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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]
Experimental — accuracy not yet measuredIn 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]
In the citing paper
“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]
In the citing paper
“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
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Blagosklonny, M. V. (2010) · Cell Cycle · doi:10.4161/cc.9.10.11872 · Cited by 106
Hu, Y., Kang, C., Zhao, J., Nie, Y., Zheng, L., Li, H., Li, X., Wang, Q., & Qiu, Y. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13338 · Cited by 100
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“Moreover, it was further showed that ROS signaling and adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation could be the common mechanism linking CR, inhibition of NS pathways and mitochondrial activity [95,96].”
BackgroundS6K links cell fate, cell cycle and nutrient response inC. elegansgermline stem/progenitor cells
Korta, D. Z., Tuck, S., & Hubbard, E. J. A. (2012) · Development · doi:10.1242/dev.074047 · Cited by 96
“Reduction- or lossof-function of these genes leads to lifespan extension (Jia et al., 2004; Pan et al., 2007; Selman et al., 2009; Vellai et al., 2003).”
BackgroundInfluentialEstrogen receptor β in Alzheimer’s disease: From mechanisms to therapeutics
Zhao, L., Woody, S. K., & Chhibber, A. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.08.001 · Cited by 103
“The age difference between sexes appears to be even smaller in rodents; in C57BL/6 mice, female mean life span was 789 ± 42 days, and male was 801 ± 39 days (Selman et al., 2009).”
Harlan, S. M., Guo, D., Morgan, D. A., Fernandes‐Santos, C., & Rahmouni, K. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.017 · Cited by 103
“Moreover, inhibition of mTORC1 signaling (via rapamycin treatment or deletion of the s6k1 gene) extends lifespan in mice (Harrison et al., 2009; Selman et al., 2009).”
BackgroundNutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease
Johnson, S. C. (2018) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-981-13-2835-0_3 · Cited by 104
Focusing on mitochondria in the brain: from biology to therapeutics
Song, N., Mei, S., Wang, X.-X., Hu, G., & Lu, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00409-w · Cited by 111
Insights into CNS ageing from animal models of senescence
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Replication of Extended Lifespan Phenotype in Mice with Deletion of Insulin Receptor Substrate 1
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“Animal husbandry Mice were maintained under exactly the same experimental conditions and protocols as previously described [12,16,26].”
MethodSelf-citationFadini, G. P., Ceolotto, G., Pagnin, E., de Kreutzenberg, S., & Avogaro, A. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2010.00642.x · Cited by 97
“Interestingly, knockout of S6K1 induced gene expression patterns similar to those seen in caloric restriction or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and was associated with AMPK activation by phosphorylation (Selman et al., 2009).”
BackgroundmTOR and Aging: An Old Fashioned Dress
Stallone, G., Infante, B., Prisciandaro, C., & Grandaliano, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112774 · Cited by 97
Caveolin-1 and Accelerated Host Aging in the Breast Tumor Microenvironment
Mercier, I., Camacho, J., Titchen, K., Gonzales, D. M., Quann, K., Bryant, K. G., Molchansky, A., Milliman, J. N., Whitaker-Menezes, D., Sotgia, F., et al. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.03.017 · Cited by 96
TOR and ageing: a complex pathway for a complex process
McCormick, M. A., Tsai, S., & Kennedy, B. K. (2010) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2010.0198 · Cited by 99
p70 Ribosomal protein S6 kinase ( Rps6kb1 ): an update
Bahrami-B, F., Ataie-Kachoie, P., Pourgholami, M. H., & Morris, D. L. (2014) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2014-202560 · Cited by 101
Gabandé‐Rodríguez, E., Heras, M. M. G. D. L., & Mittelbrunn, M. (2019) · Cells · doi:10.3390/cells9010082 · Cited by 101
mTOR signaling and Alzheimer's disease: What we know and where we are?
