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COMPLEX TIME: Adaptation, Aging, & Arrow of Time

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Dynamic Multi-System Resilience in Human Aging

From Complex Time

Category: Application Area Application Area: Human Resilience

Date/Time: November 12, 2018 - November 13, 2018

Location: Santa Fe Institute (Noyce Conference Room)

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Organizers

  • Marcel G.M. Olde Rikkert (Radboud Univ.)

  • Tim Buchman (Emory Univ./SFI)

  • Rene Melis (Radboud Univ.)

  • Jerrald Rector (Radboud Univ.)

  • Sanne Gijzel (Radboud Univ.)

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    Attendees

    Agenda/Schedule
    Click each agenda item's title for more information.
    Monday, November 12, 2018
    8:45 am Day 1 Shuttle Departing Hotel Santa Fe (at lobby) to SFI
    9:00 am - 9:30 am Day 1 Continental Breakfast (outside SFI Noyce Conference Room)
    9:30 am - 9:45 am Welcome & introduction around the Room - Marcel G.M. Olde Rikkert (Radboud Univ.), Tim Buchman (Emory Univ./SFI) Download Presentation
    9:45 am - 10:00 am WG Context under SFI Adaptation, Aging, Arrow of Time (AAA) Research Theme - Amy P Chen (SFI)
    10:00 am - 10:40 am Emergence of Aging in Natural and Synthetic Multicellular Structures - Dervis Can Vural (Univ. Notre Dame) Download Presentation
    10:40 am - 11:00 am Day 1 AM Break
    11:00 am - 11:40 am Conceptual models of human aging and resilience - Peter M. Hoffmann (Wayne State Univ.) Download Presentation
    11:40 am - 12:20 pm Multiscale modeling to help making sense of dynamical multiscale resilience - Alfons Hoekstra (Univ. Amsterdam) Download Presentation
    12:20 pm - 1:00 pm Day 1 Lunch (outside SFI Noyce Conference Room)
    1:00 pm - 1:40 pm Studies of Resiliencies to Physiologic Stressors: Need for Multilevel and Life Course Approaches - Chhanda Dutta (NIH) Presentation (Encrypted)
    1:40 pm - 2:20 pm Dynamical systems approach to studying resilience in older adults - Ravi Varadhan (Johns Hopkins Univ.) Download Presentation
    2:20 pm - 3:00 pm Developing dynamical indicators of resilience based on physiologic time series in older adult - Sanne Gijzel (Radboud Univ.) Download Presentation
    3:00 pm - 3:20 pm Day 1 PM Break
    3:20 pm - 4:00 pm Day 1 Open group discussion
    4:00 pm - 5:00 pm Day 1 Collaborative Platform Work Time - Amy P Chen (SFI)
    5:15 pm Day 1 Shuttle Departing SFI to Hotel Santa Fe
    6:30 pm Group dinner at Casa Chimayo
    Tuesday, November 13, 2018
    8:45 am Day 2 Shuttle Departing Hotel Santa Fe (at lobby)
    9:00 am - 9:30 am Day 2 Continental Breakfast (outside SFI Noyce Conference Room)
    9:30 am - 9:40 am Day 2 Opening Remarks
    9:40 am - 10:20 am Ecology for doctors: system dynamics models as a tool to understand observed behavior - Ingrid vd Leemput (Wageningen Univ.) Download Presentation
    10:20 am - 10:40 am Day 2 AM Break
    10:40 am - 11:20 am Resilience and vulnerability in a stressed system: an example from the wards - Heather Whitson (Duke Univ.) Download Presentation
    11:20 am - 12:00 pm Day 2 Open group discussion - Marcel G.M. Olde Rikkert (Radboud Univ.)
    12:00 pm - 12:40 pm Day 2 Lunch (outside SFI Noyce Conference Room)
    12:40 pm - 1:20 pm Resilience in New Mexico’s Indigenous Communities - Porter Swentzell (Institute of American Indian Arts)
    1:20 pm - 2:00 pm Physical resilience is a predictor of healthy aging in mice - Warren C. Ladiges (Univ. Washington) Presentation (Encrypted)
    2:00 pm - 2:20 pm Day 2 Collaborative Platform Work Time
    2:20 pm - 2:40 pm Day 2 PM Break
    2:40 pm - 5:00 pm Day 2 Open group discussion II - Marcel G.M. Olde Rikkert (Radboud Univ.)
    5:15 pm Day 2 Shuttle Departing SFI to Hotel Santa Fe

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    Meeting Synopsis

    The Dynamic Multi-System Resilience in Human Aging Working Group planned under the Adaptation, Aging, Arrow of Time program aims to improve understanding of the aging-related human potential to withstand, and to recover from, stressors and diseases. Over the last decades much has been learned on different ‘omics-fields’ of aging, on physical frailty, and psychosocial adaptation in aging, but now it is time to put together again the aging individual. Therefore we will focus on the aging related changes in dynamic multi-system resilience and relate this to what is known of changes in subsystem (organ based) resilience over time. Scientists from medicine, ecology, physics, mathematics, computational sciences and complexity science will interact to theoretically, methodologically and empirically push the clinically highly relevant theme of ‘Resilience in Human Aging’ a big step forward.

    Additional Meeting Information

    MEETING PREPARATION

    In preparation for the meeting, we ask all participants to read the following straw man paper which will be used to anchor the discussions during the meeting:-Olde Rikkert M.G. & Melis R.J.F, “Rerouting Geriatric Medicine by Complementing Static Frailty Measures with Dynamic resilience Indicators of Recovery Potential” currently under review in Frontiers.

