Abstracts of talks alphabetic order) · phenomenon. I will focus on kinetically constrained systems as basic models for glasses and will also describe methods based on the theory

Abstracts of talks (in alphabetic order)

International Conference: Biological Aging 16.-20.04.2018 Jacobs University Bremen

Page 2 of 36

Cost and precision in stochastic thermodynamics

Andre Cardoso Barato

Max‐Planck Institut für die Physik komplexer Systeme

Stochastic Thermodynamics is a theoretical framework under development that generalizes standard thermodynamics to systems that can be small and far from equilibrium. Examples of such systems are biological molecules like molecular motors, artificial molecular pumps, colloidal particles, and small electronic systems. The main result of the field is the fluctuation theorem, which is a symmetry on the probability distribution of a fluctuating entropy that implies the second law. In this talk, we discuss the main concepts of stochastic thermodynamics and introduce some of our findings on the relation

between energetic cost and precision. In particular, the novel thermodynamic uncertainty relation establishes a universal minimal energetic cost of precision associated with a quantity like the output of chemical reaction (or any other generic thermodynamic flux). In simple words, an uncertainty of 1% associated with such quantity hasa minimal universal cost of 20.000 k_BT. Other key contributions that will be presented in this talk are:possible applications of this thermodynamic uncertainty relation, bounds on current fluctuations,the relation between cost and precision in periodically driven systems, and a bound on the number of coherent oscillations in biochemical systems.


Page 3 of 36

Talk 1:

Basics of slow relaxation, glasses and kinetically constrained dynamics

Juan Garrahan

School of Physics and Astronomy, University of Nottingham

Glass formers ‐ such as supercooled liquids and dense colloids ‐ are the paradigm in physical sciences of systems displaying slow complex relaxation and eventual dynamical arrest. I will describe the basic phenomenology of these systems and the key questions of what we call the glass transition problem. I will discuss theoretical perspectives, in particular those that see the glass transition as a fundamentally dynamical (as opposed to thermodynamical) phenomenon. I will focus on kinetically constrained systems as basic models for glasses and will also describe methods based on the theory of large deviations that are particularly suited to study systems where the complexity lies in their dynamics rather than in their statics.

Talk 2:

Fluctuation properties of counting observables and their first passage times in stochastic systems

Juan Garrahan

School of Physics and Astronomy, University of Nottingham

I will extend recent ideas and results about general lower bounds to the fluctuations of currents in non‐equilibrium systems ‐ such as so‐called thermodynamic uncertainty relations ‐ to counting observables, that is, dynamical observables that are time‐symmetric and strictly non‐decreasing in time. I will discuss how these ideas and results ‐ obtained via dynamical large deviation methods ‐ can be further extended to consider the fluctuations of first passage times.


Page 4 of 36

Stochastic Thermodynamics of Learning

Sebastian Goldt

Institut de Physique Théorique, Université Paris‐Saclay

Unravelling the physical limits of information processing is an important goal of non‐equilibrium statistical physics. It is motivated by the search for fundamental limits of computation, such as Landauer's bound on the minimal work required to erase one bit of information. Further inspiration comes from biology, where we would like to understand what makes single cells or the human brain so (energy‐)efficient at processing information. In this talk, we analyse the thermodynamic efficiency of learning. We first discuss the interplay of information processing and dissipation from the perspective of stochastic thermodynamics. We then show that the dissipation of any physical system, e.g. a neural network, bounds the information that it can infer from data or learn from a teacher. We discuss a number of examples along the way and outline directions for future research.


Page 5 of 36

Talk 1:

Actin 101: An Introduction to the actin cytoskeleton, its properties and its decline during ageing

Campbell Gourlay

School of Biosciences, University of Kent

Actin is an essential protein that has played a crucial role in the elaboration of cell shape and function during the diversification of life. Its controlled assembly into dynamic filament systems has seen actin incorporated into the functionality of almost every cellular compartment. Efficient actin assembly is however a process that requires energy and the maintenance of a healthy cellular environment. In this session I will introduce the actin filament system, its physical properties and functionality and describe how the cytoskeleton becomes corrupted during the process of cell ageing.

Talk 2:

Killer Actin

Campbell Gourlay

School of Biosciences, University of Kent

Actin filaments are highly dynamic and must assemble and disassemble in response to specific cellular cues. A failure to regulate actin in this way is observed as cells age, leading to inappropriate behaviour and cell death. Actin dysfunction is therefore linked to a variety of disease states, including many that emerge as we age. To determine how actin dysfunction affects cells during the ageing process we have made use of the simple eukaryotic cell model Saccharomyces cerevisiae, a yeast commonly used to make bear, wine and bread. S. cerevisiae contains a fully functional actin network that underpins cell function but which becomes corrupted as the organism ages. Yeast are an attractive model for this work as they contain a single actin encoding gene and are easy to manipulate. Our research indicates that a loss of control of the dynamic properties of actin filaments leads to a failure of cells to regulate signaling networks that are essential for cell health and viability, a so‐called loss of homeostasis. Similar findings in higher eukaryotes indicate that a loss of control of actin also leads to a loss of homeostasis that may contribute to a number of age related diseases. Our findings indicate that corruption of the actin filament network may play an important role in the process of ageing.


Page 6 of 36

Systems Biology of single‐cell aging ‐ Periodic silencing dynamics control cell

aging

Nan Hao

UC San Diego Section of Molecular Biology, Division of Biological Sciences, UCSD

Program of Bioinformatics and Systems Biology, UCSD, BioCircuits Institute, UCSD

Abstract: Cellular aging is a universal biological phenomenon, but the mechanisms remain largely unclear. There has been steady progress in identifying aging‐related factors such as reactive oxygen species and genomic instability, yet an emerging challenge is to reconcile the contributions of these factors with the fact that genetically identical cells can age at significantly different rates. Such complexity requires single‐cell analyses designed to unravel the interplay of aging dynamics and cell‐to‐cell variability. Here we use microfluidic technologies to track the replicative aging of single yeast cells and reveal that the temporal patterns of heterochromatin silencing loss regulate cellular life span. We found that cells show periodic waves of silencing loss in the heterochromatic ribosomal DNA during the early phases of aging, followed by sustained loss of silencing preceding cell death. Isogenic cells have different lengths of the early intermittent silencing phase that largely determine their final life spans. We found that the intermittent silencing dynamics is important for longevity and is dependent on the conserved Sir2 deacetylase, whereas either sustained silencing or sustained loss of silencing shortens life span. These findings reveal that the temporal patterns of a key molecular process can directly influence cellular aging, and thus could provide guidance for the design of temporally controlled strategies to extend life span.


