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Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
Open accessAbstract
Mimicking Caloric Restriction: The extended life span and resistance to age-related diseases in animals exposed to caloric restriction has focused attention on the biochemical mechanisms that produce these effects. Selman et al. (p. 140 ; see the Perspective by Kaeberlein and Kapahi ) explored the role of the mammalian ribosomal protein S6 kinase 1 (S6K1), which regulates protein translation and cellular energy metabolism. Female knockout mice lacking expression of S6K1 showed characteristics of animals exposed to caloric restriction, including improved health and increased longevity. The beneficial effects included reduced fat mass in spite of increased food intake. Thus, inhibition of signaling pathways activated by S6K1 might prove beneficial in protecting against age-related disease.
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“mice deficient in S6K1 (a main mTORC1 substrate) are also long-lived”
From The Hallmarks of Aging (2013) · cites this paper as Selman et al., 2009
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“Even partial inhibition of mTORC1 in genetic mouse models (e.g., S6K1−/−, mTOR+/− mLST8+/−, mTORΔ/Δ, TSC1tg) can extend lifespan and healthspan in mice 13,17–19.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [13]
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“Studies in mice have likewise shown that genetic depletion of mTORC1 subunits, deletion of S6K1 or downstream substrates, or expression of dominant negative 4E-BP1 in specific tissues extends the lifespan and healthspan of mice 13–16.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [13]
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“However, similar evidence does not exist yet for the effects of rapamycin on mammalian aging, and other mechanisms such as inhibition of the ribosomal S6 protein kinase 1 (S6K1) implicated in protein synthesis (Selman et al., 2009), could contribute to explain the pro-longevity effects of rapamycin (see section on Deregulated Nutrient-sensing).”
From The Hallmarks of Aging (2013) · cites this paper as Selman et al., 2009
In the citing paper
“Depletion of ribosome subunits or interference with the target of rapamycin/ribosomal protein S6 kinase pathway, which functions to activate protein translation, were found to alter the lifespan of a variety of species including mammals (54–56).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [55]
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“and mice deficient in S6K1 (a main mTORC1 substrate) are also long lived.221”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [221]
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“Unlike rapamycin, which significantly increases lifespan in both male and female mice (Miller et al., 2014; Bitto et al., 2016), deletion of S6K1 extends lifespan specifically in female C57BL/6 mice, and the magnitude of this effect is less robust than that of rapamycin (Selman et al., 2009).”
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“…pituitary gland impairment (Bartke and Brown-Borg 2004), inhibition of the mechanistic target of rapamycin (mTOR) pathway (Harrison et al. 2009; Selman et al. 2009), activation of 5’ adenosine monophosphate-activated protein kinase (AMPK) (Martin-Montalvo et al. 2013), increased autophagy (Pyo…”
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“Indeed, protein synthesis is considered one of the evolutionary best conserved and most promising targets to extend the healthy lifespan of a wide range of organisms, including vertebrates (Harrison et al., 2009; Selman et al., 2009).”
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“In S6K knockout mice they have found activation of pathways regulated by PGC-1α and AMPK in some tissues, like the liver, adipose tissue, or muscles (Selman et al., 2009).”
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Genes and Pathways That Influence Longevity in Caenorhabditis elegans
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Elucidating the role of DEPTOR in Alzheimer’s disease
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“The inhibition of the mTOR pathway appears to modulate the process of aging, a well-established risk factor for AD (8,9).”
Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes
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“Furthermore, partial genetic inactivation of the mTOR pathway was known to prolong life span in different species from yeast to humans [57-61] .”
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“Moreover, TORC1 can increase protein synthesis and extends lifespan by both activating the ribosomal subunit S6 kinase (S6K) and inhibiting 4E-BP1 (a negative regulator of translation) [81, 97].”
BackgroundThe Less We Eat, the Longer We Live: Can Caloric Restriction Help Us Become Centenarians?
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“IR/IGF1R—insulin/insulin-like growth factor 1 receptor; IRS—insulin receptor sub- strate; PI3K—phosphoinositide 3-kinase; Akt—protein kinase B; mTORC1—mammalian target of rapamycin complex 1; S6K1—S6 kinase 1; AMPK—AMP-activated protein kinase; LKB1—liver kinase B1; Sirt—sirtuins; Foxo—forkhead box protein O.”
BackgroundInfluentialThe mTOR signaling pathway in cardiac aging
Dai, D., Kang, P., & Bai, H. (2023) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2023.10 · Cited by 24
“In this context, the gene expression analysis of these mice revealed alterations resembling those observed in response to caloric restriction or AMPK activation[95].”
BackgroundAging and the Mammalian regulatory triumvirate.
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“…growth factor (IGF)-signalling (IIS) pathway (Selman et al., 2011), and mammalian target of rapamycin (TOR)-signalling mutant mice (Selman et al., 2009), in order to identify the mechanisms underlying healthy lifespan and translate this knowledge into practical therapies for…”
BackgroundDietary modulation of mitochondrial DNA damage: implications in aging and associated diseases
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Insulin signaling in Drosophila melanogaster mediates Aβ toxicity
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Growth signaling and longevity in mouse models
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Role of the Mammalian Target of Rapamycin (mTOR) Complexes in Pancreatic β-Cell Mass Regulation
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“In fact, mTOR is considered a master regulator of aging in mammals and other organisms (Harrison et al., 2009; Vellai et al., 2003), and evidences link the beneficial effects of dietary restriction with mTORC1 inhibition (Selman et al., 2009).”