    PRESENTATION INSTRUCTIONS

    20 minute presentation designed for a multidisciplinary audience on respective state-of-art of fields. 5-15 slides which:


    • introduce the topic, highlighting recent state of the art at a high level
    • identify current challenges with potential for transformative breakthroughs.
    ANTICIPATED WORKING GROUP OUTCOME


    • - Inspire interdisciplinary exchanges that can fuel participants’ future research
    • - A collaborative volume published through the SFI Press: 10 short paper, 1500 words each
    • - Elaborate and build on the straw man paper (Olde RIkkert & Melis, under review in Frontiers)
    • - Build a collaborative network for future research projects
    Abstracts by Presenters

    Peter M. Hoffmann (Wayne State Univ.) - Conceptual models of human aging and resilience

    Humans are “complex biological systems consisting of multiple levels of non-linearly interacting elements”. Our bodies have astonishing powers of self-repair, and in the absence of catastrophic stress or genetic defects, can maintain homeostasis for a long time. Humans are one of the most long-lived species on the planet. However, there seems to be a “natural limit” of human life span that has not changed substantially despite the advances of medicine. Self-repair and recovery from stresses “naturally” diminish with age. Eventually, tipping points push the system into increasingly less resilient states. Are there any purely conceptual models that can describe human aging, resilience and frailty, especially the slow-down of recovery and the emergence of tipping points? This talk will provide a high-level overview of some potentially useful models and how they relate to each other – focusing on models of entropic/informational breakdown and stochastic stress response. However, while such models can capture aspects of the problem, challenges remain to connect these mathematical models to the complex, multi-hierarchical, multi-timescale, feedback-controlled system of a human body.

    Sanne Gijzel (Radboud Univ.) - Developing dynamical indicators of resilience based on physiologic time series in older adult

    The NIA recently formulated a need to develop technically and clinically feasible method to assess systemic resilience as a predictor of individual recovery in older persons. Our group applies the generic dynamical systems theory to the aging human, which gives rise to new measures of resilience. A human being, like any complex system, is permanently subject to natural perturbations from the environment. When one continuously monitors physiologic parameters, the system’s dynamic responses to perturbations can be captured. A complex system with declining resilience shows slowing down of its dynamic responses. From time series of physiological parameters exhibiting a dynamic equilibrium, dynamical indicators of resilience (DIORs) can be calculated. A lack of resilience is reflected by an increase in three DIORs: the variance, temporal autocorrelation (states becoming more correlated with states on subsequent moments), and cross-correlations between the observed fluctuations. Importantly, as DIORs tap into the dynamic behavior rather than the mean state of systems, they may be more sensitive to discriminate subtle differences in the human capacity to resist and recover from health challenges than traditional health risk indicators.This talk will outline the current state-of-the-art of the development of DIORs in aging research. Challenges in the collection, analysis, and interpretation of physiologic time series data will be outlined. By highlighting applications of DIORs in related research fields like psychology and veterinary science, potential new research leads will be formulated.

    Ravi Varadhan (Johns Hopkins Univ.) - Dynamical systems approach to studying resilience in older adults

    Resilience may be defined as the ability of a system to recover from a stressor of sufficiently large magnitude that the system is pushed into a state far from its original equilibrium state, ultimately retaining essential identity and function. In this talk, we will discuss the distinction between related concepts of homeostasis, robustness, and resilience. We will describe a dynamical systems modeling approach to studying resilience, and present some examples based on the stimulus-response experiments conducted in the Women's Health and Aging Study.

    Ingrid vd Leemput (Wageningen Univ.) - Ecology for doctors: system dynamics models as a tool to understand observed behavior

    There is common ground in analysing the health state of human beings and the state of ecosystems, especially in the need to identify conditions that dispose a system to be knocked from seeming stability into another, undesired state. In ecology, relatively simple system dynamics models have proven to be valuable to understand such dynamics. Examples include lakes that unexpectedly shift from a clear to a turbid state, or coral reefs that are suddenly overgrown by macroalgae. In this talk, I will introduce you to the world of dynamical models, and provide examples how they have proven their value in ecology. Based on that, I will discuss assumptions, benefits and limitations. Then, I will explain how the analysis of bifurcations has led to the development of Dynamic Indicators of Resilience (DIORs). Finally, I will make a bridge from ecology to health, and point to some open questions in relation to DIORs, networks, and oscillating dynamics.

    Dervis Can Vural (Univ. Notre Dame) - Emergence of Aging in Natural and Synthetic Multicellular Structures

    1. Evolution of interdependence. Neutral constructive evolution ties genes/cells/tissues/organisms together. A random walk in the space of networks leads to the most likely arrangement: random networks.
    2. Statistics of catastrophes in interdependent systems: Gompertz law, dynamics that are qualitatively independent of network structure and model details.
    3. Aging in synthetic tissues. Cells die at a slower rate when allowed to exchange goodies. Intercellular interactions are more important than chronological age or damage agents. Failures propagates from outwards in. Edges and boundaries are more susceptible to failure.
    4. Failure as a microscope: Failure times can be used to infer the structure of interdependence networks.

    Many simple organisms such as ferns, hydra or jellyfish do not age. Their mortality rates remain approximately constant at all ages. In contrast, complex organisms typically have a probability of death m(t) that increases with age, t. Furthermore, the functional form of m(t) for many different organisms show a remarkable degree of similarity. The difference between simple and complex organisms, and the universality of aging patterns among complex organisms strongly suggest that aging is an emergent phenomenon that depends not on the individual properties of biological building blocks,but rather, on the interactions between them. Indeed, we die not because we slowly run out of live cells, but because of systemic failures that manifest in complex organs. In this talk I will present a quantitative theory of aging based on evolutionary and mechanical arguments, and show how aging appears as an emergent phenomenon as one moves across the scale of complexity, from large molecules and cells, to tissues and organs. I will particularly focus on aging in synthetic tissues, since this is the simplest structure that admits controlled experimental observation of emergent systemic damage. I will end my talk by showing how failure can be used as a "microscope". Specifically, how failure times can inform us about the structure of the interdependence network.

    Alfons Hoekstra (Univ. Amsterdam) - Multiscale modeling to help making sense of dynamical multiscale resilience

    A generic approach towards multiscale modelling will be introduced, together with examples from modelling complex multiscale physiological processes. Next, based on an admittedly shallow literature review, a possible extension of this methodology towards modelling dynamical multiscale resilience will be proposed. Finally, challenges in mapping these concepts to Dynamic Multi-System Resilience in Human Aging will be discussed.