Page 7 of 36

Talk1:

Ageing as a consequence of evolutionary adaptation

Henrik Jeldtoft Jensen

Imperial College, London, South Kensington Campus, SW7 2AZ, UK

Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan

The individual based Tangled Nature model of evolutionary ecology (see e.g. [1, 2, 3]) is discussed with an emphasis on how the adaptation to the co‐evolutionary selection pressure changes the systemic properties of the ecosystems. We will e.g. discuss how two dynamical trends evolve in parallel: the strongly occupied types become more correlated while the system as a whole de‐correlates[4] and how the balance between bottom‐up and top‐down information ow change with the age of the system [5].

References: [1] H..J. Jensen and E. Arcaute. Complexity, collective e_ects and modelling of ecosystems: formation, function and stability. [2] Nikolaj Becker and Paolo Sibani. Evolution and non‐equilibrium physics: A study of the tangled nature model. EPL (Europhysics Letters), 105(1):18005, 2014. [3] Kim Christensen, Simone A. di Collobiano, Matt Hall, and Henrik J. Jensen. Tangled nature: A model of evolutionary ecology. J. Theor. Biol., 216:73{84, 2002. [4] H.J. Jensen D. Jones and P. Sibani. Mutual information in the tangled nature model. Ecological Modelling, 221:400{404, 2010. [5] Katharina Brinck and Henrik Jeldtoft Jensen. Bottom‐up versus top‐down control and the transfer of information in complex model ecosystems. Submitted to J Theo. Bio.


Page 8 of 36

Talk2:

Universal features of Ageing through Record Dynamics

Henrik Jeldtoft Jensen

Imperial College, London, South Kensington Campus, SW7 2AZ, UK

Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan

The statistics of records do not depend on the underlying probability distribution as long as independence can be assumed. We will discuss how this may explain a remarkable lack of temperature dependence of the magnetic relaxation rate in superconductors[1, 2] and also suggest that the Omori after shock law for earthquakes may be related. To illustrate interesting open questions we look at logarithmic time dependence of the on‐set of synchronisation and as an example that may not be caused by record dynamics[3].

References: [1] P.E. Anderson, H.J. Jensen, L.P. Oliveria, and P. Sibani. Evolution in complex systems. Complexity, 10:49{56, 2004. [2] L.P. Oliveira, H.J. Jensen, M. Nicodemi, and P. Sibani. Record dynamics and the observed temperature plateau in the magnetic creep rate of type ii superconductors. Phys. Rev. B., 71:104526, 2005. [3] G. Benkoe and H.J. Jensen. Logarithmically slow onset of synchronisation. J. Phys. A: Math. Theor., 43:165102, 2010.


Page 9 of 36

Induction of cellular senescence under various stress conditions

Feng Liu

Institute of Biophysics, Nanjing University, China

We explore the dynamic mechanisms for induction of cellular senescence upon stress signals. On one hand, telomeres are specialized structures protecting chromosomes against genome instability; telomeres shorten with cell division, and replicative senescence is induced when telomeres are badly eroded. We proposed an integrated model associating telomere loss with senescence trigger, and characterized the dynamics of telomere shorting and the p53‐centered regulatory network. We show that senescence is initiated in a switch‐like manner when both the shortest telomere becomes uncapped and the TRF2‐ATM‐p53‐Siah1 positive feedback loop is switched on. On the other hand, when cells are subject to DNA damage, hypoxia, glucose starvations or activation of oncogenes, normal cells may undergo cell‐cycle arrest, senescence or apoptosis, depending on the severity of stress signals. For each of the above signals, we built distinct models of cellular signaling pathways and associated the system dynamics with cellular output. We elucidated how different cell fates are triggered and maintained and how p53 and p21 play a critical role in inducing cellular senescence.

References: Q.‐H. Zhang, X.‐J. Tian, F. Liu* and W. Wang* (2014). A switch‐like dynamic mechanism for the initiation of replicative senescence. FEBS Lett. 588, 4369‐4374. X. Tian, B. Huang, X.‐P. Zhang, M. Lu, F. Liu*, J.N. Onuchic* and W. Wang* (2017) Modeling the response of a tumor‐suppressive network to mitogenic and oncogenic signals. Proc. Natl. Acad. Sci. USA 114, 5337‐5342.


Page 10 of 36

Unified thermodynamic uncertainty relations in linear response

Katarzyna Macieszczak

Cavendish Laboratory, University of Cambridge

Thermodynamic uncertainty relations (TURs) refer to recently established relations between the relative uncertainty of time‐integrated currents and entropy production in non‐equilibrium systems. For small perturbations away from equilibrium, linear response (LR) theory provides the natural framework to study generic non‐equilibrium processes. Here we use LR to derive TURs in a straightforward and unified way. Our approach allows to generalise TURs to systems without local time‐reversal symmetry, including for example scattering transport, and periodically‐driven classical and quantum systems. We find that for the case of broken time‐reversal, the bounds on the relative uncertainty are controlled both by dissipation and by a parameter encoding the asymmetry of the Onsager matrix.


Page 11 of 36

On the fate of dynamical systems under a trade‐off between costs and precision

Maximilian Voit and Hildegard Meyer‐Ortmanns

Physics and Earth Sciences, Jacobs University Bremen, P.O.Box 750561, 28725 Bremen, Germany

We consider a toy model for analyzing the influence of a fundamental trade‐off between costs and precision on the dynamical performance of a system. An essential characteristic of the dynamics is a repetitive process that should run at high precision, here chosen as an iterated reproduction of a bitstring. The trade‐off is implemented implicitly by assuming that the reproduction is inherently error‐prone and defective. It consumes energy that depends on the required precision. Without repair, the bitstring gets either randomized, or the finite accessible energy reservoir gets depleted before all original information gets lost that was stored in the initial bitstring. When the reproduction process is combined with repair, errors are corrected with a certain probability as soon as they exceed a tolerated threshold. Also error correction consumes energy. It is assumed that energy for repair is taken from the same finite reservoir as energy for reproduction. The reservoir can be refilled from time to time with the same amount, but energy for repair is at the expense of the precision of the subsequent reproduction. So it may come as a surprise that it is possible to sustain the reproduction process without exceeding the tolerated error threshold. The conditions for this to happen are derived from the bifurcation diagram of a discrete map that describes the time evolution of errors. When these conditions are violated, the fate of the system is either a lack of energy supply for further reproduction, since all energy gets absorbed by repair, or errors accumulate. This fate seems unavoidable when also repair is subject to the trade‐off and gets less effective in the course of time, unless energy would be invested in the repair of repair.


Page 12 of 36

Talk 1:

An overview of the phenomenology of physical aging

Michel Pleimling

Virginia Tech Blacksburg University

Physical aging scaling is encountered in numerous systems with slow dynamics [1]. In this talk I introduce the phenomenology of physical aging and show that many of the characteristic features of physical aging can be understood through the investigation of simple coarsening systems. Dynamical scaling of two‐time quantities like the autoresponse and autocorrelation functions is discussed for systems with a single time‐dependent length scale.

