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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
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“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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Testai, L., Citi, V., Martelli, A., Brogi, S., & Calderone, V. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105125 · Cited by 49
Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process
Khaidizar, F. D., Bessho, Y., & Nakahata, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073709 · Cited by 51
Ching, T., Paal, A. B., Mehta, A., Zhong, L., & Hsu, A. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00580.x · Cited by 48
“While no structural 4E-BP homolog is apparent in the C. elegans genome (Syntichaki et al., 2007), recent studies have shown that reducing expression of S6K ⁄ rsks-1 results in a significant lifespan extension in worms (Hansen et al., 2007; Pan et al., 2007) and mammals (Selman et al., 2009).”
BackgroundRiera, C. E., & Dillin, A. G. (2015) · Nature Medicine · doi:10.1038/nm.4005 · Cited by 48
Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson‐Gilford Progeria syndrome
Cabral, W. A., Tavarez, U. L., Beeram, I. R., Yeritsyan, D., Boku, Y. D., Eckhaus, M., Nazarian, A., Erdos, M. R., & Collins, F. S. (2021) · Aging Cell · doi:10.1111/acel.13457 · Cited by 47
“…related diseases, inhibitors of mTOR signaling components have drawn interest as potential treatments for disorders associated with deposition of insoluble protein aggregates by means of enhanced clearance through autophagic- lysosomal pathway activation (Selman et al., 2009; Wu et al., 2013).”
BackgroundM(o)TOR of pseudo-hypoxic state in aging: Rapamycin to the rescue
Leontieva, O. V., & Blagosklonny, M. V. (2014) · Cell Cycle · doi:10.4161/cc.27973 · Cited by 46
“In agreement, genetic, environmental (calorie restriction), or pharmacological inhibition of TOR extends life span in yeast, flies, worms, and mammals.(12,21,26-41) In particular, rapamycin extends life span in all experiments conducted in mice.”
BackgroundBlazing a trail for the clinical use of rapamycin as a geroprotecTOR
Konopka, A. R., Lamming, D. W., RAP PAC Investigators, Grasso, B. A., Marrah, R. C., Decker, S., Garg, N., Park, Y., Lim, S. Y., Simcox, J., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00935-x · Cited by 46
“Using genetic models, inhibition of mTORC1 signaling alone extends lifespan and healthspan [7, 8] while tissue-specific and whole body genetic depletion of mTORC2 has negative effects on metabolic health, frailty, and survival in mice [89–93].”
MethodEffects of rapamycin and TOR on aging and memory: implications for Alzheimer’s disease
Santos, R. X., Correia, S. C., Cardoso, S., Carvalho, C., Santos, M. S., & Moreira, P. I. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07262.x · Cited by 45
Spong, A., & Bartke, A. (2012) · Cell Cycle · doi:10.4161/cc.11.5.19607 · Cited by 48
André, C., & Cota, D. (2012) · Proceedings of The Nutrition Society · doi:10.1017/s0029665112000754 · Cited by 48
Sharp, Z. D., & Strong, R. (2010) · The Journals of Gerontology Series A · doi:10.1093/gerona/glp212 · Cited by 46
Ejaz, A., Mitterberger, M. C., Lü, Z., Mattesich, M., Zwierzina, M., Hörl, S., Kaiser, A. M., Viertler, H.-P., Rostek, U., Meryk, A., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.03.030 · Cited by 46
“…of IGF-1/ insulin signaling increases lifespan (Kenyon, 2010; Johnson, 2013) and knockouts of genes coding for several components of the GH/IGF-1– mTOR signaling network extend lifespan in rodents (Coschigano et al., 2000; Holzenberger et al., 2003, Taguchi et al., 2007; Selman et al., 2009).”
BackgroundA proteomic atlas of insulin signalling reveals tissue‐specific mechanisms of longevity assurance
Tain, L. S., Sehlke, R., Jain, C., Chokkalingam, M., Nagaraj, N., Essers, P., Rassner, M., Grönke, S., Froelich, J., Dieterich, C., et al. (2017) · Molecular Systems Biology · doi:10.15252/msb.20177663 · Cited by 44
“Increased detoxification (Amador-Noguez et al, 2007; Selman et al, 2009; Ewald et al, 2015; Afschar et al, 2016) and reduced translation (Selman et al, 2009; Afschar et al, 2016; Kaletsky et al, 2016) are two functional signatures consistently associated with longevity across different model…”
BackgroundSelf-citationEffects of rapamycin on growth hormone receptor knockout mice
Fang, Y., Hill, C. M., Darcy, J., Reyes‐Ordoñez, A., Arauz, E. J., McFadden, S., Zhang, C., Osland, J. M., Gao, J., Zhang, T., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1717065115 · Cited by 46
“The results revealed that rapamycin extended the life span of control N mice, as expected from previous studies (4, 22), including results of deleting the mTORC1 target, S6K1 (29), whereas the same treatment in GHR-KO mice had the opposite effect.”