    Warren C. Ladiges (Univ. Washington) - Physical resilience is a predictor of healthy aging in mice

    Physical resilience is the ability of an organism to respond to physical stress, and can be measured with various types of stress tests. The loss of resilience occurs earlier than the development of frailty. Thus, loss of resilience may result in age-related frailty. When measuring overall resilience, integrative responses involving multiple tissues, organs, and activities are desirable, so as to inform about the overall health status of the animal. Therefore, it is more likely that a battery of stress tests, rather than a single all-encompassing one, will be more informative. An ideal battery of tests should have enough dynamic range in the response to allow characterization of an individual in easily distinguishable groups as being resilient or non-resilient. Based on features of duplication as well as translational relevance, we have selected a number of stressors to investigate including the chemotherapeutic drug cyclophosphamide, sleep deprivation, wheel running, high fat diet, and pneumococcal vaccine. All stressors have quantifiable readouts, and we are showing that an age-dependent response of each individual stressor aligns with systemic physiological and geropathological  measurements. For example, the neutrophil rebound response to cyclophosphamide decreases with increasing age, and young high-responder mice have better physiological performance and less disease at middle age than young low-responder mice. We are finding similar profiles for the other stressors, and will soon begin panel testing to determine if a battery approach provides a more robust prediction of resilience to aging in mice.  We also are investigating the ability of individual stressors to measure resilience as an endpoint to anti-aging drugs. These preclinical mouse studies are aimed at development of resilience as a translational aging signature to not only predict healthy aging, but validate drug responses in middle age and geriatric populations.

    Heather Whitson (Duke Univ.) - Resilience and vulnerability in a stressed system: an example from the wards

    This talk will begin with a narrative presentation of a real-world case, taken from Dr. Whitson’s clinical practice.  The case example is offered as a “springboard” to explore the value and limitations of a model whereby the hospitalized patient is conceptualized as a complex dynamical system under duress.  Considering the case through the lens of complexity science, we will discuss potential approaches to predict and promote physical resilience to health stressors.  How should our knowledge of complex systems inform medical decision-making and how do we translate what we know into practical clinical tools?  In the second half of the talk, Dr. Whitson will present conceptual frameworks to guide clinical research on the emerging construct of physical resilience to health stressors.  The talk will also introduce two test paradigms currently under study as potential predictors of physical resilience: stimulus-response tests, and complexity-based tests on physiological output data.

    Porter Swentzell (Institute of American Indian Arts) - Resilience in New Mexico’s Indigenous Communities

    This presentation focuses on the Indigenous Pueblo nations of New Mexico. In particular, the focus is on resilience among Tewa-speaking Pueblo communities of northern New Mexico. Pueblo peoples have managed to find creative ways to survive and thrive as sedentary agriculturalists for thousands of years in the high desert environment of the southwestern United States. Through the impositions of various waves of colonialism, Pueblo people have relied on their axiologies to maintain strong linguistic and cultural traditions in the communities they have lived in for centuries. The Pueblo approach to resilience serves as an example for peoples in New Mexico and perhaps around the world.

    Chhanda Dutta (NIH) - Studies of Resiliencies to Physiologic Stressors: Need for Multilevel and Life Course Approaches

    Age-related declines in resiliencies can contribute to a variety of adverse health and functional outcomes in later life.  Consequently, it can be more difficult for an older person to recover from acute illnesses or injuries which are otherwise efficiently resolved or overcome by younger individuals.  For the purposes of this discussion, resilience is defined as a dynamic property which enables cells, organs, organisms or individuals to resist or recover from the effects of a physiologic/physical stressor.  To gain meaningful insight into the various aspects of aging changes in resiliencies to physical stressors, such as the diversity of resilient phenotypes, the underlying protective factors which preserve resilience with aging (or conversely risk factors that contribute to vulnerabilities) and the trajectories of change in these factors with age, it will be important for studies to incorporate multilevel and life course approaches.

    Regarding multilevel examinations, examples of clinical assessments which can be leveraged as dynamic measures of resiliencies spanning the whole-body to physiological systems include perturbation tests of balance, assessments of cognitive processing speed following chemotherapy, methacholine tests and tilt-table testing.  Yet, the current lack of standardized research tools to probe resiliencies at the cellular level is a major methodological hurdle to research on resiliencies and aging.  A crucial feature of such assays will be the ability to quantitatively assess cellular resilience in a person-specific manner. To this end, the literature contains examples of in vitro tests which may be adapted and validated for cellular resiliencies, such as assays of DNA repair capacity to predict sensitivity to chemotherapeutic agents, immune profiling methods to predict recovery post hip replacement, and scratch wound migration assays to predict recovery from surgical procedures.  Commonly used in vitro tests of cellular stress responses in biology of aging research (e.g., resistance to oxidative stress, inflammatory cytokine production, activation of anti-apoptotic pathways) may also serve as a basis for the development of standardized assays. Once available, these standardized tests of cellular resilience could be further translated into a novel class of personalized in vitro clinical diagnostics. 

    Moreover, insight into changes in resiliencies across the human lifespan (a gerontological perspective) could reveal aging mechanisms underlying decrements, as well as factors contributing to the maintenance of resilient phenotypes as we age.  Data from the field of regenerative medicine suggest that there may be intrinsic factors present during postnatal growth and development which confer greater resiliency in juveniles compared to adults. Specifically, data generated in various animal models indicate that juvenile organisms possess more robust defense mechanisms and more efficient repair mechanisms (though it is acknowledged that immaturity can also be associated with increased vulnerability).  In summary, the characterization of different resilient phenotypes and elucidation of age-related changes in resiliencies to specific stressors and the underlying mechanisms (cellular resiliencies) at different stages of the life span could create new translational research opportunities for the development of novel, targeted interventions to preserve and/or enhance resiliency and for promoting healthy aging in humans.    

    Post-meeting Summary by Organizer

    Coming soon.

    Additional Post-meeting Summary by Organizer


    Post-meeting Reflection by Presenter

    Marcel G.M. Olde Rikkert (Radboud Univ.) - Welcome & introduction around the Room Link to the source page

    I was amazed by the alternative vision of Dervis Can Vural about damage accumulation and aging in random network perspective. Among others it again helped me realize that downstream targeted therapies in chronic age related diseases (which mostly are directed by mechanisms of aging) probably are not to be of great help. The connections of nodes higher upstream, still being damaged or producing damage will still end up in causing the disease related decline.

    The presentation of Peter Hofmman showed an elegant 'simple model' of stochastic damage accumulation and repair. It opened the perspective of ramdoness in resilience mechanisms, when the redundancy of reserve function has depleted. The three trajectories of damage and death occurence are very interesting, and I look very much forward to the statistical analyses of these data, after repeated runs of these models.

