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      Koschei the immortal and anti-aging drugs

      review-article
      Author(s): 1 , *
      Publication date (Electronic):
      Journal: Cell Death & Disease
      Publisher: Nature Publishing Group

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          Abstract

          In Slavic folklore, Koschei the Immortal was bony, thin and lean. Was his condition caused by severe calorie restriction (CR)? CR deactivates the target of rapamycin pathway and slows down aging. But the life-extending effect of severe CR is limited by starvation. What if Koschei's anti-aging formula included rapamycin? And was rapamycin (or another rapalog) combined with commonly available drugs such as metformin, aspirin, propranolol, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors.

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          Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

          Pankaj Kapahi, Brian M. Zid, Tony Harper … (2004)
          In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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            Rapamycin slows aging in mice.

            John Wilkinson, Lisa Burmeister, Susan V. Brooks … (2012)
            Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
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              Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling.

              Yonghao Yu, Sang-Oh Yoon, George Poulogiannis … (2011)
              The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.
              Article 0 comments Cited 283 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2041-4889
                Publication date (Print): December 2014
                Publication date (Electronic): 04 December 2014
                Publication date PMC-release: 1 December 2014
                Volume: 5
                Issue: 12
                Page: e1552
                Affiliations
                [1 ]Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC, L3-312 , Elm and Carlton Streets, Buffalo, NY, USA
                Author notes
                [* ]Department of Cell Stress Biology, Roswell Park Cancer Institute , BLSC, L3-312, Elm and Carlton Streets, Buffalo 14263, NY, USA. Tel: +1 716 8458086; Fax: +1 716 8453944; E-mail: blagosklonny@ 123456oncotarget.com
                Article
                Publisher Item ID: cddis2014520
                DOI: 10.1038/cddis.2014.520
                PMC ID: 4649836
                PubMed ID: 25476900
                SO-VID: ecdfb704-d891-4c84-ba29-8c9fe6704944
                Copyright © Copyright © 2014 Macmillan Publishers Limited
                License:

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0

                History
                Date received : 16 October 2014
                Date revision received : 01 November 2014
                Date accepted : 03 November 2014
                Categories
                Subject: Review

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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