This work was supported by the U.S. National Science Foundation through grants DMR‐0904999, DMR‐1205309, and DMR‐1606814.

[1] M. Henkel and M. Pleimling, Non‐Equilibrium Phase Transitions, Volume 2: Ageing and Dynamical Scaling Far From Equilibrium (Springer, Heidelberg, 2010).

Talk 2:

Physical aging in materials: from vortex matter to skyrmion systems

Michel Pleimling

Virginia Tech Blacksburg University

In this talk I discuss physical aging in two types of systems with slow, glassy‐like dynamics: interacting magnetic flux lines in type‐II superconductors [1] and interacting skyrmion matter [2]. In a previously equilibrated system, either the temperature is suddenly changed or the magnetic field is instantaneously altered. The subsequent aging properties are investigated in samples with either randomly distributed point‐like or (for the vortex lines) extended columnar defects, which allows to distinguish the complex relaxation features that result from either type of pinning centers.Two‐time correlation functions are analyzed to study the non‐linear stochastic relaxation dynamics in the aging regime.

This work was supported by the U.S. Department of Energy, Office of Basic Energy Sciences,

Division of Materials Sciences and Engineering, under Grant No. DE‐FG02‐09ER46613.

[1] H. Assi, H. Chaturvedi, U. Dobramysl, M. Pleimling, and U. C. Täuber, Phys. Rev. E 92, 052124 (2015)

[2] B. L. Brown, U. C. Täuber, and M. Pleimling, Phys. Rev. B 97, 020405(R) (2018)


Page 13 of 36

Talk 1:

Running Histone Code on a Chromatin Computer

Sonja J. Prohaska Computational EvoDevo Group, University of Leipzig, Leipzig,Germany

Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany Santa Fe Institute of Complex Systems, Santa Fe, NM, USA

Several molecular mechanisms are responsible for epigenetic regulation, a process that involves the establishment, change and maintenance of a genome‐wide gene expression pattern and its faithful transfer to the daughter cells during cell division. One of these mechanisms is the histone modification system (HMS).

Genome‐wide studies of histone modifications are commonly based on ChIP‐seq, a high throughput sequencing method and the subsequent bioinformatics analysis. Large data sets have been generated over the past year. However, a deeper understanding of epigenetic regulation and, in particular, its dynamics is still lacking. To complement the common data‐driven approaches we have developed a simulation tool that allows us to study histone modification dynamics in a toy HMS.

Initial clues for a plausible mechanism resulted from our study on the phylogenetic distribution of HMS components across all domains of life [1]. We could devise a plausible scenario for the evolutionary origin of the histone modification system and propose that some modifications can be viewed as informational “bits", which do not exert a direct, physico‐chemical effect by themselves but associate with the appropriate “reader" domain‐containing proteins that take in influence on gene expression. This inspired us to view the HMS as a Turing machine‐like computer, that we refer to as \chromatin computer".

Th main part of the talk will focus on the rule‐based stochastic simulation system that we developed to characterize the dynamic behavior of the “chromatin computer" [2]. Conceptually, we equated a chemical modification reaction with a string rewrite rule. The core of the simulation system is based on Gillespie's algorithm. Therefore, each simulation represents one possible solution of the master equation, i.e. a trajectory in the state space. I will present our preliminary results on the behavior of a toy HMS required to perform well on the reconstruction problem.

To conclude, I will discuss pros and cons of our "Chromatin Computer" model and its potential implications in biological aging of information.

[1] Sonja J. Prohaska, Peter F. Stadler, and David C. Krakauer. Innovation in gene regulation: the case of chromatin computation. Journal of theoretical biology 265.1 (2010): 27‐44. [2] Christian Arnold, Peter F. Stadler, and Sonja J. Prohaska. Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem. Journal of theoretical biology 336 (2013): 61‐74.


Page 14 of 36

Talk 2:

Epigenetics: Regulation of a Special Kind

Sonja J. Prohaska Computational EvoDevo Group, University of Leipzig, Leipzig,Germany

Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany Santa Fe Institute of Complex Systems, Santa Fe, NM, USA

Genes and, to a small extent, environmental factors have been conceived as the determinants of phenotypic characteristics of single cells and complex organisms. However, how the genotype is translated into the phenotype bringing about several hundreds of dierent cell types and many more transient cell states in humans, for example, is still poorly understood. These days, "epigenetics" is viewed as the Rosetta stone for solving this central biological puzzle.

In this tutorial, I will first motivate the relevance of epigenetics in medical and biological research. As a central regulatory mechanism it plays a major role in many diseases ranging from rare (epi)genetic disorders to civilization diseases, such as diabetes and cancer. Furthermore, it has been proposed that epigenetics intervenes with genetics in response to external influences, such as lifestyle and eating behavior. Also cellular aging has its epigenetic hallmarks. In consequence, researchers and the general public, have high expectations concerning advances in the field of epigenetics and its application in health care.

Second, I will introduce the audience to the mechanisms underlying epigenetic regulation. More explicitly, I will address questions about the origin, function and general role of two distinct epigenetic mechanisms, DNA methylation and histone modifications. From a molecular point of view, epigenetics is a layer of chemical modifications sitting "on top of" the DNA regulating when and how genes are expressed. As such, they are changing dynamically on a lifetime scale. Both molecular mechanisms result in modification patterns along the genome that strongly suggest a role in canalization of cell differentiation from pluripotent stem cells to terminally differentiated cells during development, and establishment and maintenance of cell identity. However, they seem to have a variety of auxiliary functions in, e.g., the distinction of self and foreign DNA and in DNA repair.

In the third and last part, I will explain the mechanism and components of the histone modification system in greater molecular detail. While this will be textbook knowledge to some extent, it will give the necessary background for the associated research talk I will be giving. In addition, I will present some calculations, ideas and questions concerning the complexity of the histone modification system.


Page 15 of 36

Talk 1:

Experimental Measurement of Information‐Content in Nonequilibrium Systems

Fèlix Ritort

Facultat de Física, Universitat de Barcelona, Barcelona and Ciber‐BBN of Biomaterials and

Nanomedicine, ISCIII, Madrid, Spain

Biology is intrinsically noisy at all levels, from molecules to cells, tissues, organs, communities and ecosystems. While thermodynamic processes in ordinary matter are driven by free‐energy minimization, living matter and biology delineate a fascinating nonequilibrium state predominantly governed by information flows through all organizational levels. Whereas we know how to measure energy and entropy in physical systems we have poor knowledge about measuring information‐content in general. Recent developments in the fields of stochastic thermodynamics and thermodynamic‐information feedback combined with single molecule experiments show the way to define information‐content in nonequilibrium systems. In this talk I will describe how to measure information‐content in two classes of nonequilibrium systems. First, I will introduce the Continuous Maxwell Demon, a new paradigm of information‐to‐energy conversion, and demonstrate how work extraction beats the Landauer limit without violating the second law. Next, I will demonstrate the validity of a fluctuation theorem in nonequilibrium systems under continuous‐time feedback and show how to measure information‐content in such conditions. Second, I will introduce a mutational ensemble of DNA hairpin folders and show how to measure information‐content in this context. A definition of information‐content applicable to generic disordered populations is proposed. All results are experimentally verified in single molecule pulling experiments.