    The talk of Alfons Hoekstra, showed that the multiscale modeling is fit for supporting resilience research and so is fit for being part of the workshop (though he humbly stated that multiscale modeling might not be mature enough for this challenge). The examples Alfons showed in the time -space scaling diagrammes and the connecting interactions do inspire to connect and likewise model subsystems depending on one another and creating a meaningful representation of challenges for aging persons.

    Ravi Varadhan and Chhandi Dutta gave an excellent overview of the research grants given in the field by the NIA, and the models already published, respectively. These are excellent sources of comparison for further work.

    Second day, we had a very inspiring lecture of Ingrid vd Leemput. The theoretical and empirical reasoning and analyses of ecosystems can be of great help in studying resilience systems in aging man.

    Heather Whitson followed up with a nice clinical example. But not only the patient but also the family and physicians make up a complex adaptive system. She also paved the way to stress tests of different kinds, which was completed later on nicely by Warren Ladiges on animal models. This connection added new insights and clearly showed that beside computational models, the animal models are very valuable.

    Last but not least Porter Swetsell gave eye openers on population resilience based on his scholarly and personal experiences with pueblo population resilience over time. These all got intertwined in the group discussion, which also opened up new opportunities for collaboration.

    The meeting so far showed emergence of many new options, and warrants, inspires aand invites for further interaction and collaboration.

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    Tim Buchman (Emory Univ./SFI) - Welcome & introduction around the Room Link to the source page

    An excellent first day. We heard theory-based perspectives and came directly upon the challenges of human subjects research. The theory based perspectives from Dervis Vural, Peter Hoffmann, and Alfons Hoekstra illustrated the (relative) simplicity of models that effectively abstract and recapitulate several well-recognized characteristics of human aging and frailty. Yet human-derived data are messy, do not lend themselves easily to hypothesis testing because they are so often observational and incomplete, and are confounded by the outbred nature of humans, their varying allostatic loads, and the variety of acute-on-chronic illnesses that bring them to research studies and/or clinical care.

    The most interesting part of the second day, perhaps, was the presentation on resiliency among the indigenous peoples of NM. It became quite clear that the ability to (re)generate networks and interactions was foundational to regenerating the population. A reasonable inference , and mirroring Dervis Vural's presentation on Day 1, is that the capacity to reconstruct networks is foundational to resilience. It is unclear whether it is the ability to reconstruct some evolutionarily specified or developmental network is required, or rather a more general capacity. But "fixing a failed node" is unlikely to work unless that failed node is the foundational "network spawner".

    The need for a marker that reliably informs clinicians that the capacity to recover from perturbation is now (and forever) exhausted is apparent. The problem around end of life is acknowledging that it is indeed end-of-life, that the physiological derangement exceeds reparative capacity, with or without the stabilization that clinicians can provide. As technical medicine gets better at dealing with minutiae, such markers of inevitable collapse become even more important. As a reminder, 27% of the US Medicare budget is routinely spent in the last year of life, with a substantial uptick in the last month as part of the "rescue phantasy" to use Freud's term. "slowing" and delayed correction of spontaneous or engineered perurbations is a start, but seems by itself insufficient as a basis for clinical decision making.

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    Sanne Gijzel (Radboud Univ.) - Developing dynamical indicators of resilience based on physiologic time series in older adult Link to the source page

    During the first day, although the talks were very different, they very nicely complemented each other. It is amazing to see that we are all adopting slightly different approaches to investigating resilience in human aging but that they can all be placed in the larger framework of resilience of complex dynamical systems. We are all pioneering in this area and only sharing our struggles and recent insights was already very valuable, at least in my experience.

    During the second day, I began seeing that we are working along 2 parallel lines:

    1. Finding ways to quantify resilience / resiliencies
    2. Increasing our understanding of the dynamics of the complex system in terms of resilience

    Some reflections:

    - I liked Alfons' idea of making real-life examples of "Resilience is ........" in the form of a short narrative / artwork / graphical illustration / equations. I agree that these can be very helpful to increase our understanding of resilience and involve more people (e.g. clinicians) in the resilience thinking and discourse.

    - Marcel commented that for humans, it's clear that there are alternative stable states in health, but we do not know what are the precise perturbations and positive feedbacks causing the transition. To increase our understanding about this, I think we need to start with making mechanistic models. We can use these mechanistic models to generate new hypotheses.

    - Ingrid pointed out the difference between acute stressors (perturbations, e.g. a stimulus-response test) and slow stressors (drivers, e.g. aging).

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    Ingrid vd Leemput (Wageningen Univ.) - Ecology for doctors: system dynamics models as a tool to understand observed behavior Link to the source page

    The workshop was a good mix of theoretical and practical insights on resilience in human aging. I see a lot of parallels with the work we do on ecological resilience, and I think we could learn a lot from each other. One of the things I noticed is the different definitions of resilience used (and other semantics), which may become confusing. It would be good to make an overview of the different definitions, and to not invent new words for the same concept.

    To really get a proper understanding, and to develop well-grounded indicators of the system dynamics and resilience, a combination of the different presented methods would make a lot of sense. This ideal path in my opinion would be 1) for each 'sub-system', to develop a solid idea of the large-scale feedbacks and dynamics, and develop a mechanistic model based on that, taking into account temporal and spatial scale. This should lead to some idea on the stability, and dynamics of the particular sub-system: is the sub-system expected to have alternative stable states/ tipping points/ oscillating dynamics/ chaos/ flickering/ spiraling? 2) This basic understanding should lead to hypotheses on what type of indicators of resilience could be useful and realistic (e.g. perform stress tests, measure DIORs, potential analysis etc) 3) These hypotheses should be tested both in the field, and in more realistic, fully parameterized models, as presented by Alfons Hoekstra.

    I enjoyed the talk by Porter a lot. On one hand, it touched me personally, to see how resilience these communities can be after so much suffering, but also it reminded to think about what makes a system more resilient? We talked about feedbacks a lot, but not so much about other relevant factors, such as functional redundancy, response diversity, and connectivity. A vary obvious example of functional redundancy is, I think, the two kidneys a human being has (you can survive without one).

