Complex systems dynamics in aging new evidence c

Authors: Alan A Cohen

Publish Date: 2015/05/20

Volume: 17, Issue: 1, Pages: 205-220

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Abstract

There have long been suggestions that aging is tightly linked to the complex dynamics of the physiological systems that maintain homeostasis and in particular to dysregulation of regulatory networks of molecules This review synthesizes recent work that is starting to provide evidence for the importance of such complex systems dynamics in aging There is now clear evidence that physiological dysregulation—the gradual breakdown in the capacity of complex regulatory networks to maintain homeostasis—is an emergent property of these regulatory networks and that it plays an important role in aging It can be measured simply using small numbers of biomarkers Additionally there are indications of the importance during aging of emergent physiological processes functional processes that cannot be easily understood through clear metabolic pathways but can nonetheless be precisely quantified and studied The overall role of such complex systems dynamics in aging remains an important open question and to understand it future studies will need to distinguish and integrate related aspects of aging research including multifactorial theories of aging systems biology bioinformatics network approaches robustness and loss of complexityTwentyfive years ago Medvedev 1990 outlined more than 300 mechanistic theories of aging The question then and the question now was what to make of this diversity of theories Is one theory right to the exclusion of all others Do many mechanisms operate simultaneously Are some mechanisms downstream and others upstream such that we might identify one or a few key upstream mechanisms Do the mechanisms interact with each other and if so howTo some extent we have answers to some of these questions For example very few researchers would now contend that there is a single aging mechanism though some still argue principally for one central mechanism Barja 2014 There is both theoretical and empirical evidence for interactions among mechanisms Kowald and Kirkwood 1996 Ludlow et al 2014 However we are still far from a general consensus on a bigpicture theory for how mechanisms interact to cause aging Kirkwood 2011One integrative theory proposes a breakdown in interactions within the complex regulatory networks that maintain homeostasis Ferrucci 2005 Fried et al 2005 This idea has been around in various forms for a long time and has many names homeostenosis Taffett 2003 allostatic load Karlamangla et al 2002 McEwen 1998 and physiological dysregulation Seplaki et al 2005 Loss of complexity during aging is a related idea that has also been developed in detail Lipsitz 2004 Lipsitz and Goldberger 1992 Manor and Lipsitz 2013 These ideas are attractive and have garnered a fair amount of support particularly among clinical aging researchers though they are less familiar to some researchers focused on the molecular mechanisms of aging However the challenge has been to accumulate evidence for the importance of such complex systems dynamics in aging Precisely because the systems are complex they can be hard to measure For example measurement of allostatic load has been questioned as circular Singer et al 2004Over the last several years my lab has been working to find ways to test for the presence and importance of complex systems dynamics in aging We have been doing so at the organism level and using a particular model of physiological organization Our approach to complex systems dynamics is described in substantial detail below briefly I define complex systems dynamics as changes in the state of complex regulatory networks of molecules that a arise due to the structure of regulatory relationships within the network such as through feedback loops that b cannot be easily understood via simple maps of network structure ie that represent emergent properties of the system and that c may be sensitive to the precise structure of the network and to perturbations in it Complex systems dynamics might be implicated in aging via a breakdown in the regulatory dynamics “dysregulation” through intricate feedback effects among aging mechanisms or perhaps through other mechanisms as I will showThe objective of this article is to summarize our recent findings in an integrative way and to relate them to the broader literature on complex systems and aging I thus start with an overview of different ways that complexity has been discussed in the context of aging biology I continue with a summary of our model of physiological organization including the evidence we have generated for two particular types of complex systems dynamics emergent physiological processes EPPs and physiological dysregulation Lastly I integrate our findings into the larger literature and summarize outstanding questionsWest and Bergman 2009 proposed an expanded role for systems biology and complexity in aging but there are many directions this could take and a lack of clear terminology sometimes leads to confusion It is important to distinguish complex system dynamics our approach detailed in the next section multifactorial theories of aging Kirkwood 2005 systems biology and bioinformatics of aging more generally de Magalhães and Toussaint 2004 Kirkwood 2011 Soltow et al 2010 systemlevel robustness in aging Kriete 2013 and loss of complexity in aging Lipsitz 2004 Lipsitz and Goldberger 1992 Each of these research directions provides a critical piece of the puzzle on complexity in aging and longterm it will be important to integrate them and perhaps othersMultifactorial theories of aging posit simply that aging has many causes Weinert and Timiras 2003 most aging researchers today would subscribe to this idea at some level Aging could be multifactorial but not involve complex system dynamics For example there could be a number of different mechanisms that cause damage accumulation each proceeding largely independently Even if there are a few specific feedback effects among the mechanisms eg Kowald and Kirkwood 1996 it is not a foregone conclusion that there would be complex system dynamics The disposable soma theory and related mechanistic theories based on the accumulation of damage wear and tear etc are multifactorial but do not necessarily imply complex system dynamics Kirkwood 2005 In fact the evolutionary mechanisms referred to in the disposable soma theory imply that complex systems dynamics are not central to aging if they were aging would likely evolve based on regulatory constraints in complex networks rather than based on a large number of small tradeoffs of things like energy allocation Cohen Accepted The distinction between multifactorial theories and complex systems theories may thus also be important for inferring how aging evolved see also Kriete 2013 Wensink et al 2014

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