Davoody, S., Asgari Taei, A., Khodabakhsh, P., & Dargahi, L. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14463 · Cited by 96
“44 The life-increasing effects of mTOR inhibitor drugs may be related to the inhibition of mTORC1, and the inhibition of mTORC2 may even leave dire effects on the inhibitory effect of insulin-mediated he-patic gluconeogenesis which is controlled by mTORC2.”
BackgroundMammalian target of rapamycin signaling in diabetic cardiovascular disease
Chong, Z., & Maiese, K. (2012) · Cardiovascular Diabetology · doi:10.1186/1475-2840-11-45 · Cited by 95
Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis
Carroll, B., Korolchuk, V. I., & Sarkar, S. (2014) · Amino Acids · doi:10.1007/s00726-014-1775-2 · Cited by 99
Longevity effect of IGF ‐1 R +/− mutation depends on genetic background‐specific receptor activation
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“…Saint-Antoine, Paris 75012, France 2Université Pierre et Marie Curie, UPMC, Paris 75005, France 3Faculté de Médecine, Université Paris Descartes, Paris 75006, France 4INRA UMR7247, Nouzilly 37380, France 5CNRS UMR6175, Nouzilly 37380, France 6Université François Rabelais, Tours 37041, France”
Depuydt, G., Xie, F., Petyuk, V., Shanmugam, N., Smolders, A., Dhondt, I., Brewer, H. M., Camp, D., Smith, R. D., & Braeckman, B. P. (2013) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.027383 · Cited by 92
de Kreutzenberg, S. V., Ceolotto, G., Cattelan, A. M., Pagnin, E., Mazzucato, M., Garagnani, P., Borelli, V., Bacalini, M. G., Franceschi, C., Fadini, G. P., et al. (2015) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2015.03.007 · Cited by 94
“However, metformin clearly reduced phosphorylation of p70S6K, which is a downstream mTOR effector, mediates the anti-cancer effect of metformin [31] and interferes with ageing [32,33].”
BackgroundHasty, P., Sharp, Z. D., Curiel, T. J., & Campisi, J. (2012) · Cell Cycle · doi:10.4161/cc.22912 · Cited by 92
Frontier of Epilepsy Research - mTOR signaling pathway
Cho, C. (2011) · Experimental & Molecular Medicine · doi:10.3858/emm.2011.43.5.032 · Cited by 93
SH3BP4 Is a Negative Regulator of Amino Acid-Rag GTPase-mTORC1 Signaling
Kim, Y.-M., Stone, M., Hwang, T. H., Kim, Y.-G., Dunlevy, J. R., Griffin, T. J., & Kim, D.-H. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.04.007 · Cited by 88
Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism
Foukas, L. C., Bilanges, B., Bettedi, L., Pearce, W., Ali, K., Sancho, S., Withers, D. J., & Vanhaesebroeck, B. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201201953 · Cited by 91
“Of note, IGF-1 levels are not reduced in long-lived S6K1 mutant mice (Selman et al, 2009), which shows that reduced levels of IGF-1 is not a common feature of all long-lived mouse mutants.”
Self-citationThe Role of Rapamycin in Healthspan Extension via the Delay of Organ Aging
Zhang, Y., Zhang, J., & Wang, S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101376 · Cited by 92
Resveratrol and rapamycin: are they anti‐aging drugs?
Kaeberlein, M. R. (2010) · BioEssays · doi:10.1002/bies.200900171 · Cited by 96
“The importance of TOR signaling in mammalian aging was further solidified by a second report showing that knockout of S6k1, which encodes the TOR substrate ribosomal S6 kinase, also increases life span in mice.((26)) Like TOR, S6 kinase homologs modulate aging in yeast, nematodes, and flies, demonstrating that this is…”
BackgroundDiabetic cardiomyopathy and metabolic remodeling of the heart
Battiprolu, P. K., Lopez-Crisosto, C., Wang, Z. V., Nemchenko, A., Lavandero, S., & Hill, J. A. (2013) · Life Sciences · doi:10.1016/j.lfs.2012.10.011 · Cited by 91
“Indeed, deletion of mTOR substrates such as S6K1 is sufficient to improve insulin sensitivity and to extend lifespan inmice (Selman et al., 2009).”