Page 16 of 36

Talk2:

Q‐stat thermodynamics: a new perspective on non‐equilibrium phenomena

Fèlix Ritort

Facultat de Física, Universitat de Barcelona, Barcelona and Ciber‐BBN of Biomaterials and

Nanomedicine, ISCIII, Madrid, Spain

Nonequilibrium pervades nature. From living cells to the expanding universe virtually all energy transformation processes in nature occur in nonequilibrium conditions [1]. In this regard thermodynamic equilibrium should be seen as an approximation to describe energy transformations in nature, certainly a very good one in many cases. Yet, how to leave the safe grounds of equilibrium thermodynamics adventuring the nonequilibrium realm by retaining universal features characteristic of equilibrium systems without loosing the predictive power of thermodynamics? In this talk I will introduce Q‐stat thermodynamics as a new theoretical approach to characterize energy transformation processes in nonequilibrium systems [2,3]: when observed at twodifferent arbitrary times, nonequilibrium systems tend to partially equilibrate over the subspace of configurations with mutual two‐times correlation equal to Q [3]. I will present theoretical calculations, simulations and experimental results in small systems [4,5], from single molecules to red blood cells, testing the validity and showing the power of Q‐stat thermodynamics in physics and beyond.

[1] F. Ritort, Nonequilibrium fluctuations in small systems: from physics to biology, Advances in Chemical Physics, 137, 31‐123 (2008). Ed. Stuart. A. Rice, Wiley publications [2] A. Crisanti, M. Picco and F. Ritort, Fluctuation relation for weakly ergodic systems, Physical Review Letters, 110 (2013) 080601. [3] A. Crisanti, M. Picco and F. Ritort, Derivation of the spin‐glass order parameter from stochastic thermodynamics, Physical Review E, 97 (2018) 052103 [4] F. Ritort, Single molecule experiments in biological physics: methods and applications, Journal of Physics C (Condensed Matter),18 (2006) R531‐R583 [5] E. Dieterich, J. Camuñas‐Soler, M. Ribezzi‐Crivellari, U. Seifert and F. Ritort. Single‐molecule measurement of the effective temperature in non‐equilibrium steady states. Nature Physics, 11 (2015) 971‐977


Page 17 of 36

How the aging circadian clock affects our daily rhythms

J.H.T. Rohling

Leiden University Medical Center, Department of Cell and Chemical Biology, Laboratory for Neurophysiology Leiden, the Netherlands

The elderly are known to show disturbed sleep‐wake patterns (Van Someren, 2000). They experience problems falling asleep, frequently awake during the night and have short naps during the day. These compromised rhythms over the day are associated with higher chance of the occurrence of diseases, even Alzheimer’s disease. Our sleep‐wake patterns are for a large part controlled by our internal circadian clock. Restoring the clock rhythm in the elderly may also restore sleep‐wake patterns (Van Someren, 2000), and understanding the aging process for this clock may increase our understanding of the disturbances in sleep‐wake patterns.

The circadian clock, which is located in the suprachiasmatic nuclei (SCN) and drives the daily 24‐hour rhythms in our body, is functionally dependent on emergent network properties. While the ability of individual SCN neurons to produce 24‐hour rhythms is a cell‐autonomous property, the ability of the SCN to respond to light, to adjust to seasons and to synchronize after a jet‐lag is critically dependent upon the state of the neuronal network. The synchronized network output regulates all daily rhythms in our body and is heavily dependent on the interactions between the neurons and the network topology of the clock.

Our group has shown that the neurons themselves and the neuronal network of the SCN are altered in aged mice, resulting in attenuated amplitude of circadian oscillations in electrical activity and neurotransmitters (Farajnia et al, 2012). This reduced amplitude rhythm may not be sufficient to control the phase of circadian rhythms in other brain areas and in peripheral organs, such as the liver, kidneys and intestine. This deregulation may cause the disrupted sleep pattern and other circadian behaviors.

The change in the state of the network correlates to a modulation in the balance of excitatory and inhibitory neuronal activity in the SCN, with more excitation in the desynchronized state. We have already shown that the synchrony between the cells and the E/I balance can be altered in seasonal encoding (Farajnia et al, 2014a; Farajnia et al, 2014b), and we are currently investigating to what extend desynchronization and change in E/I balance is also observed in aging.

In order to implement strategies for healthy aging, we are also investigating measures for health. Temporal behavioral patterns and the central clock show scale invariant behavior, possibly driven by the network and the E/I balance. With disease and aging, scale invariance is lost, and also in a brain slice preparation when the clock is not communicating with other brain areas, scale invariance is absent (Gu et al, PNAS 2015). The analysis of scale invariant behavior may serve as an indicator for network and E/I balance viability.

References:


Page 18 of 36

Farajnia, S., Deboer, T., Rohling, J.H.T., Meijer, J.H., Michel, S. (2014a) Aging of the suprachiasmatic clock. Neuroscientist, 20: 44‐55 Farajnia, S., Michel, S., Deboer, T., Vanderleest, H.T., Houben, T., Rohling, J.H., Meijer, J.H. (2012) Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. The Journal of Neuroscience 32: 5891–5899 Farajnia, S., van Westering, T.L., Meijer, J.H., Michel, S. (2014b) Seasonal induction of GABAergic excitation in the central mammalian clock. Proceedings of the National Academy of Sciences of the United States of America 111: 9627–9632 Gu, C., Coomans, C.P., Hu, K., Scheer, F.A., Stanley, H.E., Meijer, J.H. (2015) Lack of exercise leads to significant and reversible loss of scale invariance in both aged and young mice. Proceedings of the National Academy of Sciences of the United States of America 112:2320–2324


Page 19 of 36

Talk 1:

Spatiotemporal reorganization of brain rhythms on slow and fast time scales with healthy aging

Dipanjan Roy

National Brain Research Centre, Manesar, Gurgaon, Haryana‐122 052, India

Introduction

One of the hallmarks of aging whether healthy or pathological is a progressive decline in anatomical connectivity of the brain. Despite this steady decline in anatomical connectivity in several functional domains such as fluid intelligence, language, and sentence comprehension etc. healthy elderlies continue to perform just as well as the younger individuals. This raises an intriguing possibility of a functional level global reorganization in the brain with healthy aging that would compensate for the structural decline. Here we have investigated the network level integration and segregation leading to age‐related frequency modulated response on different timescales (slow and fast). Our results provide first concrete evidence for the aging‐related reorganization in large‐scale integration and segregation hypothesis which posits that brain networks become increasingly segregated and integrated at the same time with aging. De‐differentiation increases by creating new modules but at the same time, the interaction among these modules becomes more integrative in nature.

