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      Answering the ultimate question “What is the Proximal Cause of Aging?”

      review-article
      Author(s):
      Publication date (Electronic):
      Journal: Aging (Albany NY)
      Publisher: Impact Journals LLC
      Keywords: MTOR, TOR, rapamycin, senescence, cancer, stroke, development, growth

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          Abstract

          Recent discoveries suggest that aging is neither driven by accumulation of molecular damage of any cause, nor by random damage of any kind. Some predictions of a new theory, quasi-programmed hyperfunction, have already been confirmed and a clinically-available drug slows aging and delays diseases in animals. The relationship between diseases and aging becomes easily apparent. Yet, the essence of aging turns out to be so startling that the theory cannot be instantly accepted and any possible arguments are raised for its disposal. I discuss that these arguments actually support a new theory. Are any questions remaining? And might accumulation of molecular damage still play a peculiar role in aging?

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          Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

          Francis Rodier, Jean-Philippe Coppe, Christopher K Patil … (2009)
          Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
          Article 0 comments Cited 752 times – based on 0 reviews     Review now
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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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              Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients.

              M Kaeberlein (2005)
              Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene-deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (iso-abbrev): Aging (Albany NY)
                Journal ID (publisher-id): ImpactJ
                Title: Aging (Albany NY)
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1945-4589
                Publication date Collection: December 2012
                Publication date (Electronic): 30 December 2012
                Volume: 4
                Issue: 12
                Pages: 861-877
                Affiliations
                Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC, L3-312, Elm and Carlton Streets, Buffalo, NY 14263, USA
                Author notes
                Correspondence to: Mikhail V. Blagosklonny, MD/PhD; blagosklonny@ 123456oncotarget.com
                Article
                DOI: 10.18632/aging.100525
                PMC ID: 3615154
                PubMed ID: 23425777
                SO-VID: 1b1c18c0-62d3-4025-a606-d490260cba77
                Copyright © Copyright: © 2012 Blagosklonny
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 20 December 2012
                Date accepted : 29 December 2012
                Categories
                Subject: Review

                ScienceOpen disciplines: Cell biology
                Keywords: mtor,tor,rapamycin,senescence,cancer,stroke,development,growth
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: mtor, tor, rapamycin, senescence, cancer, stroke, development, growth

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