    In my opinion, the mouse models, while a mouse is not a human being, can be extremely useful to get a grip on the coupling between subsystems, and the way we could approach the resilience questions in human beings.

    The last discussion was interesting, because Sanne Gijzel pointed to an example case, in which several sub-systems failed in a row. I think we can learn a lot from these type of examples (also the example of Heather Whitson) about the coupling between subsystems.

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    Dervis Can Vural (Univ. Notre Dame) - Emergence of Aging in Natural and Synthetic Multicellular Structures Link to the source page

    Noteworthy concepts and questions:

    1. Ravi: "Gerontropy". In additional to directional changes in health indicators do we get an increase in variance?
    2. Alfons: Multiscale approaches. Do multiple length and time scales really matter when they are separated? Can interdependence network approach be improved to take into account hierarchical structures of organs/tissues/cells/molecules?
    3. Ravi, Chhanda: How can theorists make themselves useful for NIH? How to communicate "theoretically driven" projects to NIH?
    4. Chhanda: Resilience builds up over time. Effect of early life history on aging. Comparative biology approaches e.g. naked mole rat
    5. Ravi, Chhanda: Very interesting plasticity effect: Physiological state does not come back exactly to the same point after perturbation. A theoretical description of physiological elasticity vs. plasticity
    6. Ingrid: Idea on multiple tipping points that are coupled. I recommend checking out Kramer's escape problem. Chhanda excellent question: Are young ecosystems more resilient, just like young people. Alfons had an excellent question: what can you say about the dynamics by knowing only qualitative causal relationships. An idea: if there are multiple models describing the same subsystems and their interactions, can these be combined/reconciled to get a result more accurate than all models individually?
    7. Peter: Potentially useful model but one should be careful about drawing conclusions from single runs. e.g. Flipping coins would also yield similar ups and downs if one looked at individual runs. It would be good to check if the model gives Gompertz (exponential) mortality curves or Weibull. I would also have critical questions about sensitivity to parameters and system size, i.e. if the damage rate was close to repair rate I suspect that the system would never collapse (given large system size).
    8. Heather. Very interesting conceptual graph derived from a real patient where multiple systems failing at different times at different rates. This resonates with Chhanda's observation that resilience is not one thing, but a multi-dimensional vector.
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    Heather Whitson (Duke Univ.) - Resilience and vulnerability in a stressed system: an example from the wards Link to the source page

    As a clinician, it resonated with me to hear Dr. Vural describe that in his models, sometimes "strategic repair" may be necessary in order to re-stabilize a complex system that is progressing toward critical decay (but has not yet reached the critical point). I like the notion that success or failure of the whole system could depend on the order of which nodes are repaired first. I am often faced with the clinical challenge of multi-organ failure and often an intervention that would benefit one organ system might put another at risk, so it is hard to know what sub-system to prioritize. If we could understand the human system better and it could guide "strategic repair," this could have real clinical utility.

    It also resonated with me to hear Dr. Hoekstra's description of a similar stressor resulting in vastly different outcomes in his model systems. If there are feature of the system BEFORE or JUST AFTER the stressor that reliably indicate which outcome is going to occur, that would be very useful for prognostication and for making treatment decisions.

    Dr. Gijzel's descriptions of data management challenges when dealing with time series human data was helpful (and also cathartic, because I deal with the same challenges). The tension about whether analytical decisions should be guided by conceptual framework and clinical judgment, as opposed to empirical decisions, was something I recognized.

    I feel more strongly that the field will benefit from semantic harmonization and precise terminology.

    My perspective has changed in that I will be more attentive to opportunities to study resilience changes across the lifespan. I learned about childhood metabolic changes I was not aware of. I learned a new parameter for characterizing temporal autocorrelation across varying lag times.

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    Ravi Varadhan (Johns Hopkins Univ.) - Dynamical systems approach to studying resilience in older adults Link to the source page

    Alfonse Hoekstra's discussion of multiscale resilience was fascinating to me. The network simulation models of Dervis and Peter Hoffman were very interesting and provide useful insights, but to mimic the complexity of human physiology, we would need hierarchically structured networks. I wonder if there are some invariance principles in multi-scale resilience that could reduce the degree of complexity of this type of modeling. The principles and results of hierarchy theory could be relevant here.

    Sanne's talk on DIORs (dynamic indicators of resilience) was also quite interesting. There are several open questions here: how to model temporal autocorrelation; how to handle non-stationary time series; how to do systems identification with DIORs, i.e. how can we predict responses of frail/nonfrail using estimates of DIORs. I also think the idea of reactive tuning to stimulus can be examined using novel metrics of DIORs. I would be interested in exploring these ideas in my work!

    The second day's talks were also very interesting. Heather's case history was captivating, highlighting the challenges of treating a human being as a complex physiological system. I liked her point that we need to observe and let the system tell us what needs to be done. Ingrid's talk was very informative on the modeling of complex ecological systems. Porter's talk on the resilience of the Pueblo Indian nation to colonization was very educational for me. I can relate to my own Hindu/Indian culture's resilience in having survived several invasions and colonization over the centuries. The idea of axiology, the systems of values which provide the core resilience to a culture, was most interesting. Warren presented some exquisite data on mouse resilience. To me, tlis hehighlighted the huge potential of using mouse models to develop a comprehensive modeling framework for resilience.

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    Peter M. Hoffmann (Wayne State Univ.) - Conceptual models of human aging and resilience Link to the source page

    I was concerned that “high-level” models would not be useful in this context, but that turned out not to be the case. It was fascinating to see how actual physiological data can potentially be analyzed and understood in the context of metastable states, complexity, networks, critical states, 1/f noise etc. A full understanding how these things connect and how they relate to real data is still in its infancy, which should make this an exciting area to think about.

    The goal will be to "marry" conceptual models and data collected from real systems. How can conceptual models capture stress and perturbation responses, time scales, tipping points & attractors, feedback loops, variability, noise and complexity seen in real systems? Conceptual models should be helpful if we want to learn what measured signals (transient, noise etc.) can tell us about the structure and dynamic state of the underlying system.