Methods

We analyzed resting‐state magnetoencephalogram data of 650 healthy individuals (age 18‐88, 322 female) collected as a part of a cross‐sectional adult life‐span study by Cambridge Centre for Ageing and Neuroscience (Cam‐CAN). Spectral power of neuronal oscillations was estimated using Welch’s method. Frequency in the alpha band having maximum power was taken to be the representative peak alpha frequency (PAF). We estimated global coherence as a measure of global covariation among the sensors. Since variation in global coherence in delta and theta band with age was similar which was also the case for alpha and beta oscillations we broadly divided the oscillations into two bands i.e. slow oscillations (1‐5 Hz) and fast oscillations (10‐20 Hz). Upon visual inspection, we found that the overlap in sensor topographies corresponding to alpha and beta oscillations decreased with aging. We established the separation of alpha and beta oscillations sensor level representation with aging by estimating the angle between these topographies and correlating it with age.

Results

We found that global beta power i.e. power in the beta band averaged over all the sensors was higher in elderly population compared to the younger population. PAF was significantly negatively correlated with age. Interestingly we found a set of sensors in the anterior part of the brain where PAF stayed invariant across life‐span. The global coherence of slow oscillations increased with age whereas global coherence of fast oscillations decreased with age. PAF derived from global coherence analysis also significantly decreased with increase in age. The angle between vector representations of alpha and beta sensor topographies was positively correlated with age.


Page 20 of 36

Discussion

Increase in beta power in older population has been well documented and is considered to be the cause of greater motor inhibition in aged individuals. Invariance in PAF in the prefrontal cortex may be reflective of healthy aging. Differential relationship of global coherence of slow and fast oscillations, combined with separation of alpha and beta topographies support the integration and segregation theory of aging. Source level analysis of this data may give insights into the specific brain regions responsible for this spatiotemporal reorganization.


Page 21 of 36

Talk 2:

Metastability, Causality and Synchronization in the aging brain: a new perspective

Dipanjan Roy

National Brain Research Centre, Manesar, Gurgaon, Haryana‐122 052, India

Introduction

The human brain undergoes both structural and function changes across the lifespan. It is important to know the dynamics of these changes. Synchronization among the various frequencies is believed to be the means through which the brain communicates between its different areas. Metastability, on the other hand, can be defined as an extended persistence of the brain in an unstable equilibrium state. Together, synchronization and metastability provide good measures for brain processes which can be viewed as constantly jumping between various ‘locked’ (synchronized) states via intermediate metastable states.

While these concepts have been studied extensively in the last decade, they have not been carefully looked at from the perspective of aging; i.e.: how do the synchronization and metastability change as the brain gets older? In this work we use a generative model of cortical oscillations to study metastable properties of the brain and its alteration with age.

Furthermore, functional connections within resting‐state networks weaken while connections between resting‐state networks strengthen with aging. A recent study by Tsvetanov et.al (2016) shows that effective connectivity within and between large scale functional networks changes over the healthy lifespan. However, the contribution of thalamus in these age related changes is not adequately explored. In particular, very few studies have investigated how thalamo cortical structural and functional connectivity changes with age and how such changes are associated with changes in cognitive functions (Goldstone 2017). Using effective connectivity measures on resting state FMRI data, we examine the age related changes in cortico‐cortical and thalamo cortical causal interactions within and between resting state networks.

Methods

We use a network of coupled Kuramoto oscillators located at the Salience (SN), Central Executive (CEN) and Default Mode Networks (DMN). The couplings between the nodes of these spatially extended networks are derived from empirical DTI (Diffusion tensor imaging) data collected from 25 young and 25 old subjects. The oscillating phases of the various nodes, which simulate neuronal dynamics on a faster time scale, is converted to the ultra‐slow frequency Blood level oxygen dynamics (BOLD) signals by the Balloon‐ Windkessel model. We thereby calculate the Functional Connectivity (FC) matrix, which is compared to the empirical FC matrix collected from the same subjects. The free parameters in this model are ‘global coupling’ and ‘time‐delay’, which are scanned in the appropriate ranges to give us ‘parameter maps’ for the various measures of brain dynamics. Finally we selected 68 cortical regions and subcortical thalamic regions using Desikan Killiany parcellation atlas. Various centrality measures are applied on average FC and SC matrix for finding out the most central nodes( hubs). Community structure of these matrices are identified using the algorithm by


Page 22 of 36

Blondel et al.(2008). The three of core cognitive networks DMN, SN, CEN networks are identified by spatially matching of hub regions with the important RSNs in the literature. Multivariate GCA is performed to test for causality index between ROIs with and without the thalamus . Pairwise granger causality indexes are calulated for within network and between network causality analysis. We have also calculated the distribution of weighted net granger causal outflow with the 100 bootstrap sample of Granger Causality matrix. We have performed nonparametric Mann‐whitney U test to test whether there is any significance difference between net causal outflow for two different age groups with and without the thalamus.

Results

We calibrate the phenomenological model to the empirical observations from the BOLD fMRI signals by correlating the model generated and empirical FC. The parameter maps were explored for aging related changes in the synchronization and the metastability dynamics, both at the neural and the BOLD timescales. In both age groups we observe a well‐defined region of high synchronization and low metastability. The region of highest FC correlation lies close to this region of high synchrony in both groups. We observe an increase in metastability in the older population as compared to the young group.

In structural and functional connectivity analysis we have found that structural modularity prevails better than functional modularity with aging. Also re‐organizations of functional hubs are going on with the age. In context of effective connectivity, we see that causal connections are changing with age. Within network causal connections become weaker, but between network causal connections are getting stronger with aging. Net causal outflows of several nodes are significantly higher in young compared to old population for within network analysis. Significant changes are seen in causal connections and net causal outflows in presence of thalamus.

Discussion

An increase in metastability with age may be attributed to various factors. Most importantly, as the brain ages, there is a deterioration of the neuronal connectivity among the different regions of the brain. This could result in the loss of synchronization among different areas of the brain, which shows up as increased metastability. In the integration‐segregation paradigm, there is evidence of the brain showing higher integration tendency with age. This fits well with the increase in metastability, which means that, with age, the brain spends less time in specific task‐synchronized states while spending more time in the unsynchronized, in‐between‐tasks states. Some other intriguing phenomenon also emerge when we compare the synchronization and metastability profiles at the two temporal levels. While some features such as metastability are preserved across the scales, other feature such as synchronization may be different at the two scales. The underlying causes and mechanisms for this are not fully explainable by current theories of the brain and remain open questions.

