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Archived Comments for: Network strategies to understand the aging process and help age-related drug design

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  1. History of Research in Aging Networks

    Tarynn Witten, Virginia Commonwealth University

    4 December 2009

    While an interesting paper, this paper ignores the significant previous literature in the field of aging networks, reliability theoretic applications to aging networks and purports to be the first to generate the ideas of using hubs and other network concepts to understand the behavior of aging processes. Unfortunately, the ignored literature significantly overlaps the results in this paper.

    The work of Witten, as far back as the early 1980's represents the actual first publication of the concepts of central elements and centrality of networks using graph theoretic concepts in aging.

    Witten, T.M., A return to time, cells, systems, and aging: II. Relational and reliability theoretic aspects of senescence in mammalian systems, Mech. Aging and Dev., 27 (1984) 323--340.

    This work documented the idea of what is now called essential genes (Witten called them critical elements) and highly connected hubs. This work was followed by a number of publications applying network and reliability theory to aging networks:

    Witten, T.M., Reliability theoretic methods and aging: Critical elements, hierarchies, and longevity---Interpreting survival curves, (in) The Molecular Biology of Aging (eds.) A. Woodhead, A. Blackett, and R. Setlow (Plenum Press, N.Y. 1985).

    Witten, T.M., A return to time, cells, systems and aging: III. Critical elements, hierarchies, and Gompertzian dynamics, Mech. Ageing and Dev., 32 (1985) 141--177.

    More recently, these methods were extended using the Bonchev-Witten algorithm to determine potential longevity-related genes in longevity-gene networks.

    Witten, T.M. and Bonchev, D.G. (2007). Predicting aging/longevity-related genes in the nematode C. elegans. Chemistry and Biodiversity, 4: 2639-2655.

    The following paper provides a history of the work:

    Witten, T.M. (2007). (M,R)-systems, (P,M,C)-nets, hierarchical decay and biological aging: Reminiscences of Robert Rosen. Chemistry and Biodiversity, 4 (10): 2332-2344.

    Most recently, Witten's doctoral student Managbanag along with the research team at U of Seattle, using the methods developed by Bonchev and Witten published the following paper:

    Managbanag, J.R., Witten, T.M., Bonchev, D.G., Fox, L.A., Tsuchiya, M., Kennedy, B.K. & Kaeberlein, M. (2008). Shortest-path network analysis is a useful approach towards identifying genetic determinants of longevity. PLoS ONE, 3 (11):e3802. doi:10.1371/journal.pone.0003802

    It is extremely disturbing to discover that all of these works were ignored in the reference list of the Simko et al (2009) paper [also ignored in other papers published in other locations] and that the current paper Simko et al (2009)purports to present the idea that they are the originators of ideas whose core was published by Witten over 20 years ago. We hope that this lack of attention to the core literature in the field of networks in aging will be rectified in the future by these and other authors.

    Competing interests

    No competing interests.

  2. Response to Dr. Tarynn M. Witten's comment

    Peter Csermely, Semmelweis University

    27 January 2010

    We would like to thank for the comment of Dr. Witten to our paper. First, we would like to apologize for Dr. Witten for not citing any of the listed contributions. Indeed, the 1984 Mech. Aging Dev. paper represents one of the first uses of network theory in aging, which deserves citation, as we will do in our later papers. This work is extended by its sequel, the 1985 Mech. Aging Dev. paper. In 1984 the complex network structure of the cell was obviously unknown, and therefore, the centrality of the critical elements defined by Witten is rather a general central position of a systems theory-type network than the refined versions of betweenness and other types of centralities of the interactome or metabolic type networks attracting the focus of research today. Obviously at that time Witten¿s general notion of centrality could not be tested on a real network, and, therefore was not attached to any types of essential genes. However, the early idea to use network theory to the identification of critical cellular elements is indeed, important.

    The recent PLoS ONE paper of Managbanag et al. is a nice representation of the graph theoretical tools to identify longevity genes. Similarly, the Witten-Bonchev Chemistry and Biodiversity paper gives an important contribution to the topics of longevity-networks also described by others simultaneously. We consider it a very unfortunate oversight not to cite these papers in our review. We will certainly cite these contributions in our later, relevant publications.

    As a final note, carefully re-reading our paper we did not find any statements inferring our role as originators of any ideas covered by Dr. Witten¿s publications. Since our paper was a review paper the references ¿ including self references ¿ gave the source and verification of the given statement, and could by no means regarded as any claim for priority. The limitation of references and the focus to the most recent papers published makes it generally very difficult to cite all primary references in these, not extensive, but mini-reviews.

    On behalf of all co-authors: Peter Csermely

    Competing interests

    No competing interests.