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    Warren C. Ladiges (Univ. Washington) - Physical resilience is a predictor of healthy aging in mice Link to the source page

    The talks today brought out insight into the theory of resilience, based on historical concepts of aging. The focus was on connecting these concepts to human clinical conditions, and how to measure resilience based on response to artificial as well ass naturl sressors

    Several specific questions are of interest. The concept of protective factors was presented but how these protctive factorws would actually be measured is of great interest. A second question is the challenge of how to define the variation that would separate out resilience snd nonresilience. A third question is hwo to address the epigencitc impact that environemtn might have on resilience, or lack of resilience.

    The multiscale modeling concept is of interest to apply to mouse studies, since it could enable preliminary study data with a more structured format that would provide more translational impact. It would be especially of interest to pursue multiscale sublevel interactions in relation to data already generated to see if future effort would be productive.

    One of the points of the second day was the global view of social networks and how interactions and connections could be viewed as resilience models. In addition, clinical and preclinical presentations were made that showed ways of aligning more naturally occurring stressors with stress situations at the population or ecosystem levels. An indepth discussion on how to develop markers of resilience in humans was very productive, but uncertain what the next steps will be. More discussion after my talk on mouse modeling was informative as to the potential of applying specific stressors to predict resilience to aging in mice to clinical situations. Dual tasks assessments in people are currently being done to determine risk for such things as Alzheimers dementia, and other age related conditions. A focus should be to to connect these with other healthy aging paramters to determine variation and risk for developing age-related conditions.

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    Porter Swentzell (Institute of American Indian Arts) - Resilience in New Mexico’s Indigenous Communities Link to the source page

    There was fascinating information presented during the first day. My background is not in the field of geriatrics or human aging so I learned a great deal during the course of the day. I was particularly interested in systems theory and its connection with aging and stress factors. This information resonated strongly with my own thoughts regarding human societies and cultures through time. My own interest is in social systems and I wonder what these findings mean for aging within these systems. How do specific social systems promote or degrade resiliency? What is the role of culture in the study of human aging? How often are cultural differences considered in bio-medical studies of aging?

    The presentations during the second day gave some practical insights into resilience. The presentation of ecological models by Ingrid Leemput were useful analogues in thinking about human aging and resilience. I cannot help but think about how human experiences are often extracted out of ecology and perhaps vice versa. How do perturbances in our environments impact human resilience in multiple ways? Heather Whitson's real-life example resonated with many of my own experiences and made the idea of resilience much more visceral. I appreciated the discussion of mice aging in comparison with human aging. Overall, lots of food for thought.

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    Chhanda Dutta (NIH) - Studies of Resiliencies to Physiologic Stressors: Need for Multilevel and Life Course Approaches Link to the source page

    The first day consisted of an excellent range of thought provoking presentations. An important issue which was raised was the need for further discussion on the usage of words such as robustness since it may have been used in slightly different contexts by different speakers. Also the group discussions seemed to focus on the characterization of resilient vs. non-resilient (vulnerable) individuals. There too some clarity is needed. It is likely that people will differ in their resiliencies and vulnerabilities to different stressors and display different degrees of resiliencies. Thus tests of resiliencies at any level, should consider graded tests (i.e., stressor is applied at diff intensities, magnitude, duration) so that such tests can distinguish between different degrees of resiliencies. This would be especially pertinent to assessing changes in the degree of resilience over time (e.g., longitudinal studies) and especially for the testing of potential therapies intended to improve resiliencies.

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    Post-meeting Reflection by Non-presenting Attendees

    Rene Melis (Radboud Univ.) Link to the source page

    Overall, it became clear to me how much perspectives there are from which you can study the subject of resilience and how valuable and complementary each of these perspectives is. I have identified a number of axes along which we can organize each of these perspectives to create some structure:

    - Axis 1: from Understanding resilience to Diagnosis and prediction of levels of resilience in individuals.

    - Axis 2: from Systemic to Subsystemic resilience(s) (links to spatial scale) and from longitudinal, long term trends to Short-term dynamics (links to temporal scale)

    - Axis 3: from (in silico) Modeling of theory to Empircal data collection and validation

    - Axis 4: from Between individual to Within individual differences

    From this I expect we can think of a number of initiatives we can take together:

    - Developing a measurement tool box to capture in a standardized way data we need to empirical study systemic and subsystemic resilience in human aging. This toolbox should begin to identify which core (organ) systems and physiological processes are (based on theory) involved to emerge resilience from. Then we can identify the stimulus-response test, time-series to follow (to calculate multiscale entropy and DIORs from) and crucial outcomes/function to be studied for each of the core systems involved.

    - Standardization of perturbation quantification

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    Jerrald Rector (Radboud Univ.) Link to the source page

    First day: I learned about modeling strategies that can be used to better understand potentially universal properties of damage and repair of the dynamic system. Some were compared to empirical data. Hormesis was introduced (in the context of bone health) as an important consideration in modeling resilience. Open questions included that some patterns/observations obtained from simulations remain to be explored further (e.g., three 'trajectories': die, recover/die, & recover). Still open for me is how to actually apply some of the great ideas discussed today. For example, I had already considered the life-course in outcomes in (older) adults, but still don't have a good handle on how to actually incorporate or study this in an already aged population, or if it's possible. I have some of the same questions regarding the most useful (pre-)processing of time-series data. However, the 'middle out' approach seems to be a useful way to reduce the dimensions of complexity associated with modeling.

    Second day: The extended discussion on the differences in the definition of resilience (e.g., engineering vs. ecological) and the addition of the concept of reserve further highlighted the need for standardization of definitions to make sure researchers are all on the same page. Mechanistic models and mice models show promise of better understanding the dynamics of the (aging) human, but caution is advised in trying to translate these interpretations. A case study brilliantly demonstrated that apply these concepts to 'real life' situations (e.g., patient care) requires much more thought. This was reinforced by another case that was interesting, not only from a network interaction standpoint, but also because the patient often knows their state/potential outcomes better than typical 'objective' tests.

    Particularly impactful for me was the example of resilience on a community level in the Pueblo people. I find it a wonderful model to follow for understanding what factors contribute to the resilience in other contexts.

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    Luis Amaral (Northwestern Univ.) Link to the source page

    Fascinating, multi-level, presentations and discussions.

    Some points that have come to mind for me. Concerning Dervis' model, I was thinking how having the nodes have an internal structure, that is, each node would have a network structure -- self-similar structure -- would affect the dynamics... I think such an approach would connect nicely to the other presentations concerned with the multi-scale organization of the system.