To the best of our knowledge, no previous study have addressed the role of thalamus in causal connectivity analysis for resting state networks. Hence, what emerge from causality analysis on the same dataset that thalamus indeed has an important causal role in within and between network connectivity. This influence also changes with aging. Our findings with the effective connectivity measures strengthens the hypothesis that balancing between within network connectivity and between network connectivity is an important neural marker to maintain the functionality of brain with aging.


Page 23 of 36

Talk1:

Origin of common dynamical aspects in glassy materials and biological ecosystems: a qualitative discussion

Paolo Sibani

FKF, University of Southern Denmark, DK5230 Odense M, Denmark

Systems very different in terms of microscopic variables and interactions have similar aging dynamics (Sibani13). This point is illustrated with examples from hard sphere colloids (Boettcher11), spin‐glasses (Sibani06), bacterial evolution (Lenski94), and, finally, the Tangled Nature Model of ecological evolution (Hall02,Becker14). Each system is only briefly described and the common key feature emphasized is the observed logarithmic dependence of macroscopic averages. The latter implies a rate of changer ̴ 1/t, wheret is the time elapsed from the initial event starting the aging process.

As aging proceeds, increasing periods of time are spent in `punctuated equilibria' (Eldredge), pseudo‐stationary configurations encircled by growing free‐energy barriers. The statistics `quakes', the intermittent and spatially heterogeneous events marking the transition from one state to the next, is explained by 'Record Dynamics', which posits a hierarchy of barriers and that overcoming a record high barrier triggers a quake (Sibani93}.

References: [Sibani13] Paolo Sibani and Henrik Jeldtoft Jensen,Stochastic Dynamics of Complex Systems: from Glasses to Evolution. Imperial College Press, 2013. [Boettcher11] Stefan Boettcher and Paolo Sibani, Ageing in dense colloids as diffusion in the logarithm of time, J. Phys.:Cond. Matter, 23:065103, 2011. [Sibani06] P. Sibani, G. F. Rodriguez and G. G. Kenning, Intermittent quakes and record dynamics in the thermoremanent magnetization of a spin‐glass, Phys. Rev. B 74:224407, 2006. [Lenski94] R. Lenski and M. Travisano, Dynamics of adaptation and diversification: A 10,000‐ generation experiment with bacterial populations, Proc. Natl. Acad. Sci.: 91: 6808, 1994. [Hall02] Matt Hall, Kim Christensen, Simone A. di Collobiano, and Henrik Jeldtoft Jensen. Time‐dependent extinction rate and species abundance in a tangled‐nature model of biological evolution. Phys. Rev. E 66, 011904, 2002. [Becker14] Nikolaj Becker and Paolo Sibani, Evolution and non‐equilibrium physics: A study of the Tangled Nature Model, EPL, 105:18005, 2014. [Eldredge] The term was introduced by Niles Eldredge and Stephen Jay Gould in 1972 to describe species evolution, but we find it equally fitting for a variety of dynamical systems with multiple metastable states. [Sibani93] Paolo Sibani and Peter B. Littlewood, Slow dynamics from noise adaptation, Phys. Rev. Lett., 71: 1482, 1993.


Page 24 of 36

Talk2:

From micro‐ to macro: Record Dynamics as a coarse graining tool for aging systems

Paolo Sibani

FKF, University of Southern Denmark, DK5230 Odense M, Denmark

Aging dynamics is simpler when analyzed on a logarithmic time scale:`quakes', configurational jumps from one metastable state to the next, are uniformly distributed on a logarithmic time axis, and the `logarithmic waiting times' between successive quakes are, to a good approximation, independent stochastic variables with a common exponential distribution. In other words, quaking can be described as a log‐Poisson process, i.e. a Poisson process whose average has a logarithmic time dependence. This is explained by Record Dynamics, see e.g. [Anderson04, Sibani13,Robe16], a theoretical coarse‐graining approach linking micro‐ and macroscopic phenomena in aging systems. We illustrate Record Dynamics with examples from colloidal systems [Robe16, Sibani18], the Edwards‐Anderson spin glass [Sibani18a} and the Tangled Nature Model [Becker14]. We conclude with an application to the non‐stationary aging dynamics in ant societies [Sibani11].

References: [Sibani13] Paolo Sibani and Henrik Jeldtoft Jensen, Stochastic Dynamics of Complex Systems: from Glasses to Evolution, Imperial College Press, 2013. [Anderson04] Paul E. Anderson, Henrik Jeldtoft Jensen, L. P. Oliveira and Paolo Sibani, Evolution in complex systems, Complexity 10:49‐56, 2004. [Robe16] Dominic M. Robe, Stefan Boettcher, Paolo Sibani and Peter Yunker, Record dynamics: Direct experimental evidence from jammed colloids, EPL 116: 38003, 2016. [Sibani18] Paolo Sibani and Carsten Svaneborg, Work in progress. [Sibani18a] Paolo Sibani and Stefan Boettcher, Mesoscopic real space structures in aging spin‐glasses: the Edwards‐Anderson model, ArXiv:1803.06580 & Phys. Rev. B, in press. [Becker14] Nikolaj Becker and Paolo Sibani, Evolution and non‐equilibrium physics: A study of the Tangled Nature Model, EPL 105:18005, 2014. [Sibani11] Paolo Sibani and Simon Christiansen, Non‐stationary aging dynamics in ant societies, Journal of Theoretical Biology 282, 36‐‐40, 2011.


Page 25 of 36

The temporal scaling of C. elegans ageing

Nicholas Stroustrup

Centre for Genomic Regulation, Barcelona

Aging produces a wide distribution of lifespan even among isogenic individuals housed in controlled environments. Analyzing high‐resolution demographic data collected using our automated method, we find that diverse interventions in aging alter C. elegans lifespan of through an apparent stretching or shrinking of time: a temporal scaling of the survival curve. Interventions producing this effect include changes in diet and temperature, exposure to oxidative stress, and the disruption of genes including the insulin/IGF‐1 pathway components daf‐2. In certain cases, a temporal scaling of survival curves is statistically indistinguishable from several other parametric models previously proposed to describe the quantitative effect of interventions in aging. So, to differentiate between these models, we investigated the effect of transient interventions applied early in adulthood. We observed that early‐adulthood changes in temperature produce temporal shifts of the survival curve, distinct from the temporal scaling produced by whole‐life exposure. The magnitudes of these shifts were accurately predicted by a model in which interventions produce a temporal scaling of a single aging process during any period of exposure, in which the rate of all physiologic changes influencing lifespan are altered in concert.Clearly, the interventions we characterize produce diverse changes at molecular level and differential effects across various "health‐span" phenotypes. It is therefore surprising to see all the physiologic determinants of lifespan, whatever they may be, appearing to respond in such a uniform way across many interventions. In a series of simulations, we find that temporal scaling can arise as a general behavior of complex networks, in which the interdependence of components serves to propagate the consequences of declines in functions of small sub‐networks across the whole network. Perhaps such network phenomena may help explain other aspects of aging, and provide the basis for an empirically‐grounded, quantitative framework that links molecular interventions to their systemic effects in aging.