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The roles of MTOR and miRNAs in endothelial cell senescence
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mRNA Translation Is Dynamically Regulated to Instruct Stem Cell Fate
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“…other targets of mTOR have been implicated, S6K or eIF4E reduction, or 4EBP overexpression, can contribute to lifespan extension, suggesting that decreased translation rates are at least partly responsible (Hansen et al., 2007; Syntichaki et al., 2007; Selman et al., 2009; Zid et al., 2009).”
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“Depletion of S6K1 (a downstream target protein of mTOR) in mice increased lifespan and maintained insulin sensitivity (Selman et al., 2009; Um et al., 2004).”
The Combined Deletion of S6K1 and Akt2 Deteriorates Glycemic Control in a High-Fat Diet
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Constitutive and induced functions of the p53 gene
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Protein synthesis as an integral quality control mechanism during ageing
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“It has been previously reported that the protein kinase mTOR (mTOR) signaling pathway may have an important role in the aging process (8,9).”
Interaction of polyamines and mTOR signaling in the synthesis of antizyme (AZ)
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Reproductive Experience may Positively Adjust the Trajectory of Senescence
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“The TOR—Sch9 pathway is conserved as a mechanism in Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus (in these organisms, Sch9 is S6 K; Kapahi et al. 2004; Doonan et al. 2008; Selman et al. 2009).”
BackgroundReduced insulin signaling in neurons induces sex-specific health benefits
Baghdadi, M., Nespital, T., Mesaros, A., Buschbaum, S., Withers, D. J., Grönke, S., & Partridge, L. (2023) · Science Advances · doi:10.1126/sciadv.ade8137 · Cited by 24
Self-citationResveratrol Inhibits Protein Translation in Hepatic Cells
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Hoseini, R., Hoseini, Z., & Kamangar, A. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05836-0 · Cited by 20
“It has long been known that mice lacking the S6 kinase, a downstream target of mTORC1, live longer and display increased AMPK signaling, illustrating the intersection of mTOR and energy-sensing pathways [116 ].”
Inhibition of mTOR/S6K1/4E-BP1 Signaling by Nutraceutical SIRT1 Modulators
Bianchi, S. E., & Giovannini, L. (2018) · Nutrition and Cancer · doi:10.1080/01635581.2018.1446093 · Cited by 20
Age-related mechanisms in the context of rheumatic disease
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Restoring Age-Related Cognitive Decline through Environmental Enrichment: A Transcriptomic Approach
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“In line with this, aging-related up-regulation of Rps6ka1, a hub gene in the senescent SAMP8 mice [83], is associated with Alzheimer’s disease development, and experimental down-regulation (as here demonstrated by late-onset EE), ameliorates associated deficits in synaptic plasticity and spatial memory [84] and increa…”
Background
Metadata
- Authors
- Selman, C., Tullet, J. M. A., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., Woods, A., Robinson, I. C. A., Schuster, E., Batterham, R. L., Kozma, S. C., Thomas, G., Carling, D., Okkenhaug, K., Thornton, J. M., Partridge, L., Gems, D., & Withers, D. J.
- Affiliations
- University College London (GB)
- European Bioinformatics Institute (GB)
- Institute of Healthy Ageing, Centre for Diabetes and Endocrinology, Department of Medicine, University College London, London WC1E 6JJ, UK.
- Medical Research Council (GB)
- Babraham Institute (GB)
- Imperial College London (GB)
- University of Cincinnati (US)
- Corresponding author
- Selman, Colin
- Withers, Dominic J.
- ORCID
- Venue
- Science
- Published
- 2009-10-02
- Volume
- 326
- Issue
- 5949
- Pages
- 140-144
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4954603
- OpenAlex
- W2014892893
- Cited by
- 1,120
- References
- 29
- Citations by year
- 2026: 26 · 2025: 28 · 2024: 38 · 2023: 64 · 2022: 50 · 2021: 59 · 2020: 57 · 2019: 58 · 2018: 73 · 2017: 65 · 2016: 57 · 2015: 82 · 2014: 84 · 2013: 90 · 2012: 107
- FWCI
- 29.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BIROn (Birkbeck, University of London) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust (066750)
- Biotechnology and Biological Sciences Research Council (BBS/E/B/0000C236, BBS/E/B/0000M979)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- ribosomal protein S6 kinase 1, mTOR signaling, caloric restriction, aging, lifespan, AMPK, age-related bone loss, immune dysfunction, motor impairment, insulin resistance
- MeSH terms
- Aging, Animals, Female, Gene Expression Regulation, Insulin, Liver, Longevity, Male, Mice, Inbred C57BL, Motor Activity, Protein Kinases, Transcription, Genetic, Signal Transduction, Bone Density, Gene Expression, T-Lymphocyte Subsets, Gene Deletion, Muscle, Skeletal, Caloric Restriction, Ribosomal Protein S6 Kinases, 90-kDa, Mice, Adipose Tissue, White, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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