    Concerning the analysis of physiologic signals and the ability to extract different types of information, the site https://physionet.org contains a lot of useful information and may even include a community for discussion of issues (sadly, I haven't worked in this area for a while now).

    Ingrid's talk has raised many interesting questions about the different types of models and their different purposes. My thought is that we need research occurring at all types of models with the understanding that each type can contribute to the others. For example, the parametrized, complex climate/ecological models enable us to conduct computational experiments that otherwise would be impossible. However, because of the complexity of the model it is impossible to gain insight on which specific experiments to conduct. Simpler, stylized models, that could be developed and tested against the complex models, could provide the insight to select what computational experiments to conduct.

    Axiology is an extraordinarily interesting concept. Knowledge is a responsibility not a right for the Pueblo peoples. When we talk about resilience, what are the things we are valuing... Resilience of Pueblo peoples to colonial injuries: system had developed redundant relations that can prevent failure in case of injury to system.

    Porter's talk reminded me of a study of mortality in Chicago some decades ago during a particularly extreme heat wave. Tow communities with similar socio-economic, ethnic and educational characteristics had very different outcomes -- the strength of the social networks was the aspect that distinguished the communities and the one that predicted the outcomes.

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    Susan Fitzpatrick (JSMF) Link to the source page

    Notes from day 1

    In general I think we need to have the core theory group come up with terms and definitions that would be used consistently across all the working groups so words like robustness, resilience, homeostasis, energy, etc are understood to mean the same thing in different topics.

    Regarding the challenges to resilience - some recent work by Eve Marder is relevant. She has some knockouts in the crab STG that have wide molecular variability but produce the same phenotype - except under conditions of environmental variability. One of t(e conditions she looked at was temp since crabs in the wild naturally experience a range. The KOs crashed at different points - so stressors can separate out variants that would not be seen under controlled conditions.

    A question I had was differentiating homeostasis from resilience from persistence from perseverance.

    I also though it might be interesting to look at how ideas, fields, disciplines, and academic institutions age?

    I like that Dervis raised the issue of how systems break - this linked back to the Breaking Brains working group.

    I may be making a spurious connection here but the idea that you need 65 % of nodes to avoid failing reminded me that whole brain energy metabolism has to be about 65% to maintain conscious awareness.

    Peter’s talk also made me think about what cells we should be paying attention to in the brain - so much of the focus is on neurons but what do we know about the aging of the heterogeneous cells in brain tissue?

    Another challenge we have is going back and forth between general theories and empirical case studies. At some point in the future be nice to test theory with very specific case study data.

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    Reference Materials by Presenting Attendees

    Marcel G.M. Olde Rikkert (Radboud Univ.) - Welcome & introduction around the Room

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    To adapt or not to adapt: consequences of declining adaptive homeostasis and proteases with age 0 3

    Tim Buchman (Emory Univ./SFI) - Welcome & introduction around the Room

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    The community of the self3 Timothy G. Buchman Nature 2002 143 2
    The community of the self Timothy G. Buchman Nature 2002 143 4
    The community of the self2 Timothy G. Buchman Nature 2002 143 4
    Community of the Self 0 0
    Uncoupling of Biological Oscillators 0 2

    Sanne Gijzel (Radboud Univ.) - Developing dynamical indicators of resilience based on physiologic time series in older adult

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Early-warning signals for critical transitions Marten Scheffer, Jordi Bascompte, William A. Brock, Victor Brovkin, Stephen R. Carpenter, Vasilis Dakos, Hermann Held, Egbert H. Van Nes, Max Rietkerk, George Sugihara Nature 2009 1,682 16
    Dynamical Resilience Indicators in Time Series of Self-Rated Health Correspond to Frailty Levels in Older Adults Sanne M.W. Gijzel, Ingrid A. Van De Leemput, Marten Scheffer, Mattia Roppolo, Marcel G.M. Olde Rikkert, René J.F. Melis Journals of Gerontology - Series A Biological Sciences and Medical Sciences 2017 12 6
    Critical slowing down as early warning for the onset and termination of depression3 0 12

    Alfons Hoekstra (Univ. Amsterdam) - Multiscale modeling to help making sense of dynamical multiscale resilience

    Arthur Guyton's computer model of the cardiovascular system

    Hummod model, see http://hummod.org

    BioGears, see https://www.biogearsengine.com

    Dervis Can Vural (Univ. Notre Dame) - Emergence of Aging in Natural and Synthetic Multicellular Structures

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Aging in complex interdependency networks Dervis C. Vural, Greg Morrison, L. Mahadevan Physical Review E - Statistical, Nonlinear, and Soft Matter Physics 2014 15 27
    A Tissue Engineered Model of Aging: Interdependence and Cooperative Effects in Failing Tissues A. Acun, D. C. Vural, P. Zorlutuna Scientific Reports 2017 3 10
    Inferring network structure from cascades Sushrut Ghonge, Dervis Can Vural Physical Review E 2017 2 13
    Interdependence theory of tissue failure: Bulk and boundary effects Daniel Suma, Aylin Acun, Pinar Zorlutuna, Dervis Can Vural Royal Society Open Science 2018 0 17

    Heather Whitson (Duke Univ.) - Resilience and vulnerability in a stressed system: an example from the wards

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Physical resilience in older adults: Systematic review and development of an emerging construct Cathleen S. Colón-Emeric, Harvey J. Cohen, Heather E. Whitson, Kenneth E. Schmader, Miriam C. Morey, Wei Duan-Porter Journals of Gerontology - Series A Biological Sciences and Medical Sciences 2016 43 4

    Ravi Varadhan (Johns Hopkins Univ.) - Dynamical systems approach to studying resilience in older adults

    The volume by Howard Pattee entitled "Hierarchy Theory; The Challenge of Complex Systems.", which was published in 1973 could be very relevant to the work on multiscale resilience that Alfonse Hoekstra presented.