Page 26 of 36

Talk 1:

Thermodynamics of Biochemical Copying

Pieter Rein ten Wolde, AMOLF Amsterdam

The process of copying information is central to life. Examples are to be found in DNA replication, gene expression, but also in cell signalling. Since the work of Maxwell, Demon, Sziland, Bennett and Landauer, it is known that copying has a fundamental thermodynamic cost. In this talk, I will first discuss how a biochemical copy protocol, as found for example in cell signalling, can be mapped onto a computational copy protocol. I will then show that biochemical networks can some surprisingly close to the fundamental thermodynamic bound on the energetic cost of copying.

Talk 2:

Theory on the optimal design of cell sensing systems

Pieter Rein ten Wolde, AMOLF Amsterdam

Experiments in recent years have vividly demonstrated that living cells can measure chemical concentrations with remarkable accuracy. Importantly, these concentrations often vary on the timescale of the response of the system. In this talk, I will discuss the optimal design of cell sensing systems. I will show that not only receptors and readout molecules fundamentally limit the accuracy of sensing, but also time and power; each of these resources imposes a fundamental sensing limit, which cannot be enhanced by raising another resource. This observation leads to a novel design principle for the optimal allocation of cellular resources in systems that need to detect time‐varying signals. This principle predicts that the optimal design depends on the timescale and the variance of the input signal. This prediction is tested for the chemotaxis system of the bacterium E. coli.


Page 27 of 36

Talk 1:

Information processing in neural and gene regulatory networks

Gasper Tkacik

Biophysics and Neuroscience, Institute of Science and Technology, Austria

Life depends as much on the flow of information as on the flow of energy. Efforts to make this intuition precise started already in the 1950s, very soon after Shannon formulated his information theory, but progress was limited by the quality and quantity of experimental data. Recent advances allow us to measure the information transmitted by small biological networks, as well as to read it out and reconstruct the network inputs. Developing in parallel with this data‐driven approach has been the theoretical idea of “efficient representation”: the idea that biological systems could be optimized, through the course of evolution or learning, to transmit the maximal amount of (useful) information. In my talk I will highlight the unity of these theoretical ideas across two very different biological systems: a network of retinal ganglion cells encoding visual information, and a gene regulatory network responsible for the early development of the fruit fly. I will present examples of how biophysical constraints and stimulus statistics shape the functioning of these systems, and conclude by describing our early efforts to build a quantitative and predictive theory for biochemical regulatory networks.

Talk 2:

Intrinsic limits to gene regulation by global crosstalk

Gasper Tkacik

Biophysics and Neuroscience, Institute of Science and Technology, Austria

Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF–DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis‐regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low‐specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements.


Page 28 of 36

Aging as stress response: examples from bacteria and higher eukaryotes

Ala Trusina

Niels Bohr Institute, University of Copenhagen

While aging is typically associated with inevitable deterioration at the level of the individual, it may be a beneficial trait in a population facing unpredictable changes in the environment. The two illustrative examples are the bacterial aging through asymmetric damage segregation and stress induced telomere shortening in higher eukaryotes. Common for both is that proliferative potential of the cell depends on its history of stress exposure. I will discuss how inheriting damaged DNA and proteins allows propagate information about stress exposure through generations and the resulting consequences for population stress adaptation.


Page 29 of 36

Abstracts of Contributed Talks (in alphabetic order)


Page 30 of 36

Ageing, translation and noise ‐ are they related?

Tailise C. de Souza Guerreiro, John McCarthy

University of Warwick

Analysis of the biological processes that influence ageing is crucial to developing a full understanding of the mechanisms underpinning it. Saccharomyces cerevisiae has been shown to be a key model for ageing research since the pathways for the ageing process are highly conserved between eukaryotes, from yeast to man. Previous reports have demonstrated the role of translational control in life span modulation. Calorie restriction increases life span by a mechanism mediated by Target of Rapamycin (TOR) signaling, which in turn reduces ribosome protein production as well as global translation activity. Proteomic analysis at the single‐cell level has shown that proteins involved in translation exhibit lower‐than‐average levels of gene expression noise. In this study, we have applied an innovative approach combining cell wall staining, flow cytometry and microfluidics, to investigate at a single‐cell level whether the noise characteristics of yeast cells change with increasing age and to what extent individual components of the translation machinery contribute to the relationship between ageing and noise. We find that gene expression noise generally increases as cells age, but that deletion of eIF4G (translation initiation factor 4G) both restricts age‐dependent increases in noise and extends life span, thus indicating that translation, gene expression noise and replicative ageing are linked.


Page 31 of 36

Task‐specific adaptation of a living flow network

Philipp Fleig , Mirna Kramar, Michael Wilczek, Karen Alim

Max Planck Institute for Dynamics and Self‐Organization

Living flow networks such as the animal vasculature or fungal networks actively adapt their morphology over time. Here, the adaptation activity can be seen as a measure of aging. In this work we investigate the phenomenology of adaptation in the unicellular slime mould Physarum polycephalumas a model for adaptive living flow networks. A key component of adaptation is the cytosol flow through the network, caused by active contractions of the cell’s actomyosin cortex. Using principal component analysis we decompose these network‐spanning contractions into a basis of modes. In particular, we show that adaptation of the network such as growth or movement is coordinated via switching between different modes. The activation of modes is task‐specific and follows a distinctive time course. Our approach enables us to identify key differences between changes in adaptation caused by aging and external stimuli.


Page 32 of 36

Relaxational kinetics in red blood cell mechanics: linking physical to biological aging

Marta Gironella, Felix Ritort

Departament de Física de la Matèria Condensada, Facultat de Física, Universitat de Barcelona, Carrer Martí i Franquès, 1, Barcelona 08028, Spain and 2. CIBER‐BBN, Instituto de

Salud Carlos III, 28029 Madrid, Spain

Red blood cells (RBC) are one of the most abundant and simplest cells in human body. Only composed of a lipid bilayer and an spectrin cytoskeleton, their shape, mechanics and aging are fundamental features to understand and treat the majority of blood diseases. In this project we study relaxational processes in the mechanics of RBC using optical tweezers. We use two different approaches in order to understand the viscoelastic response of the RBC: 1) Pulling experiments, where we pull and push the RBC at different maximum forces and different pulling velocities to extract information of the force‐distance curves and; 2) Relaxation experiments, where we apply a force jump to the RBC and measure force relaxation. From these two kind of experiments we are able to characterize four different time‐scales, three of them related to membrane‐cortex interaction, the other one (which is the longest) shows a stiffening of the RBC that we hypothesize it is linked to aging in the RBC. The correlation between the time‐scales allows us to globally understand the temporal evolution of RBC and link physical to biological aging.