ResultFasting and fasting-mimicking diets for chemotherapy augmentation
Brandhorst, S. (2021) · GeroScience · doi:10.1007/s11357-020-00317-7 · Cited by 50
Dalton, H. M., & Curran, S. P. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007520 · Cited by 43
Dabour, N. A., Bando, T., Nakamura, T., Miyawaki, K., Mito, T., Ohuchi, H., & Noji, S. (2011) · Development Growth & Differentiation · doi:10.1111/j.1440-169x.2011.01291.x · Cited by 45
“In the case of S6k, small body size was observed in S6k1) ⁄ ) mouse mutant (Selman et al. 2009) and dS6K ª 2011 The Authors ferentiation ª 2011 Japanese Society of Developmental Biologists Drosophila mutant (Montagne et al., 1999).”
BackgroundSun, J., Mu, Y., Jiang, Y., Song, R., Yi, J., Zhou, J., Sun, J., Jiao, X., Prinz, R. A., Li, Y., et al. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0441-0 · Cited by 44
TOR Signaling Pathway in Cardiac Aging and Heart Failure
Daneshgar, N., Rabinovitch, P. S., & Dai, D. (2021) · Biomolecules · doi:10.3390/biom11020168 · Cited by 44
“Ribosomal protein S6, the substrate of S6K1, has been widely used as a marker of mTORC1 activity [62].”
BackgroundInfluentialImplications of Sphingolipids on Aging and Age-Related Diseases
Li, S., & Kim, H.-E. (2022) · Frontiers in Aging · doi:10.3389/fragi.2021.797320 · Cited by 47
“Disrupting S6K1, a mediator of mTOR signaling recapitulates metabolic profiles of caloric restriction (Choudhury, 2009), which is one of the most reliable ways of inducing prolonged lifespan in mammals (Madeo et al.”
BackgroundBlagosklonny, M. V. (2013) · Cell Cycle · doi:10.4161/cc.25062 · Cited by 44
Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo
Fenton, T. R., Gwalter, J., Ericsson, J., & Gout, I. T. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.11.022 · Cited by 46
“On an organismal level, the recent finding that S6K1 controls lifespan in mice (Selman et al., 2009) is of particular interest, since our data raise the possibility that the sirtuin deacetylases may exert effects on lifespan not only through FoxO deacetylation (Brunet et al.”
BackgroundMendelsohn, A. R., & Larrick, J. W. (2011) · Rejuvenation Research · doi:10.1089/rej.2011.1238 · Cited by 45
Sensory Perception and Aging in Model Systems: From the Outside In
Linford, N. J., Kuo, T.-H., Chan, T. P., & Pletcher, S. D. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154240 · Cited by 45
“…signaling cascades are strong candidates because of their prominent roles in controlling energy metabolism, reproductive signals, homeostatic regulation of food intake, and aging in response to nutrient availability (Greer et al. 2007, Kapahi et al. 2004, Selman et al. 2009, Zoncu et al. 2010).”
BackgroundDeficiency in mTORC1‐controlled C/EBPβ‐mRNA translation improves metabolic health in mice
Zidek, L. M., Ackermann, T., Hartleben, G., Eichwald, S., Kortman, G., Kiehntopf, M., Leutz, A., Sonenberg, N., Wang, Z., von Maltzahn, J., et al. (2015) · EMBO Reports · doi:10.15252/embr.201439837 · Cited by 48
The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview
Brown, R. R., McKelvey, M. C., Ryan, S. M., Creane, S., Linden, D. A., Kidney, J. C., McAuley, D. F., Taggart, C. C., & Weldon, S. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.589553 · Cited by 46
The contradictory role of branched-chain amino acids in lifespan and insulin resistance
He, Y., Li, K., Wei, J., Lin, Y., & Liu, Y. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1189982 · Cited by 46
Li, X., Thomason, P. A., Withers, D. J., & Scott, J. (2010) · BMC Systems Biology · doi:10.1186/1752-0509-4-175 · Cited by 43
“By contrast Nnat expression in WAT is substantially reduced in lipodystrophic, in lean S6kko mice and in mice fed conjugated linoleic acid, which induces weight loss[ 16-18 ].”
BackgroundSelf-citation
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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