Animals, Antioxidants, Glucose, Insulin, Insulin-Like Growth Factor I, Longevity, Mitochondria, Proline, Stress, Physiological, Signal Transduction, Caenorhabditis elegans, Reactive Oxygen Species, Gene Expression Profiling, Models, Animal, Caenorhabditis elegans Proteins, Mice, Transcriptome
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