Page 33 of 36

Length dependence of the elastic properties and secondary structure of single‐stranded DNA

Xavier Viader‐Godoy, Maria Manosas, Felix Ritort

Departament de Física de la Matèria Condensada, Facultat de Física, Universitat de Barcelona, Carrer Martí i Franquès, 1, Barcelona 08028, Spain and 2. CIBER‐BBN, Instituto de

Salud Carlos III, 28029 Madrid, Spain

Single‐stranded DNA (ssDNA) plays a major role in several biological processes, such as replication or transcription. Therefore, it is of fundamental interest to understand the elastic response of this biological polymer. Besides, force spectroscopy techniques have been widely used to study biochemical and enzymatic processes involving DNA. The interpretation of the results obtained by these experiments requires an accurate description of the elastic properties of ssDNA. However, a large dispersion on the elastic parameters is obtained from different methods and sequences. .

In this work, we study the elastic properties of ssDNA using molecules with different sequences and lengths comprising 4 orders of magnitude (from 60bases to 14kbases). Two regimes arise in general: at high forces a simple non‐interacting polymer response; at low ones a condensation transition is observed corresponding to the formation of secondary structure. .

Focusing on the regime without secondary structure and using the inextensible Worm‐Like Chain model we proof that the apparent discrepancy found in the previous works arises mainly from the different range of forces used to fit long and short molecules. The different sequences studied also allowed us to test pyrimidine/purine content, which present different elastic behavior. .

Regarding the secondary structure regime, we develop a two‐state model that recovers the phenomenological formula proposed in A. Bosco et al.(2013) and captures the dependence of the secondary structure on molecule length and salt concentration. From this description we obtain an energy associated to base‐pairing that is in the order of kBT and depend on the salt concentration, as expected.


Page 34 of 36

Dose‐rate scaling laws in a generic cellular stress response model

Darka Labavic, Mohamed Tahar Ladjimi, Quentin Thommen, Benjamin Pfeuty

Lab. de Physique des Lassers, Atomes at Molécules, Université de Lille, CNRS, Lille, France

We study a model of an intracellular network that controls stress‐induced decisions. Regardless of the perturbation source and the cell death modality, the cellular decision to survive or die upon stress exposure involves a complex signaling and regulatory networks. On the one hand, maintenance of the cellular homeostasis typically involves a core negative feedback mechanism, which counteracts the damage production in response to various sources of stress ranging from radiative, oxidative, heat or metabolic. On the other hand, the stress‐induced death outcomes involve the cooperation of many caspase‐dependent positive feedback loops, which trigger irreversible bistability. Our aim is to study how these nonlinearities and timescales determine or influence the dose‐rate response defined as how cell death/survival probabilities depend on both the duration and rate of the (stress) dose.

We, therefore, develop a simple generic model consisting of two coupled loops, a positive and a negative feedback loop, corresponding to the decision making and the adaptation processes, respectively. We first investigate the importance of the relative time scales associated to damage, adaptation and death dynamical processes. In general, we find a power law behavior of the dose‐rate response curves, with different exponents depending on the stress duration. For well‐separated time scales, we derive analytically these scaling laws, with an explicit dependence on the model parameters. The simple power law of the Haber's rule used in toxicology and dosimetry appears to be valid in a broad range of timescales. However, much more complex patterns appear when we consider the case of nonlinear adaptation.


Page 35 of 36

Interaction Analysis of Longevity Interventions Using Survival Curves

Jonas Rzezonka Stefan Nowak, Joachim Krug, Ivan G. Szendro ‐ Institut für Theoretische Physik, Universität zu Köln, Germany

Johannes Neidhart ‐ MBR Optical Systems, 42279 Wuppertal, Germany

Rahul Marathe ‐ Dept of Physics, Indian Inst. of Technology Delhi, New Delhi, India

A long‐standing problem in ageing research is to understand how different factors contributing to longevity should be expected to act in combination under the assumption that they are independent. Standard interaction analysis compares the extension of mean lifespan achieved by a combination of interventions to the prediction under an additive or multiplicative null model, but neither model is fundamentally justified. Moreover, the target of longevity interventions is not mean life span but the entire survival curve. Here we formulate a mathematical approach for predicting the survival curve resulting from a combination of two independent interventions based on the survival curves of the individual treatments, and quantify interaction between interventions as the deviation from this prediction.


Page 36 of 36

Beyond asymmetry: the evolutionary advantages of an active damage retention mechanism

Niek Welkenhuysen, Johannes Borgqvist, Barbara Schnitzer, Qasim Ali, Marija Cvijovic

Chalmers University of technology and University of Gothenburg

In mammalian cells rejuvenation of certain cell types, such as stems cells, is required to restore the lifespan of the progeny. Similar, S. cerevisiae mother cells produces rejuvenated daughter cells to maintain viability in populations over time. During cell division, damaged proteins are inherited asymmetrically such that most are retained within the mother cell. We have developed fast and versatile computational framework to study phenomena of ageing and rejuvenation and to understand to what extent and under which circumstances retention of damage is beneficial to the cells on both single cell and population level. We argue that, while symmetrically dividing organisms can cope with higher damage formation rates, asymmetrical division leads to bigger populations in favorable conditions, which gives rise to a higher biological fitness. We also predict that rejuvenation is likely to occur to cells with active damage retention mechanism under the high damage accumulation rate. These findings can be confirmed by observing the lifespan of mother and daughter cells. Microfluidic systems have emerged as key tools to study the dynamics of processes, since it allows time lapse (fluorescence) microscopic imaging and have been driving the emergence of single cell analysis techniques. Therefore, we are developing a microfluidics platform which can immobilize and observe a mother and its offspring over a lifetime. This platform would be able to capture the complete replicative lifespan of a mother and daughter cells under controllable conditions. Our results suggest that S. Cerevisiae has evolved a complex regulation of size division asymmetry in order to partially gain a higher population of cells when conditions are favorable. Finally, we are developing experimental systems to study cell lineages on a single cell level. Our work sheds light on asymmetric cell division and rejuvenation in yeast and can be valuable for understanding similar phenomena in other organisms.

Documents

Abstracts of talks alphabetic order) · phenomenon. I will focus on kinetically constrained systems as basic models for glasses and will also describe methods based on the theory