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Stimulus-response paradigm for characterizing the loss of resilience in homeostatic regulation associated with frailty3 R. Varadhan, C. L. Seplaki, Q. L. Xue, K. Bandeen-Roche, L. P. Fried Mechanisms of Ageing and Development 2008 61 4
    Hierarchy theory: the challenge of complex systems2 H.H. Pattee 1973 0 5

    Peter M. Hoffmann (Wayne State Univ.) - Conceptual models of human aging and resilience

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Reliability Theory of Aging and Longevity Leonid A. Gavrilov, Natalia S. Gavrilova Handbook of the Biology of Aging 2005 54 0
    Reliability Theory of Aging and Longevity4 Leonid A. Gavrilov, Natalia S. Gavrilova J. Theor. Biol. 2001 54 15

    Porter Swentzell (Institute of American Indian Arts) - Resilience in New Mexico’s Indigenous Communities

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Rethinking resilience from indigenous perspectives Laurence J. Kirmayer, Stéphane Dandeneau, Elizabeth Marshall, Morgan Kahentonni Phillips, Karla Jessen Williamson Canadian Journal of Psychiatry 2011 158 5
    Health beliefs and the politics of Cree well-being Naomi Adelson Health 1998 23 3
    Reference Materials by Non-presenting Attendees

    Rene Melis (Radboud Univ.) Link to the source page

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    The resilience framework as a strategy to combat stress-related disorders2 Raffael Kalisch, Dewleen G. Baker, Ulrike Basten, Marco P. Boks, George A. Bonanno, Eddie Brummelman, Andrea Chmitorz, Guillén Fernàndez, Christian J. Fiebach, Isaac Galatzer-Levy, Elbert Geuze, Sergiu Groppa, Isabella Helmreich, Talma Hendler, Erno J. Hermans, Tanja Jovanovic, Thomas Kubiak, Klaus Lieb, Beat Lutz, Marianne B. Müller, Ryan J. Murray, Caroline M. Nievergelt, Andreas Reif, Karin Roelofs, Bart P.F. Rutten, David Sander, Anita Schick, Oliver Tüscher, Ilse Van Diest, Anne Laura Van Harmelen, Ilya M. Veer, Eric Vermetten, Christiaan H. Vinkers, Tor D. Wager, Henrik Walter, Michèle Wessa, Michael Wibral, Birgit Kleim Nature Human Behaviour 2017 29 2
    The resilience framework as a strategy to combat stress-related disorders3 Raffael Kalisch, Dewleen G. Baker, Ulrike Basten, Marco P. Boks, George A. Bonanno, Eddie Brummelman, Andrea Chmitorz, Guillén Fernàndez, Christian J. Fiebach, Isaac Galatzer-Levy, Elbert Geuze, Sergiu Groppa, Isabella Helmreich, Talma Hendler, Erno J. Hermans, Tanja Jovanovic, Thomas Kubiak, Klaus Lieb, Beat Lutz, Marianne B. Müller, Ryan J. Murray, Caroline M. Nievergelt, Andreas Reif, Karin Roelofs, Bart P.F. Rutten, David Sander, Anita Schick, Oliver Tüscher, Ilse Van Diest, Anne Laura Van Harmelen, Ilya M. Veer, Eric Vermetten, Christiaan H. Vinkers, Tor D. Wager, Henrik Walter, Michèle Wessa, Michael Wibral, Birgit Kleim Nature Human Behaviour 2017 29 4
    The resilience framework as a strategy to combat stress-related disorders 0 2

    Luis Amaral (Northwestern Univ.) Link to the source page

    The Goldberger et al papers review of the Physionet resource and some of the types of analysis that we were performing in the lat 1990s. The Fukuda et al reviews a particular approach to deal with nonstationary time series.

    The Amaral et al PNAS presents a simplified network model for generating complex dynamics.

    The Amaral PNAS reviews the use cartographic representations of large, complex multilevel networks to summarize information on those network and gain insight.

    The Goyal and Maslov paper proposes a model for explaining the structure and resilience of microbial communities. The Stouffer et al papers discusses models of food web structure.

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Social embeddedness in an online weight management programme is linked to greater weight loss Julia Poncela-Casasnovas, Bonnie Spring, Daniel McClary, Arlen C. Moller, Rufaro Mukogo, Christine A. Pellegrini, Michael J. Coons, Miriam Davidson, Satyam Mukherjee, Luis A.Nunes Amaral Journal of the Royal Society Interface 2015 14 0
    Diversity, Stability, and Reproducibility in Stochastically Assembled Microbial Ecosystems Akshit Goyal, Sergei Maslov Physical Review Letters 2018 5 0
    A truer measure of our ignorance 0 4
    PhysioBank, PhysioToolkit, and PhysioNet : Components of a New Research Resource for Complex Physiologic Signals 0 11
    Fractal dynamics in physiology: Alterations with disease and aging 0 6
    Heuristic segmentation of a nonstationary time series 0 0
    Emergence of complex dynamics in a simple model of signaling networks 0 2
    A robust measure of food web intervality 0 2

    Susan Fitzpatrick (JSMF) Link to the source page

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Asking the Right Questions in Alzheimer’s Research Susan Fitzpatrick Issues in Science and Technology 2018 0 0

    General Meeting Reference Material

    Title Author name Source name Year Citation count From Scopus. Refreshed every 5 days. Page views Related file
    Uncoupling of biological oscillators: A complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome Paul J. Godin, Timothy G. Buchman Critical Care Medicine 1996 274 9
    Physical Resilience: Not Simply the Opposite of Frailty Heather E. Whitson, Harvey J. Cohen, Kenneth E. Schmader, Miriam C. Morey, George Kuchel, Cathleen S. Colon-Emeric Journal of the American Geriatrics Society 2018 3 10
    Resilience Versus Robustness in Aging Svetlana Ukraintseva, Anatoliy I. Yashin, Konstantin G. Arbeev 2016 0 1
    Dynamical indicators of resilience in postural balance time series are related to successful aging in high-functioning older adults 0 3
    Critical slowing down as early warning for the onset and termination of depression4 0 2
    Quantifying Systemic resilience of humans and other animals Marten Scheffer, J. Elizabeth Bolhuis, Denny Borsboom, Timothy G. Buchman, Sanne M. W. Gijzel, Dave Goulson, Jan E. Kammenga, Bas Kemp, Ingrid A van de Leemput, Simon A. Levin, Carmel Mary Martin, René J F Melis, Egbert H. van Nes, L. Michael Romero, Marcel G M Olde Rikkert 2018 0 4

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