BackgroundBeyond controlling cell size: functional analyses of S6K in tumorigenesis
Wu, X., Xie, W., Xie, W., Wei, W., & Guo, J. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05081-4 · Cited by 96
“This effect is evidenced by reduced weight and adipose tissue mass in homozygous EPRS S999A knock-in mice, which also exhibit a longer lifespan resembling that of S6k1-deficient mice [36].”
BackgroundInfluentialRedmann, M., Darley-Usmar, V. M., & Zhang, J. (2016) · Aging and Disease · doi:10.14336/ad.2015.0820 · Cited by 93
“This work was supported by NIHR01-NS064090 (to JZ).”
BackgroundSphingolipids and lifespan regulation
Huang, X., Withers, B. R., & Dickson, R. C. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.08.006 · Cited by 89
Metallothionein and the biology of aging
Swindell, W. R. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.09.007 · Cited by 89
Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to
Blagosklonny, M. V. (2012) · Aging · doi:10.18632/aging.100461 · Cited by 91
Regulation of mTOR Activity in Snell Dwarf and GH Receptor Gene-Disrupted Mice
Dominick, G., Berryman, D. E., List, E. O., Kopchick, J. J., Li, X., Miller, R. A., & Garcia, G. G. (2015) · Endocrinology · doi:10.1210/en.2014-1690 · Cited by 79
“Furthermore, it has been shown that a deletion of the S6K1 gene can also extend lifespan in mice, although apparently only in females (32).”
BackgroundProteomics and metabolomics in ageing research: from biomarkers to systems biology
Hoffman, J. M., Lyu, Y., Pletcher, S. D., & Promislow, D. (2017) · Essays in Biochemistry · doi:10.1042/ebc20160083 · Cited by 90
“While lab-based genetic studies have gone from success to success [3,5,6,20], the same is not true for genome-wide association studies (GWAS) designed to identify alleles that account for variation in lifespan in human populations [21,22].”
BackgroundmTORC1 Overactivation as a Key Aging Factor in the Progression to Type 2 Diabetes Mellitus
Guillén, C., & Benito, M. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00621 · Cited by 91
Build-UPS and break-downs: metabolism impacts on proteostasis and aging
Ottens, F., Franz, A., & Hoppe, T. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-020-00682-y · Cited by 88
Brandhorst, S., Wei, M., Hwang, S., Morgan, T. E., & Longo, V. D. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.02.016 · Cited by 89
“, 2009) and S6K1 (Selman et al., 2009), demonstrate the central role of intracellularmitogenic pathways downstreamof IGF-I in regulating lifespan and stress resistance while simultaneously reducing tumor growth (Garcia et al.”
InfluentialInsulin Signaling Mediates Sexual Attractiveness in Drosophila
Kuo, T.-H., Fedina, T. Y., Hansen, I., Dreisewerd, K., Dierick, H. A., Yew, J. Y., & Pletcher, S. D. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002684 · Cited by 89
“…a clearer picture of the links between IIS and attractiveness because female attractiveness, unlike male, is less influenced by behavior and because the effects of IIS manipulation on lifespan and reproductive output are better understood, pheno-typically and genetically, in females [28,29].”
Age‐related anabolic resistance after endurance‐type exercise in healthy humans
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“However, the diminished anabolic responsiveness of older individuals to amino acids, as well as the uncertain effects of long-term high protein/amino acid diets on deleterious signaling in tissues other than skeletal muscle (86, 87), implies that increasing anabolic sensitivity is the preferable approach.”
BackgroundMetabolic characteristics of long-lived mice
Bartke, A., & Westbrook, R. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00288 · Cited by 90
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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